Each month, the PharmedOut Newsletter publishes PharmedOut fodder, which covers a pressing issue on the industry's influence on the medical world. You can read all of the Fodders on this page.

March 2024: Proposed bill on off-label promotion gets pulled

By Judy Butler

Last month, Maryland legislators introduced a bill to allow pharmaceutical companies to promote medical products off-label, for conditions other than (or populations other than) what the Food and Drug Administration (FDA) has approved them for. PharmedOut was scheduled to testify in opposition, but the sponsors subsequently withdrew the bill.

Federal regulations allow promotion only for approved, on-label uses of drugs, and the Maryland bill would have skirted that prohibition. It’s not the first bill and it won’t be the last, thanks to the Goldwater Institute, a libertarian think tank with undisclosed funders. They’re promoting model state legislation allowing off-label promotion as a way to challenge the FDA restrictions. Arizona enacted such legislation in 2017 and Tennessee followed suit the following year. A handful of other states have considered bills but have not passed them.

Drug companies are fighting hard for off-label promotion for the same reason that restriction is necessary – it creates a lucrative market of people who may not benefit from the drug. Off-label uses haven’t undergone the agency’s stringent scientific review of risks and benefits, which is why off-label promotion is illegal.

Off-label prescribing, however, is legal and common. And sometimes it’s necessary. For example, most drugs aren’t tested in children or pregnant women, but we still need to treat diseases in these groups. But most off-label drug prescription is unnecessary and risky.

About three-quarters (73%) of off-label prescriptions are written for conditions with little or no scientific support, exposing patients to drugs that may be ineffective or harmful. One study estimates a 44% higher likelihood of adverse events in adults when using drugs off-label. In children, off-label use of drugs is associated with an increased number and severity of adverse effects.  

About 20% of prescriptions are already written off-label, with rates over 50% for some anticonvulsants, psychiatric medications and antiasthmatics. That’s way too high. Every drug has harms, and one can’t calculate a risk-benefit ratio if the benefits are unknown. Of course, if there’s proof of benefit for a new use, the company can and should seek a label change. But it’s a lot easier and cheaper for a company to spread rumors of benefit than to perform clinical trials necessary for FDA approval. Many companies have been sued for off-label promotion – but that hasn’t deterred companies, perhaps because even multi-billion dollar fines constitute only a fraction of the profits made on off-label sales.

Industry has had success in expanding FDA guidance on communications with doctors about off-label uses for individual patients. They have also won favorable lower court decisions that recognize off-label marketing statements as protected commercial speech. Even with these industry gains, however, FDA maintains its authority to regulate off-label promotion. Enacting state laws is the most recent industry strategy to push against restrictions on off-label promotion.

Ironically, proponents cite the lack of evidence as reason to support off-label promotion. Because there is an “information deficit,” the Goldwater Institute argues it’s “important to remove the barriers that prevent physicians and other providers from having the best available timely and accurate information about off-label uses.” So their model legislation provides that “a pharmaceutical manufacturer or its representatives may engage in truthful promotion of off-label uses.”

It’s hard to argue against sharing truthful information. But what counts as true in the absence of data? Hope, enthusiasm, and a promising mechanism aren’t lies, exactly, but neither are they truth. As one legal scholar describes it, “The truthfulness of off-label information is speculative, unknown, or inaccessible.” The only way to know if off-label information is truthful is to have objectively assessed data from human trials. In some cases, drug companies have performed trials on a drug for a specific indication and when the trial was negative, so they couldn’t obtain a labelled indication, they sold the drug off-label anyway. Right now, that’s illegal.

But if a company can promote off-label uses, there’s no reason for them to seek approval for those uses. And, without an approval process that objectively assesses published and unpublished data, there’s no certainty about whether benefits eclipse risks.

Off-label promotion of drugs undermines rational medicine. An FDA-approved label is the best protection patients have against unproven treatments. 

Judy Butler is a Research Fellow at PharmedOut.

February 2024: Painful Presentaion: KOL gives problematic lecture on opioids

By Judy Butler

Imagine, in 2023, a physician teaching medical school students that opioids rarely cause addiction in patients without risk factors. Or that a patient demanding higher doses of opioids is experiencing “pseudoaddiction” rather than addiction and should be prescribed more opioids. That’s what first-year medical students at Nova Southeastern University College of Osteopathic Medicine were taught last fall.

The pain lecture by Dr. Martin Hale had all the earmarks of an industry presentation by a key opinion leader (KOL). That’s not surprising given that Hale was a KOL for OxyContin manufacturers and has a long history of receiving payments from opioid companies.

In fact, Hale authored a 1998 Purdue Pharma-sponsored research study of OxyContin for osteoarthritis that concluded “that opioids were well tolerated with only rare incidence of addiction” and that tolerance to analgesic effects was not a problem with long-term use. There was no evidence for either statement. The study lasted only a month – nowhere near long enough to make any conclusions about long-term use. There was no reported data on addiction, and many patients dropped out of the study due to adverse effects. Nonetheless the study was used by Purdue to promote the benefit of starting OxyContin early for everyday arthritis.

Hale went on to work with other opioid companies, several of which were criminally convicted or fined for improperly marketing opioids. He gave talks encouraging opioid prescribing and allowed companies to ghostwrite deceptive medical journal articles that were published under his name.

Hale did not disclose any conflicts of interest to the medical students. But one student had researched opioid marketing messages in medical literature and recognized that discredited messages were being taught in this lecture, so they alerted PharmedOut.

For example, Hale stated the risk of addiction for patients prescribed opioids was rare and cited a one-paragraph letter to the editor published in 1980 in the New England Journal of Medicine. The Porter and Jick letter offered no evidence that addiction was rare with long-term opioid therapy, yet it was cited repeatedly by Purdue to reassure physicians that it was fine to prescribe opioids for common pain syndromes, including low back pain and osteoarthritis. Hale then added that prolonged exposure to opioids does not produce addictive behaviors, this time citing the 1996 work of Russell Portenoy, another industry KOL. Portenoy, however, has since admitted to making statements without evidence in order to destigmatize long-term opioid prescribing.

Hale went on to define “pseudoaddiction” as a “preoccupation with achieving adequate pain relief secondary to inadequate or inappropriate meds.” In fact, “pseudoaddiction” is a discredited industry concept created to distract physicians who recognized signs of addiction in their patients. By renaming addiction “pseudoaddiction”, physicians became more comfortable with increasing doses of opioids in patients who were manifesting obvious signs of addiction. Hale cited the original paper defining pseudoaddiction which was written by KOLs, one of whom, David Haddox, went on to work for Purdue Pharma. The paper provided no evidence for chronic opioid prescribing but only described the condition of one hospitalized cancer patient. Along with the Porter and Jick letter, the pseudoaddiction article was used by Purdue to support the false claim that chronic pain patients did not become addicted and to allay physician concerns about prescribing higher and higher doses of opioids.

Besides misinformation, Hale’s lecture relied on typical industry strategies used to minimize perceptions of risks of promoted drugs and disadvantage competing therapies. Early in the lecture, Hale disparages the use of clinical practice guidelines, stating that they don’t reflect real clinical practice; he implies that advocating for individual patients can mean going against guidelines. Similarly, he emphasizes that all treatments have risks, equating the risks of opioids with those of ibuprofen, other non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (Tylenol). He finishes the lecture with a set of fictional case studies that encourage students to question how they had thought about opioid prescribing.

Upon introducing the case studies, the students are asked to guess which of several patients will be convicted of drug trafficking. Students are expected to choose the scruffy patient who smokes and wears sunglasses in the exam room. Spoiler alert! It’s the innocent-seeming elderly woman with chronic low back pain asking for only one Percocet a night (it turns out she sees multiple doctors and sells the extra pills). The scruffy smoker was prescribed 30 Percocet/week when his pain was unresponsive to NSAIDs, physical therapy or muscle relaxants. He now rates his pain as 8/10, tells stories of lost and stolen pills, has alcohol on his breath, and is asking for more opioids. The correct course of action? More opioids! When this patient is titrated to adequate pain medication (which Hale does not define) the patient returns to work, stops losing pills, and stops drinking alcohol. Hale concludes this patient was suffering from pseudoaddiction and notes that students should never assume a patient in pain is a drug seeker.

When the course director and Nova Southeastern administrators were notified of the concerns with Hale’s lecture, the university determined the lecture was consistent with best practices for pain management and asserted that lecturers do not need to disclose conflicts of interest. Upon further pressure to take action on the misinformation presented to students, Nova Southeastern responded that the term pseudoaddiction is still in the literature and students need to know the definition. The university offered four instances of the term pseudoaddiction appearing in 2023. However, three of these articles related to palliative and hospice care and the fourth noted that pseudoaddiction may lead to increased doses of opioids that increase harm.

Bizarrely, Nova Southeastern claimed that Hale spent only 30 seconds on the topic of pseudoaddiction and neither espoused or denied the definition. That, however, disregards his pointed case study on pseudoaddiction. And a limited amount of time spent on a discredited concept doesn’t make it more credible.

The Hale lecture and the ill-advised institutional response to criticism of it illustrate why it’s so difficult to root out opioid marketing messages from physician education. Misinformation is still being disseminated today.

KOLs are chosen and paid by industry precisely because they already support the industry point of view. Industry gives KOLs a greater platform, and they become the prominent “experts” who shape the views of prescribers. Even when they stop receiving payments from specific companies, they continue to promote industry messages. Physicians and medical students aren’t trained to recognize marketing messages, which are hidden under a veneer of factual information.

When you know what to look for, the misinformation is glaring. Because one student had researched misleading and deceptive claims about opioids, they could immediately identify them in the Hale lecture.

It’s appalling that a medical school would offer a lecture with dangerously false information about opioids and then be unwilling to rectify the error. Nova Southeastern should be publicly shamed. In how many other medical schools are students being taught lies about opioids? Opioids are appropriate and necessary for some acute pain, cancer pain, and end-of-life care but they are not appropriate for chronic pain. We’ve seen what happens when doctors are misled about opioids—hundreds of thousands of patients become addicted—and we can’t let it happen again.

Judy Butler is a Research Fellow at PharmedOut.

December 2023: Rexulti ads: both depressing and

agitating

By Judy Butler

“Proven to reduce depression symptoms 62% more than antidepressants alone” boasts ads for Rexulti (brexpriprazole). That’s not so, says the Food and Drug Administration (FDA), calling the efficacy claim false and misleading. Through an untitled letter sent in October to Rexulti’s manufacturer, Otsuka Pharmaceutical, the agency declared the ad in violation of the Federal Food, Drug, and Cosmetics Act (FD&C Act). Otsuka had 15 days to respond either with a list of all promotions containing the claim and a plan for discontinuing those communications or a rebuttal. As of December 15, no response letter had been posted on FDA’s site.

The FDA’s letter specifically cites a 2023 TV ad, See the Signs, but the 62% claim appears on TV ads that have been airing since 2020. In addition to direct-to-consumer ads, the false claim was also prominently featured on Otsuka’s websites for both consumers and health care professionals as recently as November 8, but has since been removed. 

Rexulti, an atypical antipsychotic, gained approval in 2015 as both an add-on treatment to antidepressants for major depressive disorder (MDD) and for schizophrenia. Using the 60-point clinician-rated Montgomery Åsberg Depression Rating Scale (MÅDRS), the treatment group improved by 31.1% while the placebo group improved by 19.2%, so Rexulti was only 11.9% more effective than placebo.

Not surprisingly, Otsuka has done everything to present – or misrepresent – the data in Rexulti’s favor. Instead of comparing how the treatment and placebo groups changed with respect to the baseline – the primary outcome – they simply did a relative comparison of how the final outcomes of the treatment and placebo groups compared to each other. That is, relative to the placebo outcome (19.2%), the treatment outcome (31.1%) is 62% larger. A relative comparison can make a small absolute treatment difference appear large and is particularly misleading when both treatment and placebo groups improve.

FDA noted the misleading claim was especially concerning because of the “multiple serious, potentially life-threatening or irreversible risks” associated with Rexulti. Rexulti carries a Black Box warning, reserved for drugs with the most serious risks, for increased mortality in elderly patients with dementia-related psychosis and increased risk of suicidal thoughts and behaviors in patients aged 24 and younger. The drug label also lists another dozen warnings and precautions for risks including neuroleptic malignant syndrome, a potentially fatal condition, and tardive dyskinesia, a potentially irreversible movement disorder. 

Given increased deaths in elderly dementia patients, it’s even more concerning that Otsuka is using the same misleading calculations to promote Rexulti for its newest indication, agitation associated with dementia due to Alzheimer’s disease (AAD). 

Antipsychotics have long been prescribed off-label for agitation in dementia patients, and have long been causing harm. After an FDA meta-analysis revealed a 70% increased risk of death among elderly patients with dementia receiving antipsychotic treatment, the black box warning was added and efforts were made to reduce prescribing of antipsychotics to elders. In a controversial decision this May, the FDA determined the benefits of Rexulti outweighed the risks for the treatment of AAD.

Otsuka claims that there’s a 31% greater reduction in frequency of agitation symptoms with Rexulti on its site for health care providers. As with MDD, both treatment and placebo groups improved, and in this case, the difference between the endpoints was very small, only 5.3 points on a 174 point scale for which a 17 point change is considered clinically meaningful. When efficacy is calculated by the change from baseline, there’s only a 6.6% absolute difference between treatment and placebo.

Even ascribing a 6.6% efficacy to Rexulti is generous. It’s unlikely that caregivers would notice a difference with treatment. In fact, there’s little evidence that Rexulti is any more effective or safer than other antipsychotics. Yet now Otsuka can market Rexulti for AAD – and they’re spending heavily. At $21.6 million, Rexulti was the drug with the fourth highest TV ad spending in October. 

It took three years for the FDA to flag Rexulti’s false claim. But if - like almost every other country - the US prohibited direct-to-consumer ads, the FDA wouldn’t have to respond to these misleading ads. And then they would have more time to focus on misleading promotional claims made directly to health care providers

Judy Butler is a research fellow at PharmedOut.

October 2023: Pharma-funded groups pressure Medicare to cover obesity drugs

By Judy Butler

Obesity drug manufacturers are upset that Medicare, the single largest payer for health care in the United States, doesn’t cover weight loss treatments. With up to 41.5% of 66 million Medicare enrollees considered as obese, that’s a significant untapped market. Congress could require the Centers for Medicare and Medicaid Services to cover expensive weight loss drugs, so Novo Nordisk and Eli Lilly – makers of weight loss drugs poised to earn billions of dollars – are asking them to do just that. The drugmakers spent over a million dollars on lobbying firms for that purpose in the first half of 2023. But they weren’t the only ones lobbying for Medicare coverage during that time. Among those other groups was the Health Equity Coalition for Chronic Disease (HECCD), a coalition of organizations of color, which bought $80,000 in lobbying services.

While drugmakers have a clear incentive to lobby for wider coverage for their products, the motivations of consumer advocacy organizations would be expected to be driven by public health concerns rather than profit concerns. Yet, although the HECCD provides no funding information on its website, almost all of its member organizations acknowledge financial ties to weight loss drug manufacturers. For example, the Black Women’s Health Imperative, a HECCD co-chair, leads the Novo Nordisk-funded campaign Reclaim Your Wellness, and did a webinar that promoted “anti-obesity medications” and pushed viewers to support the Treat and Reduce Obesity Act noting that everyone should care about Medicare even if they are not Medicare age because when Medicare covers something, other payers follow.

Setting up a “Coalition” makes it seem that there is widespread support for a specific view, but the HECDD has all the hallmarks of an industry initiative, and we know that industry funding only flows to those organizations that deliver industry messages.

Despite its expansive name, the sole focus of HECCD is its Obesity Care Now campaign. And that campaign has the singular objective of expanding Medicare coverage. The Obesity Care Now campaign was originally launched in June 2021 by the Obesity Care Advocacy Network (OCAN), a group which includes Novo Nordisk and Eli Lilly. OCAN publicized the NAACP's endorsement of the campaign in October 2021. By April 2022, the Obesity Care Now campaign was taken on by the newly formed HECCD and links to OCAN disappeared. (In what appears to be an oversight, one can find a mock-up of the HECCD About Us section still available on the web that prominently displays OCAN, suggesting that deep-sixing OCAN was a deliberate decision.) Curiously, although the Obesity Care Now is HECCD’s “first year initiative”, it has continued well into HECCD’s second year and there’s no indication the coalition is taking on any other health equity concerns.

Of course, the campaign is not just lobbying Congress, it’s also directly pressuring the Centers for Medicare and Medicaid Services (CMS): publishing op-eds, releasing reports, organizing conferences, and coordinating petitions to Congress. Success in forcing Medicare to cover these drugs will undoubtedly carry over to other insurers that follow Medicare’s lead.

The HECCD argues that “obesity is a chronic disease that requires medical treatment” and that “excluding FDA-approved anti-obesity medications from Medicare Part D coverage” has “life or death consequences.” Their white papers are peppered with references to publications with industry funding and articles featuring industry-funded doctors.

Here’s how that industry messaging is misleading. While obesity is correlated with some health conditions, that doesn’t necessarily mean an obese individual will have those health conditions. Plenty of fat people are healthy, and plenty of thin people aren’t. Obesity can be a surrogate marker for lack of exercise, poor nutrition, or poverty, among other factors. And even if an obese person has a health condition, it’s an unproven assumption that weight loss itself improves health. For one reason, the majority of people that lose weight regain it; and those who repeat this process of weight cycling can have worse health consequences than just staying fat. Certainly exercise and a healthful diet should be emphasized in everyone, but health outcomes can be improved without losing weight. Research supports a weight-neutral strategy for obesity treatment.

The new weight loss drugs work only as long as people take them; those who stop treatment will regain weight and lose cardiometabolic improvements. It’s uncertain whether the weight loss will be maintained even for those who continue treatment. In a 2-year clinical trial, the longest to date, weight plateaus at 60 weeks and appears to be trending upward near the end of the trial. A potential 20% weight loss – which will not necessarily achieve a “healthy” weight – is unlikely to be worth the tradeoff of a lifetime on these drugs. There are significant adverse effects, including gastroparesis (stomach paralysis that can leave food in the stomach for days) and suicidal ideation.

And there is even less evidence that these drugs will help the elders covered by Medicare. Clinical trials only included 8.8% of subjects aged 65 to 75 and 0.9% over 75. Given that people of color were poorly represented as well, there’s even less known about elders of color.

Compared to a younger population on these drugs, the risks for elders are more concerning. Moderate obesity may in fact be protective against cardiovascular risks in adults over 65. And the decreased muscle mass associated with these drugs could be serious for many obese older adults who already have low muscle mass, which increases the risk of falls and fractures. Although the obesity trials do not provide data on harms by age group, diabetes trials using lower doses of the drug found that more elderly patients reported adverse effects and prematurely discontinued treatment.

There are certainly health equity issues, including ones related to obesity, that need to be addressed in the United States. Access to weight loss drugs under Medicare is not one of them.

Judy Butler is a research fellow at PharmedOut.

September 2023: Is the Alzheimer's Association guiding patients to an early grave?

By Judy Butler

The Alzheimer’s Association, hitting a new low in undermining the best interests of patients, recommends diagnosing Alzheimer’s in perfectly normal people. Their proposed new guidelines define Alzheimer’s “biologically”, using plasma biomarkers: A person with abnormal biomarkers will be diagnosed with Alzheimer’s whether or not they have any cognitive loss.

The assumption is that people with abnormal amyloid and tau levels will eventually have impaired cognition, and if they live their whole lives without ever developing cognitive issues, then they just didn’t live long enough to experience their preprogrammed cognitive decline. This is simply untrue. In fact, most people with amyloid-beta plaque are not cognitively impaired. And while amyloid-beta is a hallmark of Alzheimer’s, there’s insufficient evidence to support the theory that it actually causes the disease.

The proposed guidelines dovetail with the arrival of new drugs for the early stages of Alzheimer’s disease that remove amyloid-beta plaque. Eisai/Biogen’s lecanemab (Leqembi) gained full approval in July and Eli Lilly’s donanemab will likely do so by year’s end. Medicare will cover lecanemab for eligible patients enrolled in a registry and major health systems are expected to offer the drug.

At the same time, a handful of blood tests are now available to assess amyloid-beta, including one that can be purchased directly online by consumers. No test has yet received approval from the Food and Drug Administration (FDA).While neither the testing companies nor advocacy groups recommend diagnosis by blood test alone at this point, they anticipate the possibility of doing so and are already signaling their enthusiasm for tests they think will revolutionize the diagnostic process.

To date, assessment of amyloid plaque has been determined either by a PET scan or analysis of cerebrospinal fluid (CSF) collected by lumbar puncture. PET scans are expensive and available only in metropolitan areas; lumbar punctures are invasive, uncomfortable, and can cause severe headache and other side effects.

The recent availability of drugs and blood tests explain the timing behind the Alzheimer’s Association update. As one of the authors explained, now “it is completely feasible to diagnose the disease biologically at a mass scale” and “there’s something you can actually do about the disease.” In other words, access to blood tests will funnel patients to expensive amyloid-busting drugs.

Unfortunately, leading patients to these drugs will result in significant death and disability, with no actual chance of improvement. In clinical trials, patients in both treatment and placebo groups continued to decline, and the small difference between them in terms of rate of decline was not clinically meaningful. Anti-amyloid drugs cause serious harms, including brain bleeds and brain shrinkage. A minimum of three patients died in clinical trials for each of the new drugs, suggesting a rate of 1 to 2 deaths per 1,000 patients in the healthier-than-normal clinical trial population. Among the general population, this death rate is likely to be higher. In addition, the drugs, and the costs associated with treatment, are expected to cost $82,500 a year per patient. Almost all patients receiving this drug are on Medicare, so most of these costs will be borne by taxpayers.

The American Geriatrics Society (AGS) comments on the proposed guidelines challenged the Alzheimer’s Association’s expansion of the guidelines from research-only into clinical care, asserting a lack of supporting evidence and warning of the potential for overdiagnosis. The AGS also questioned the heavy inclusion of industry participants – as well as others with significant conflicts of interest – in the workgroup. And, unlike earlier guidelines that utilized workgroups co-convened with the NIH’s National Institute for Aging (NIA), it appears that the content of proposed guidelines is now controlled solely by the Alzheimer’s Association. Yet the proposed document still includes NIA as a co-sponsor. Given that the proposed expanded use of the guidelines is inconsistent with the NIA’s mission, the AGS recommended that the NIA reconsider whether the document should continue to carry the NIA name.

Diagnosis by blood test makes sense if the goal is to identify many patients as soon as possible. Of course drug companies want to expand the pool of people eligible for an early Alzheimer’s diagnosis, because the new drugs are approved only for early disease. Currently, a diagnosis of Alzheimer’s involves multiple steps, including cognitive assessments, and there are a limited number of specialists with the requisite expertise to confirm the diagnosis. That’s the way it should be. With the new anti-amyloid drugs indicated only for the early stages of Alzheimer’s and, corporate hopes that these drugs will be used for pre-symptomatic treatment, industry and industry-funded advocacy groups have set their sights on streamlining the process in a way that will maximize the number of patients eligible for treatment.

But if many patients with a biomarker never experience cognitive impairment, then what exactly is being diagnosed, argues one geriatrician. And, because patients are, naturally, most concerned about actual symptoms, not how much of a biomarker is in their bodies, an epidemiologist notes that removing the biomarker can “cure” the disease without resulting in any improvement in a patient’s life.

It is an unwise investment to spend billions of dollars – sales of the two new drugs alone are projected to reach $5.5 billion globally by 2030 – to remove a biomarker without evidence it is a causal factor for a disease. Instead, those dollars could be spent on resources to improve known modifiable risk factors, including hypertension, hearing impairment, and diabetes, that account for around 40% of worldwide dementias. What’s worse than the misspent dollars, however, is the false hope patients and their families are being given as they are rushed to drugs that have shown no clinically meaningful benefit and have significant harms.

Judy Butler is a research fellow at PharmedOut. 

August 2023: Who's really behind the weight loss drug hype?

By Judy Butler

The hype over new weight loss drugs may have led to a flurry of prescriptions, but few people know that two-thirds – 68%– of patients quit within a year. That’s according to a recent analysis of pharmacy claims for patients newly prescribed GLP-1 (glucagon-like peptide-1agonist) drugs for weight loss. The analysis included all of Novo Nordisk’s suite of GLP-1 agonists: injected semaglutide (Wegovy and Ozempic), liraglutide (Saxenda) and oral semaglutide (Rybelsus). This real world data stands in stark contrast to the 6.8% dropout rate in clinical trials where patients were carefully selected and supported. Although data was not collected on reasons for discontinuation, analysts speculate the severity of side effects and/or an inability to afford co-pays or deductibles may have contributed to such decisions.

Patients in this analysis all had insurance coverage for the drug and were not diabetic. However, rates of discontinuation are high among diabetic users of these drugs as well. For example, after two years only 45% of diabetic patients were still on the drugs in a recent analysis from Spain, consistent with an older US study in which the figure was 47%.

Once patients stop using GLP-1 drugs, they quickly regain lost weight. And that comes with its own health costs. Weight cycling, which describes a repeated cycle of losing and regaining weight, is associated with numerous adverse health outcomes – including increased mortality. So, not only are these drugs financially expensive – the drugs can cost more than $1000 per month – but they may come with health costs as well.

The undisputed explosion of positive social media coverage has been credited as the driving force behind demand for these weight loss drugs, but that distracts from Novo Nordisk’s heavy investment in promoting its marketing messages. Within 72 hours of approval of Wegovy in June 2021, the sales team was in the field. That, combined with virtual training sessions for 5,000 health care professionals (HCP) within a week of approval, resulted in more than 50% of HCPs being aware of Wegovy’s brand name without prompting. Once Wegovy was on the market, demand quickly exceeded supply.

Novo Nordisk still spends heavily on drug marketing, making $34 million in general payments to HCPs in 2022 according to Open Payments data released in June. That includes $9 million on more than 457,000 meals – for Novo to market its drugs in person to doctors and other prescribers. And meals are proven to influence prescribing: receiving an industry-sponsored meal is associated with an increased rate of prescribing for the targeted drug.

Food and beverage payments are widespread, but more targeted payments are made to key opinion leaders (KOLs) – the teachers who deliver marketing messages to other prescribers and often act as expert sources for media and policymakers. In 2022, Novo Nordisk’s payments for a category which includes faculty and speaking engagements was $18.5 million while its payments for consulting were $2.6 million.

KOLs will argue that they don’t change what they say by getting industry money, but they don’t have to – if they’re not delivering the message the company wants them to deliver, they simply won’t get paid. Meanwhile, these KOLs pop up everywhere, often not being identified as having a conflict of interest.

Take continuing medical education (CME) for example. CME isn’t regulated as promotion, but it may be the most cost-effective form of advertising pharmaceutical companies have. Payments made by Novo Nordisk for education was a mere $58,000. But whether it’s CME offered free by Medscape, FreeCME,or Pri-Med or by a professional organization such as the Obesity Medicine Association, the Obesity Society, or the American Association of Nurse Practitioners, there are faculty or program chairs with financial ties to Novo Nordisk, and marketing messages within the activities.

HCPs are not the only ones hearing from Novo Nordisk’s KOLs. Consider Driving Change in Obesity Care, an event at the annual meeting of the Professional Society for Health Economics and Outcome Research (ISPOR). Novo Nordisk paid for and reviewed the content of the unbranded symposium, yet stated the information and views were solely those of the presenters. Unsurprisingly, the audience was told that non-invasive treatment of obesity may not only improve the lives of individuals but also reduce economic burden. The proof they offered came from a Novo Nordisk sponsored research study, the stated purpose of which was “to demonstrate a need for improved health insurance coverage for anti-obesity medications.”

And while there are lots of voices behind the social media buzz, HCPs that accept money from Novo Nordisk are among them. One Novo Nordisk consultant is one of the many accounts that TikTok recently banned for violating community guidelines on disordered eating or dangerous weight loss behaviors or ads for weight loss drugs or supplements. His account has since been reinstated.

Novo Nordisk’s marketing message that obesity is a chronic disease translates into a lifetime on their weight loss drugs. They’ll keep investing in prescribers who will deliver that message and feeding those that hear it. After all, it would be good for business if patients took their drugs for the rest of their lives. But, with a target market of more than 100 million US adults, it doesn’t matter that most patients stop taking the drug within a year. As long as new prescriptions get written, there is money to be made. In a world of weight loss, it’s all gain for Novo Nordisk.

Judy Butler is a research fellow at PharmedOut. 

June & July 2023: Why we're salty with Jazz Pharmaceuticals and the AHA

By Judy Butler

Once again, the American Heart Association (AHA) is taking money from Jazz Pharmaceuticals to disseminate marketing messages on sleep disorders and heart health. Jazz sells Xywav, a narcolepsy drug with $1 billion in sales in 2022. Jazz first funded AHA in 2020, the same year Xywav was approved, with $250,000 for online content and podcasts. With the additional (undisclosed) amount of money, AHA will convene a scientific advisory board, create patient videos, and bring together sleep-focused advocacy organizations to expand the campaign’s reach.

Aided by the AHA, Jazz is attacking its own older drug Xyrem (sodium oxybate, now available as a generic) in order to advantage its newer drug, Xywav (calcium, magnesium, potassium & sodium oxybates). Jazz markets Xywav as offering 92% less sodium than Xyrem. For almost 20 years, Jazz’ aggressive patent maneuvers ensured that Xywav was the only drug approved to treat cataplexy in patients with narcolepsy. Jazz now calls Xyrem the “high sodium elephant in the room.” Jazz claims, without evidence, that the differences in sodium content between Xywav and Xyrem will be clinically meaningful in reducing cardiovascular diseases in many people who take sodium oxybate.

Jazz is using the same heart health marketing message to counter the May 2023 approval of Avadel’s Lumryz, an extended-release version of sodium oxybate. When Xywav was approved, Jazz was granted seven years of Orphan Drug Exclusivity (ODE), a status that protects the manufacturer of a rare disease drug from any competitor seeking approval of the same product for the same disease -- unless the new drug is clinically superior. The Food and Drug Administration (FDA) found that Lumryz’s once nightly dosing made it clinically superior to Xywav, which requires twice-nightly dosing. So Jazz sued the FDA in June, claiming the approval was unlawful. One reason, they argue, is because of Xywav’s greater safety due to its reduced sodium. Jazz asserts that Lumryz shouldn’t be assumed to be as safe as Xywav without a direct comparison of the two drugs. Ironically, the lack of a head-to-head trial of Xywav and Xyrem has not stopped Jazz from making claims about Xywav’s superiority.

Sodium may be the least of a Xywav patient’s concerns. The active ingredient of Xywav is oxybate, also known as gamma-hydroxybutyrate (GHB), an addictive central nervous system depressant known on the street as a ‘date rape’ drug. For that reason, the drug comes with a black box warning for respiratory depression as well as for abuse and misuse. And a year’s supply of the highest dose of Xywav costs more than $200,000.

While there’s no information about the risks of Xywav on the AHA site, until June 27th their page on narcolepsy and heart health flagged the downsides of other narcolepsy drugs. Exaggerating risks of competitors is a typical pharmaceutical company tactic. AHA noted that stimulants increase heart rate and blood pressure, antidepressants make cardiovascular events more likely, and “one commonly prescribed medication for narcolepsy includes up to 1640mg of sodium” surpassing AHA’s ideal recommendation of 1500mg. AHA went on to deliver the money line for Jazz: “However, there is hope for narcolepsy patients who are concerned about their health. The FDA recently approved a lower-sodium medication, so if you have narcolepsy, consult your doctor.”

The AHA should be ashamed of taking money for advertisements disguised as education. It’s not clear that the AHA’s recommendation of 1500mg of sodium daily will improve cardiac health for narcolepsy patients. That’s certainly what Avadel argues, pointing out that studies of sodium oxybate use in narcolepsy patients have shown low frequency of cardiovascular adverse events and no overall association with cardiovascular risk.

Many medications contain sodium, and a systematic review that looked at the effect of sodium-containing medications on cardiovascular risk found mixed results; two long-term studies found no effect; two others showed increased risk. All studies were in people with diabetes, hypertension or other comorbidities; all were ingesting more than 1500mg sodium a day in medications.

It’s not clear that cutting salt intake to 1500 mg would improve heart health in people who don’t have hypertension. While there’s agreement that high sodium intake is unhealthy, there’s disagreement about just how low sodium recommendations should be for entire populations. Some researchers argue that the relationship between sodium intake and cardiovascular risk is a J-shaped curve. A 2021 evidence review found that a moderate range of dietary sodium (<5 g/day) is not associated with increased cardiovascular risk and that increased risk is seen with sodium intake greater than 5g/day or less than 3g/day. Others, however, challenge those data in favor of a linear relationship, arguing for recommended intake below 2g/day.

The jury is still out on salt and cardiovascular disease, but one thing we do know is that Jazz has made a business decision to invest in the AHA. So take anything AHA says about sleep disorders and heart health with a grain of salt.

Judy Butler is a research fellow at PharmedOut.

May 2023: Why are opioids approved for chronic pain when they don’t work?

By Judy Butler

The Food and Drug Administration (FDA) is still vainly searching for evidence that long-term opioid treatment is effective for chronic pain. For decades, opioids have been approved for the treatment of chronic pain– pain lasting longer than three months – despite the fact that no study of opioids for chronic pain lasted more than three months. This dearth of evidence caused the Centers for Disease Control and Prevention (CDC), the United States Agency for HealthCare Research and Quality (AHRQ), and the Department of Veterans Affairs and the Department of Defense (VA/DoD) all to conclude that there is limited evidence for long-term effectiveness of opioids and substantial evidence of risk of serious harm.

The FDA’s peculiar perspective stems from the fact that FDA is responsible not only for drug approval, but also for the regulation of advertising and promotion of drugs. And drugs can only be marketed for uses consistent with the product’s labeling – so-called “on-label” uses. That’s why the FDA’s decision to keep an indication for chronic pain when there’s no evidence of efficacy matters. The current label allows industry to claim, legally, that opioids are safe and effective for chronic pain without any proof that that’s true. If the label were changed, health care providers could still prescribe opioids off-label. But because it is illegal for companies to promote drugs off-label, healthcare providers just wouldn’t be subject to messaging from industry that opioids are effective for chronic pain. Odds are, opioid prescriptions for chronic pain would decrease.

Ten years ago, the FDA required manufacturers of extended-release/long-acting (ER/LA) opioids to conduct post-marketing studies to assess the effectiveness of long-term opioid therapy. Specifically, they were to determine whether opioids remain effective analgesics over periods longer than 12 weeks and to document the extent of harms, including opioid-induced hyperalgesia (OIH), associated with long-term use. To date this post-marketing requirement (PMR) has yielded no data; the only trial initiated was terminated primarily due to an inability to recruit patients.

In April 2023, the FDA convened an advisory committee to evaluate study design options for the post-marketing requirement. The committee, as well as speakers in the open public hearing, pushed back on the FDA’s proposal to use what is called an enriched enrollment randomized withdrawal (EERW) study, in which all subjects are given the opioid for an extended period – enough time to become physiologically dependent – and those who found the opioid helpful are then randomized to continue on the drug or be switched to placebo. The design tips the scales in favor of opioids, first by weeding out those who don’t tolerate or respond to the opioids and second, by rendering patients dependent on opioids and then subjecting those switched to placebo to withdrawal symptoms, which, by the way, can include pain. That experience is hardly representative of how opioids are used in the general population. For the proposed ER/LA efficacy trial, the pre-randomization phase adjusted the opioid dose over 6 weeks and then maintained subjects at that dose for 36 weeks. Once randomized, those assigned to placebo would be tapered over1 to 8 weeks.

Unsurprisingly, opioid companies support EEWR studies. They made that clear to FDA representatives at lavish, small, invitation-only meetings focused on designing clinical trials for pain treatments. The events were hosted by IMMPACT, an organization created in 2002 and funded by annual fees from drug companies to the tune of hundreds of thousands of dollars. Not only has FDA relied on EEWR studies for opioid approvals since 2006, the agency has resisted appeals to stop using them. Of the drugs approved for chronic pain from 1987 to2018, four of five (81%) relied on EEWR results, a figure that rose to 100% for 2012 to 2018.

And now FDA is proposing EEWR for determining the long-term efficacy of opioids.

That opioids were initially approved for -- and continue to be indicated for -- the long-term treatment of chronic pain without evidence that the benefits outweigh the risks largely reflects the continued influence of the opioid industry. Outrageous examples abound. Opioid manufacturers managed to expand the initial indication of OxyContin beyond cancer pain to those with musculoskeletal pain. Later, an FDA advisory committee tasked with considering a narrower indication for OxyContin 2002 included 8 out of 10 members with industry ties. The committee advised against the narrower indication. More recently, FDA asked opioid manufacturers to develop continuing medical education as part of FDA’s Risk Evaluation and Mitigation Strategy (REMS) for opioids – unsurprisingly, these activities are rife with marketing messages. And, of course, industry influenced FDA’s use of EEWR for approval of new drugs. Rather than fruitlessly searching for evidence that long-term opioid treatment is effective for chronic pain, FDA could revise the label to indicate uses for the conditions that opioids actually benefit including relief from severe pain from a life-limiting illness.

In April, FDA did announce new label changes for opioids. They include warnings about opioid-induced hyperalgesia and the increased risk of overdose with higher dosages. And, although the indication for ER/LAs will change, the new language will still allow manufacturers to claim opioids are safe and effective for chronic pain.

Another opportunity missed.

Judy Butler is a research fellow at PharmedOut. The author would like to acknowledge Andrew Kolodny, MD whose remarks at the FDA advisory committee on this issue inspired this column.

April 2023: Breathtaking Unbranded Marketing from Amgen

By Judy Butler

Should people with asthma be talking about it more? Asthma drug makers think so. Amgen recently launched an unbranded campaign, “The Air Between Us All”, featuring Lori Gottlieb, a media-savvy therapist now counseling patients to share their asthma concerns more often. An Amgen-funded survey in partnership with the Allergy and Asthma Foundation of America (AAFA) notes that few patients discuss their condition with others.

Amgen’s injected biologic, Tezspire (tezepelumab-ekko), is an expensive, injected monoclonal antibody: each monthly injection costs $3800. And it’s not even a stand-alone treatment. Tezspire is approved only as an adjunct (add-on treatment) to standard asthma medications for severe asthma. The drug is administered monthly in a doctor’s office or is available in a pre-filled pen for home use. Amgen’s website notes that “Starting a new medication can be a bit confusing, and you might have questions about cost and support with paying for treatment.” It’s probably not a coincidence that the next sentence mentions “nurse educators”, who are nurses paid by pharmaceutical companies to keep patients on drugs. One wonders whether these ersatz health care providers are also helping patients con insurance companies into paying for this outrageously-priced drug.

Amgen has gotten into lawsuit trouble with nurse educators before. That may explain why the term “nurse educators” is attached to this asterisked explanation: “nurse educators are nurses by training, but they are not part of your treatment team or an extension of your doctor's office.” The site is oddly confessional in other ways, noting that the personality profiles of the animated characters on its site (“Although Geraldine is an electrical engineer by trade, her love of classic cars never drifted”, “Amaia is Puerto Rican and grew up in small-town Georgia…”, “Originally from the Samoan island of Upolu, Kai never would have imagined leaving the tropics for a city with an honest-to-goodness winter…”) do not represent actual patients.

Tezspire blocks a cytokine called thymic stromal lymphopoietin, part of the immune system that is crucial for fighting off parasitic worms and may also be important in fighting viruses and cancers. Tezspire’s ads warn against receiving live vaccines and tells patients to inform their doctors about any parasitic infections. (It’s hard to imagine that conversation; if you suspected you had worms, wouldn’t that be first on the problem list?)

Still in its early stages, the “Air” campaign looks to connect with people with asthma on social media. There have already been pieces in the Washington Post, Huffington Post and Buzzfeed that, although identified as sponsored by Amgen, borrow from the credibility of those publications while directing readers to sponsored resources. While several of these paid ads include a link to theairbetweenusall.com, the website still appears to be under construction.

Only about 5-10% of Americans with asthma have severe asthma, defined as unresponsive to usual treatment. For some patients, Tezspire may be an effective adjunctive treatment by one measure; in clinical trials tezepelumab reduced the annualized asthma exacerbation rate compared to placebo, although all the numbers were low. It’s not clear that patients benefited from the drug. When it came to measures of patient reported outcomes, most patients in the treatment group (as high as 82%) reported improved symptom scores – but so did those in the placebo group (as high as 77%). The improvement in symptoms was small – often not meeting a “minimal clinically important difference” standard – and improvement was comparable between treatment and placebo.

“Air” complements Amgen’s “Break the Cycle”, an unbranded disease awareness campaign that encourages patients to question whether their asthma is uncontrolled. It’s hard to imagine that patients are somehow unaware that their asthma is not controlled. At any rate, “breaking the cycle” appears to involve seeing a specialist listed on the site and becoming educated through an external link to the Tezspire website. In addition, patients are asked to share their asthma story to inspire (get it?) others.

The new “Air” campaign takes the next step and urges patients to tell those stories to the non-asthmatic people in their lives. Advising people to talk about their chronic diseases is becoming a specialty for Lori Gottlieb. It’s not the first time Gottlieb has been paid by a pharma company with an expensive treatment to counsel patients to overshare about their ailments. Horizon Therapeutics hired her to encourage conversation around thyroid eye disease (TED) with “Dear TED”, part of their unbranded disease awareness campaign “Listen to Your Eyes.” In a Horizon-sponsored story in USA Today, Lori Gottlieb explains that patients who share their experience will seek care sooner. That’s good news for Horizon’s drug Tepezza, approved for a condition that usually resolves when the underlying hyperthyroidism is adequately treated. Tepezza runs up to $500,000 for treatment.

No doubt Amgen wants patients to seek care sooner too. Perhaps that’s why they’re concerned that 56% of people with asthma don’t share their asthma status if they don’t have to or that 80% say their family and friends are not very involved in their asthma management. Maybe those patients have it right. Not only are there more interesting conversational topics than reciting symptoms and triggers, but oversharing isn’t the answer. If pharmaceutical companies really wanted to help asthmatics, they would fight air pollution, fund anti-smoking programs, and lead the way on eradicating cockroaches. Allergy to cockroaches is far more common than allergy to cats or dogs and is the most significant contributor to asthma-related hospitalizations in inner cities.

Judy Butler is a research fellow at PharmedOut. 

March 2023: Novo Nordisk outed for veiled marketing through third parties

By Judy Butler

Novo Nordisk is under investigation by the Food and Drug Administration (FDA) after a complaint was filed that a 60 Minutes news story about the company’s weight loss drug Wegovy was an ad. Not surprisingly, Novo Nordisk claims innocence by arguing that they did not pay the network for the segment and had no involvement in the content.

Of course, a direct payment isn’t necessary to influence what is said. Drug companies favor business relationships aligned with their own best interests. And the U.S. isn’t the first country to call out Novo Nordisk’s covert advertising methods. Novo Nordisk earned a public reprimand from the self-regulatory arm of the British pharmaceutical industry for “a large-scale Saxenda promotional campaign which Novo Nordisk knowingly paid for and was disguised.”

The British case, brought to the Prescription Medicines Code of Practice Authority (PMCPA) concerned a free weight management course advertised on LinkedIn with no mention of Novo Nordisk’s sponsorship. The company violated seven clauses of the code in its actions, including the use of training content as promotion.

Novo Nordisk claims it was not responsible for the training content because it had been created by and was owned by the training provider which had sought sponsorship from the company. The PMCPA disagreed. The sponsorship contract stipulated that Novo Nordisk would review the materials for medical and factual accuracy. That meant Novo Nordisk – before deciding on whether or not to fund the project – would have been aware that Saxenda (liraglutide) would be the primary medical treatment discussed, and would be covered positively. Furthermore, during the appeal process, Novo Nordisk agreed that the training material would have violated the code had it been created by the drug company. The PMCPA concluded that “Novo Nordisk had knowingly supported an activity that it knew it could not undertake itself.”

With industry-funded “education”, it’s not a matter of whether or not the content of the training is inaccurate. Rather it’s a matter of what is emphasized, what is de-emphasized, what is excluded – and the impressions a trainee would walk away learning. The speaker notes that a trainer used to narrate the slides is particularly important. For one slide featuring three pharmacological treatments, the speaker notes mentioned no side effects for Saxenda while emphasizing side effects and their consequences for the others.

The balance of time spent on any treatment also influences perceptions. Module 3 of the webinar, with 21 slides, focused on liraglutide’s mechanism of action, evidence for use, and administration; no other drug was covered in similar detail. Speaker notes for Module 4 included: how to talk to patients about obesity, assess eligibility for Saxenda, and if suitable, explain how it works; evidence supporting its use; and expected results. The module did note, that there were side effects in 40% of people, but also reassured viewers that these side effects usually settled within a month.

Now under an audit to determine any additional penalties for the illicit promotion of its weight loss drug, Novo Nordisk offered an apology of sorts – via an article in the Financial Times. Although the article stated that the company “sincerely apologizes”, the CEO’s rationalization was much longer: “It’s really important to understand that unless there is investment in educating physicians, there is a risk that physicians are not being updated on the latest advancements. And that’s where, of course, there’s a fine line about how you do that.”

Nope, it’s not a fine line: when industry is paying, it’s not education.

In the British Saxenda case, Novo Nordisk’s complicity in promotion was difficult to challenge because the company had reviewed the content. In contrast, although the FDA appears to be taking the investigation into Wegovy seriously, without direct evidence of coordination there may be little room for regulatory action. Besides, the most common way FDA enforces advertising violations is merely to send a letter asking the drug company to remove the ad and stop the unlawful behavior. That hardly rises to even a slap on the wrist.

Drug companies regularly promote drugs through third parties, utilizing physicians, professional societies, and medical education and communication companies to convey marketing messages disguised as education. The FDA should regulate industry-funded education as promotion.

Judy Butler is a research fellow at PharmedOut.

February 2023: Bite-sized sponsored education is still advertising

By Judy Butler

Streaming videos are not just for entertainment. They’re now the latest way pharma is targeting health care providers (HCP). Evermed, a company that licenses software to create a personalized, Netflix-like hub for HCPs, boasts that they work with 8 of the top 10 pharma companies. And in December they partnered with the global healthcare marketing agency Havas Health & You (HH&Y) to reach more HCPs.

Just like a Netflix account, Evermed’s software offers on-demand video content that’s curated based on viewing preferences. This “education streaming” serves up short form content including mini-docuseries, vignettes, and animation videos, that run from 3 to 15 minutes long. Some content features physician influencers known as key opinion leaders (KOL) who respond to questions posted in a comment section.

Videos influence the decision making of one in two HCPs. Evermed’s strategy is for pharma companies to build trust with physicians by providing unbranded “educational” videos on diseases as well as broader topics including clinical trials and health care disparities. At the same time, the Evermed software allows pharma clients to track a provider’s viewing content and hone their marketing pitch accordingly. Evermed assures potential clients that if they are strategic about the educational content they offer, “doctors are more than happy to learn about the new drugs.”

Because it is a marketing agency rather than a pharma company, HH&Y could create one hub supported by multiple pharmaceutical company clients. That could make it even harder to recognize that pharma funds the content.

Amazon Prime has gotten into the act too. Asserting that the amount of medical information is estimated to double every 73 days (sounds like cancer cells…), Amazon Web Services pitches its media and entertainment platforms as a way to personalize medical content to physicians. They propose separate channels for different medical specialties, each with a host who combines clinical credentials with “the ability to entertainingly deliver informative content.”

This industry-sponsored streaming content has all the same problems as industry-sponsored continuing medical education (CME) – it’s just bite-sized. Either format may be referred to as education, but sponsored content always relates to the sponsor’s business. Like CME, streaming content doesn’t promote a specific drug, but promotes specific diagnoses and perspectives that lay the groundwork for HCPs receptivity to subsequent drug pitches.

In fact, that’s exactly the strategy Evermed describes: start with a “pull mindset”, dangling education to HCPs to create trust, and “only then talk about your product.” Years before a new product launch a pharma company could “use educational videos to establish an unmet need.” Because HCPs can’t detect commercial bias in content that doesn’t mention drugs, they don’t see that they are being primed for a sales pitch. (It bears noting that every study that has examined industry-sponsored CME for marketing messages has found them.)

Industry has no place in education – even if it’s bite-sized.

Judy Butler is a research fellow at PharmedOut.

January 2023: Overweight and Over Wegovy

By Judy Butler

In January, CBS’ 60 Minutes ran a segment endorsing Wegovy, Novo Nordisk’s weight loss drug, and advocating for broader insurance coverage for the drug. The brief acknowledgement that Novo Nordisk was a major advertiser of the show, and that the doctors interviewed were paid by Novo Nordisk, did little to balance what was essentially a long advertisement for Wegovy.

Along with 60 Minutes, Wegovy has been garnering headlines and viral social media coverage, all of which touts the company’s marketing message: obesity is a chronic, serious disease, largely out of a patient’s control, and now there is an effective treatment which should be covered by insurance.

The marketing messages frame the problem to set up Wegovy as the answer. If obesity is a chronic, dangerous disease, then it makes sense that the treatment is a pharmaceutical that lowers weight. Wegovy is one of a growing class of GLP-1 agonists that reduces appetite by slowing digestion and the rate at which the body takes up glucose. In combination with calorie restrictions and increased physical activity, clinical trial participants on Wegovy lost had an average of 15% of their body weight; those in placebo lost 2.4%. What’s not mentioned in the marketing message is that these potential benefits come with a black box warning for thyroid cancer, as well as other risks such as acute pancreatitis and gallbladder disease. If any adverse events are mentioned, they tend to be nausea, diarrhea, and vomiting. Another important point is that keeping the weight off means staying on the drug – if the drug is stopped, the weight is regained.

In fact, it’s unclear whether weight loss should be the primary focus of obesity treatment. A 2021 review challenges the conventional wisdom that high BMI increases mortality risk and makes the case that repeated weight loss attempts may contribute both to weight gain and weight cycling, which is associated with significant health risks. Instead, the authors argue for a weight-neutral strategy for obesity treatment, focused on increasing physical activity and improving cardiorespiratory fitness – both of which are associated with greater reduction in risk of all-cause and cardiovascular disease mortality than intentional weight loss.

Similarly, other researchers argue that a focus on BMI distracts from the structural factors that lead to poor health. Given Wegovy’s price tag of $1300/month, and the need for lifelong treatment, there’s potentially billions of dollars that could be otherwise invested. With other drugs positioned to hit the market soon, analysts are predicting that obesity treatment could grow from a $2.4 billion category in 2022 to $54 billion by 2030.

Without a significant market challenge yet, Novo Nordisk’s marketing has relied on unbranded campaigns that act as de facto Wegovy ads. Central to all is a focus on the stigma of obesity. And the messengers are doctors, celebrities, and organizations funded by Novo Nordisk.

There’s It’s Bigger Than Me with Queen Latifah, the You’re Not Alone video released for World Obesity Day, the Truth About Weight campaign with links to obesity care providers, Stop Weight Bias, and a site for health care providers, Rethink Obesity. The industry-supported Obesity Action Coalition reinforces these messages and organizes would-be patients to lobby for insurance coverage.

While these campaigns purport to destigmatize obesity, advocates argue that they co-opt the concept and transform it into a marketing tool. Ragen Chastain, an advocate for size acceptance and Health at Every Size, describes Novo Nordisk’s campaigns as a wolf in sheep’s clothing, using the language of stigma to sell weight loss rather than to reduce discrimination.

What’s more, Novo Nordisk leverages its ad spending to gain favorable media coverage and endorsement of its campaigns. That’s what happened with The Mighty, an online health community touting the power of the patient voice. Chastain, a long-term content contributor to The Mighty, called out the platform for partnering with and promoting It’s Bigger Than Me. The editorial editor explained that they “fulfill these partner requests as a way of navigating the balance between editorial independence and the funding The Mighty receives through pharmaceutical sponsorships.” In this instance, The Mighty pulled its sponsorship and ran Chastain’s critique, but it lays bare the power of industry influence on editorial decisions.

With billions of dollars at stake, Novo Nordisk is investing in a major marketing campaign that creates the conditions for the drug to sell itself. If obesity as a disease, the idea that a drug is needed to treat it goes unspoken. It’s not the first time pharma has used this tactic, and it won’t be the last.

Judy Butler is a research fellow at PharmedOut.

2022

December 2022: Pharma's Payout to Nurse Practitioners and Physician Assistants

By Judy Butler

More than 1 out of 3 advanced practice clinicians (APC) – a group of prescribers that includes physician assistants (PA) and nurse practitioners (NP) – took payments from drug and device makers in 2021. Industry targets whoever holds the prescription pad, and APCs write a substantial proportion of prescriptions. APCs accounted for 36% of providers in 2020 and are estimated to make up 45% of providers by 2030. In 2015 PAs and NPs wrote 676 million prescriptions – 17% of all retail prescriptions. By 2020 that rose to a billion prescriptions – 30% of retail prescriptions.

APCs are now included in the federal government’s open payments program, which began tracking physician payments in 2013. It turns out that APCs are remarkably similar to their physician counterparts in both the percentage of prescribers accepting payment and how frequently they interact with industry, according to two recent analyses.

More than 90% of general payments to APCs or doctors are food and beverage payments. Few APCs cash in on the most lucrative general payments. That’s also true for physicians. Education, consulting, gifts, and commercial payments go to 5% or fewer of the doctors accepting payments, yet they account for $1.6 billion of the $1.9 billion total in general payments. In contrast, ACPs accept $49 million in non-food and beverage payments, mostly for education.

Making millions of small payments and tens of thousands of large payments is a consistent and carefully calculated industry strategy. Those receiving large payments are often teachers or influencers who impact the broader environment in which decisions about drugs or devices are made while those receiving small payments change their own prescribing behavior.

Research on the influence of payments on prescribing has primarily focused on physicians, but  APCs respond similarly. One study of data from Washington DC found that payments to APCs impact prescribing. In comparison to those not taking gifts, the average cost per Medicare prescription was significantly higher among PAs and NPs who received gifts.

Small gifts matter. Accepting even one meal was associated with an increase in the rate of prescribing of a targeted drug. A 2020 meta-analysis found many studies showing that food and beverage gifts affect prescribing habits.

PAs and NPs have long been targets of these small gifts. According to industry tracking data, they received roughly 20 million drug rep visits in 2006, a 20% increase from 2004. Indeed, 96% of NPs surveyed in 2010 had regular contact with drug reps and attended industry-sponsored continuing education courses; most believed the content was reliable.

Ironically, open payments data may be more useful to industry in refining marketing strategies than it is in creating public transparency. Researchers publish a handful of scholarly analyses, but there is an entire data analytics industry that packages and sells these data to pharma. As IQVIA points out in its sales pitch, “there is a big difference between having access to 78 million records and making sense of those records.” Plus, data companies can combine open payments data with additional proprietary data such as KOL mapping. Not only can companies assess their own marketing, but they can learn what their competitors are doing.

Open payments data capture many of a prescriber’s interactions with pharma, but there are many marketing strategies that influence prescribing that are not quantifiable or simply not included. For example, open payments collects no information on samples, one of pharma’s most important promotional tools. Nor does it specifically track exposure to industry-sponsored CME or webinars.

One needs to look no further than Point of Care Network (POCN), the largest NP/PA network, to see all the ways pharma targets these prescribers. By registering a free account – and providing personal and professional data that will be shared with third parties – APCs can access industry-sponsored continuing education, get paid for activities from market research to speaking, request drug and product samples or discount cards, or become a POCN Ambassador and be first in line for speaking and research openings.

Pharma companies that want to reach APCs need only contract with one of the several businesses that sell databases of verified contact information for these prescribers. Or hire one of the marketing companies selling multiple services specifically tailored for APCs from virtual detailing, digital marketing, to key opinion leader (KOL) identification and mapping. One company, NP/PA Engage, boasts of over 70 pharmaceutical and medical device clients.

Pharma also influences professional membership organizations, including the American Association of Nurse Practitioners (AANP) and the American Academy of PAs (AAPA). Members of AANP’s corporate council gain access to AANP leadership as well as marketing channels. Partnership opportunities with AAPA offer similar access.

The problem with all types of pharma marketing is that it promotes prescriptions of the most profitable drugs, which are not necessarily the most effective drugs.

Studies consistently show payments to physicians and APCs influence prescribing for the worse.  The answer is glaringly obvious. One study found that in the very few states that enacted gift bans, “physicians are less likely to prescribe costly new medication that have few advantages over existing alternatives” and more likely to “select drugs that work and ignore those that do not.” Gift bans should be enacted in all states. If only politicians didn’t also accept gifts from pharma…

Judy Butler is a research fellow at PharmedOut.

November 2022: Selling drugs and patients' bodies

By Judy Butler

Ro, the online direct-to-patient healthcare company that offers easy access prescriptions for Viagra, Plenity, and other drugs, is getting into the business of recruiting patients for clinical trials. After all, it already has data on millions of patients who entered comprehensive health information into Ro’s custom-built electronic medical record (EMR), and those patients agreed to terms of use that grant Ro broad latitude in using these data.

Ro approached the National Institute on Aging (NIA) about a partnership last year after a study suggested Viagra may lower the risk for Alzheimer’s Disease. Although further research found Viagra ineffective, NIA took up Ro’s offer to mine its extensive health data to identify subjects for its registry of patients eligible for and willing to enter Alzheimer’s trials. A feasibility study will be conducted – and funded – by Ro.

Tens of thousands of Ro’s patients who live within 50 miles of NIA’s facilities in Bethesda and Baltimore may be surprised when Ro contacts them because their medical history indicates they may be at risk for Alzheimer’s. For those willing, surveys and cognitive tests will determine eligibility for the registry. The goal is to identify and include 700 patients with an emphasis on underrepresented minorities.

The partnership with NIA may be Ro’s first step in using its data and technology to enter the patient recruitment field, a growing subset of the multi-billion dollar business of clinical trials.

Ro and other companies that collect patient data through EMRs or through patient communities (for example, Health Union) can target specific patient populations for clinical recruitment. Other for-profit companies offer “free” search engines to patients looking for clinical trials. For example, EmergingMed, which describes itself as an “innovator in clinical trial enrollment optimization” is a pioneer in monetizing the matching of patients to clinical trials.  It  makes money by charging monthly subscription fees for developing and hosting privately branded clinical trials databases to institutions, foundations, and nonprofits, including the American Association for Cancer Research, the Melanoma Research Foundation, and the Alzheimer’s Association.

Recently, an “advisory panel”, including industry representatives, of people concerned about slow recruitment to trials for Alzheimer’s drugs, issued recommendations to address recruitment challenges. Apparently, only 20% of patients who are aware of trials consider participating. About 78%-88% of willing volunteers with “prodromal” or “preclinical” dementia-related conditions are screened out due to comorbid conditions. For those successfully screened, risks of experimental therapies scare many away from entering a trial.

Recommendations for capturing more patients, including those who are asymptomatic, included cognitive screening, biomarker testing, and public awareness campaigns. Recommendations did not address mitigating patient concerns about drug risks.

Experimental Alzheimer’s drugs have significant risks and uncertain benefits. That was true for aducanumab (Aduhelm), despite its controversial conditional drug approval. It may well be true  for lecanemab, which will be considered for approval early next year. Recent investigative reporting from STAT uncovered one death of a trial participant that an investigator concluded was due to the drug. Although manufacturers touted the drug’s success in a press release, the jury is out until full trial data becomes available.

Convincing more people – especially those with no symptoms – to enter clinical trials of Alzheimer’s drugs is unlikely to make any difference in addressing the disease. It will, however, help the biopharmaceutical industry.

The stakes are high. There are 143 drugs in clinical trials for Alzheimer’s. The interests of biopharmaceutical companies, which sponsor two-thirds of the late-stage Phase 3 trials, are obvious – a successful drug could be a blockbuster. But other entities stand to gain as well. The Alzheimer’s Association and other advocacy groups are eager to claim a cure. Research funding supports academic medical centers. And the companies that monetize clinical trials also stand to gain.

The highest stakes belong to the Alzheimer’s patients. It’s possible, though unlikely, that one of these drugs will be a miracle cure. But what can help now is addressing the potentially modifiable risk factors that foster dementia. Investing in education, hearing aids, reducing hypertension or improving air pollution would prevent many cases of dementia, improve many lives in many ways, and would be far more cost-effective than pursuing elusive cures.

Judy Butler is a research fellow at PharmedOut.

October 2022: Health Union? More like, Stealth Union

By Judy Butler

Imagine being chronically ill, looking to social media for support and finding a friendly, inviting website just right for your condition. Attractive graphics, article after article on the day-to-day issues you’re dealing with, a forum where a moderator quickly responds with validation for your concerns, and hundreds of people with the same health concern who can share their experiences and support each other. 

Too good to be true? Probably. While users may feel like they’re simply sharing with other patients, they’re also sharing with pharmaceutical companies. In fact, it’s through paid relationships with pharmaceutical companies that Health Union and similar businesses can make online communities available. Because ultimately these sites help sell drugs.

Pharma sales reps build personal relationships with physicians because messages from a trusted source don’t sound like sales pitches. These websites – oriented toward consumers rather than prescribers – also aim to be trusted sources. Health Union operates over 40 condition-specific online communities for illnesses as common as allergies and asthma and as unusual as hidradenitis suppurativa and neuromyelitis optica. Along with a website, each community is on Facebook, Twitter, and Instagram. Patients can read and comment on articles, share their thoughts or ask questions in forums, respond to polls, or sign up for emails.

Branded ads on these sites indicate pharma’s presence. Health Union tells its pharmaceutical company customers that ads “drive action in the moments that matter most.” Having won patients’ trust with the services it provides patients, Health Union reassures pharma that patients are “open to hearing partner messages in our community.” Creating these communities is a strategy to maximize drug sales – “Driving interest in a prescription therapy takes education and motivation, at a point in time when those messages are most relevant.”

But Health Union isn’t just targeting advertising to patients; it’s collecting data on users and user communities and peddling these data to pharma as “deep insights that make a difference for clients’ brands and businesses.”

Data is collected anytime users interact with Health Union’s communities. By creating an account, completing a user profile, commenting on articles, posting in forums, or responding to surveys, participants generate data. Signing up for email and responding to any of the “opportunities” to participate in market research, surveys, or clinical trials, to receive special offers, or to attend events produces more data. Then, of course, there’s the data tracked by third-party services.

Patients are trading this data, perhaps inadvertently, simply by using the website. Health Union argues this is a win-win, because patients are getting a valuable resource and pharma can better develop and market its treatments. That justification, of course, is based on an assumption that the latest pharmaceutical drug is the best. And, even though all advertisements and sponsored content within the communities are clearly marked, the communities themselves are carefully designed to make those messages more actionable.

These online communities are not Health Union’s only efforts to support pharma marketing. Last year Health Union bought WEGO Health, gaining access to its large network of patient leaders, who can act as paid patient influencers. Health Union has also worked with industry-supported advocacy groups, including the US Pain Foundation, to conduct surveys.

Anyone tempted to use one of these sites should first read Health Union’s pitches to pharma, which provide a good picture of the company’s true purpose – using patients and patient data to sell expensive drugs.

Judy Butler is a research fellow at PharmedOut.

September 2022: Does $500,000 a year for a drug make your eyes bulge? We have a drug for that...

By Judy Butler

A new and highly problematic drug to treat “thyroid eye disease” (dubbed TED) has been introduced, and while Tepezza (teprotumumab) may be useful in a few selected cases, this drug should not be widely used. Nonetheless, Horizon Therapeutics, which makes Tepezza, is bent on expanding the market for an expensive drug with significant harms and questionable long-term benefits.      

When Tepezza became the first FDA-approved treatment for thyroid eye disease in 2020, the company estimated the market to be 15,000-20,000 patients. At a treatment cost of $200,000 to $500,000 for a six-month course of infusions, the drug brought in $1.66 billion in 2021. In 2022, Horizon increased its target market to 100,000 patients. It bears noting that there was no epidemic of hyperthyroidism that could account for the increased potential market, but the new estimate increased potential sales by 500% and projected revenue to $3.6 billion. That’s good news for investors – but not necessarily for potential patients. 

Abnormally bulging eyes, or exophthalmos, is usually due to an overactive thyroid gland (hyperthyroidism); it is called Graves’ disease orbitopathy, Graves’ ophthalmopathy, thyroid-associated orbitopathy, or thyroid eye disease. The latter term is a bit misleading: “thyroid eye disease” often improves or stabilizes when the hyperthyroidism is treated, so the primary treatment for this condition is treating the underlying disease causing the symptoms. Smoking is a risk factor, and smoking cessation can stabilize symptoms and decrease the active duration of the disease.

Bulging eyes can get irritated, so lubricant eye drops are important, and taping eyelids shut at night can help. Sometimes steroids are needed, and occasionally eye surgery is necessary,  because in serious cases, exposure of the cornea can cause vision loss. Certainly an effective drug has a place in treatment, but Horizon’s estimate of the patient pool for Tepezza is grossly overstated. TED may have an annual incidence of 15,000, but the vast majority of patients will experience only mild symptoms, which usually resolve when hyperthyroidism is treated. No more than 5-6% of all cases are moderate to severe and require aggressive treatment. For those whose disease has stabilized but have persistent symptoms, many can be treated with the therapies mentioned above. All groups are being targeted by Horizon, but Tepezza – at $14,900 per treatment – is not appropriate for most of these patients.

That hasn’t stopped Horizon from an all-out marketing blitz. Months before the drug’s approval, Horizon teamed up with a patient advocacy group and then launched “Listen to Your Eyes,” an unbranded disease awareness campaign with a website and Facebook group. The unbranded campaign expanded after Tepezza hit the market to include television ads, podcasts, social media campaigns, educational videos and celebrity spokespeople. When there’s just one drug approved for a condition, disease awareness campaigns serve as product marketing. 

Of course, there’s also a branded campaign with websites for patients and health care providers as well as television ads. Horizon’s commercial chief explains the goal of both campaigns “was to drive people to … find an eye specialist who treats thyroid eye disease.” Unbranded or branded, both strategies win because the only FDA-approved treatment for TED is Tepezza. 

Disease awareness campaigns are a growing business, with ad spending of $430 million in 2016. It’s worth it to manufacturers, especially because the FDA does not regulate disease awareness campaigns, even when they encourage self-diagnosis and refer to specialists known to prescribe specific drugs. When Horizon ran its first unbranded national television ad in December 2020, Google searches for thyroid eye disease jumped dramatically. So did visits to both the unbranded and branded Horizon websites. December accounted for more than 60% of the 1 million website visits in 2020, along with 120,000 uses of Horizon’s physician finder. It’s a good bet those searches led to the 65% of physicians targeted by Horizon who reported that they were highly likely to prescribe Tepezza.

Hyperthyroidism, including Grave’s disease, affects about 1.3% of the population in the U.S.; it is not a rare disease. Exophthalmos is a sign of the disease that affects a subset of people with hyperthyroidism, but why should that be considered a “rare disease” (defined as a condition that affects less than 200,000 patients)? 

Follow the money. Drugs for rare diseases were once known as orphan drugs, because companies were not interested in developing drugs with a small market and thus a low profit potential. So the government stepped in, offering Food and Drug Administration (FDA) designations with incentives for drug development. Horizon’s Tepezza garnered three designations – orphan drug, fast track, and breakthrough therapy – with benefits including federal grant money and tax breaks, 12-year biologic exclusivity, expedited evaluation and approval, and smaller trial requirements. 

Ironically, the government’s efforts to help rare disease patients may put them at risk from under-tested drugs with high price tags and misleading marketing campaigns. Tepezza was approved with clinical trial data that included only 84 drug-treated subjects – and no direct comparisons to the standard treatment of care. That led to justified concerns about prescribing by researchers and a non-preferred designation by some health plans. 

Tepezza has substantial risks. Not only can it aggravate inflammatory bowel disease, cause or worsen diabetes, and cause muscle cramps and hair loss, but Tepezza causes hearing loss in many patients. A recent study reported even higher rates of adverse events than originally reported in the clinical studies, including hearing loss (23% vs 10%) and muscle spasms (58% vs 25%). Symptoms persisted in 30% of patients at follow-up; 12% stopped treatment. And it’s not clear whether any benefits last; 37% of trial participants followed up at 48 weeks had already experienced relapse.

Not only do drugs for rare diseases receive special advantages in the drug approval process, but nothing prevents a company from expanding the market after the drug is approved. Indeed, Horizon counts Tepezza’s broad label for thyroid eye disease as a growth driver. As one FDA advisory committee member warned, “If we okay a hammer among the physicians, we're going to find a lot more nails, and some of those nails might be kind of small.” Some patients with severe TED who have not responded to other therapies may benefit from Tepezza. But with a marketing campaign aimed at driving as many patients as possible to an industry-vetted eye specialist more likely to prescribe their drug, there are far more harms than benefits in store for most people receiving Tepezza. 

Judy Butler is a research fellow at PharmedOut.

August 2022: Will California's opioid guidelines cave to industry pressure?

By Judy Butler

The Medical Board of California is updating its guideline for prescribing opioids for chronic pain, an action that has caught the attention of those who oppose constraints on opioid prescribing.

Like the draft guideline from the Centers for Disease Prevention and Control (CDC), the California guideline offers evidence-based dosing guidance and addresses the unique needs of patients who have been on opioids long-term. The criticisms voiced at the Board’s hearing in July, however, allege the guidelines will deny needed access to opioids. Their arguments are based on timeworn industry marketing messages, including: 1. Opioids are necessary for chronic pain. 2. Dosing limits are arbitrary and without credible evidence. 3. Prescribers need to be able to use their own judgment to treat pain. 4. Overdose deaths now reflect a problem with illicit drugs, not prescription opioids.

State medical board guidelines matter because they set the norms for practice for physicians licensed and regulated by these boards – and can have a big impact on prescribing. There’s a long history of opioid industry involvement in state guidelines and legislative policies. In 1994, California held a Summit on Effective Pain Management: Removing Impediments to Appropriate Prescribing, co-sponsored by the Medical Board. The summit opened with a presentation from an industry key opinion leader, who addressed the undertreatment of pain and the role of opioids. Several months later, the Medical Board unanimously adopted the nation’s first statement promoting the broad use of opioids for pain without fear of discipline. Next came “New, Easy Guidelines on Prescribing” designed to help physicians “reach a level of comfort about appropriate prescribing.”

California’s guidelines became a model for other states. At the same time, two industry-backed organizations, the University of Wisconsin’s Pain and Policies Studies Group (PPSG) and the Federation of State Medical Boards (FSMB), focused on the adoption of medical board policies that supported opioid prescribing for chronic pain without fear of disciplinary action. PPSG’s 1991 survey of medical board members found that only 12% described prescribing opioids for chronic non-cancer pain as a “lawful and generally acceptable medical practice.”  FSMB set out to change that perception.

In 1998, the FSMB widely distributed its industry-friendly Model Guidelines for the Use of Controlled Substances for the Treatment of Pain. The Model Guidelines were supported with a grant from the Robert Wood Johnson Foundation – which draws resources from opioid manufacturer Johnson & Johnson shares – and involved collaboration with a slew of opioid-funded organizations. Legal complaints charge that FSMB acknowledged the guidelines were produced “in collaboration with pharmaceutical companies” and that they described opioids as “essential” for the treatment of chronic pain. Within four years, twenty-four states had adopted or endorsed the model guidelines, most of which had at least one medical board member who had participated in an FSMB training.

The FSMB model guidelines went on to become the basis for their “Responsible Opioid Prescribing: A Physician’s Guide” that was produced and distributed with industry funding. By 2009, the University of Wisconsin School of Medicine and Public Health offered an online continuing education course based on that guide, with yet more industry funding.

In 2007, when Washington state proposed guidelines with opioid prescribing limits, an industry work group agreed to pay a public relations consultant $85,000 to implement a strategy to get the FSMB’s model guidelines adopted instead. They also convinced the state medical board to distribute the FSMB guide.

In 2022 these actions may seem like old news, but they are still relevant because the same arguments – chronic pain patients need unfettered access to opioids – are still used. Although most pain patients are not paid by industry, they are conveying messages that were created by industry. Those arguments worked before and, unfortunately, after decades of overprescribing, now the patients who are dependent on opioids do need to continue taking them. California’s guidelines – and the CDC’s – acknowledge the special consideration due these “legacy” patients. But the  guidance governmental entities also may protect a new generation by preventing expansion of  the pool of opioid-dependent patients. Medical boards shouldn’t be taken in again by industry marketing messages – no matter who delivers them. 

Judy Butler is a research fellow at PharmedOut.

July 2022: "Have your cake and eat it too": wood pulp for weight loss

By Judy Butler

“Who said you can’t eat what you love while losing weight?” asks ads for Plenity, a weight management aid from Gelesis. To drive the point home, the message appeared on an “edible billboard” made of thousands of individually wrapped cakes offered free to passers-by. Clever advertising, with a message that sounds too good to be true. As with most pharmaceutical marketing messages, there’s plenty of missing information.

Oh, wait, Plenity’s not a pharmaceutical drug, it’s considered a medical device, just one of the many things that make no sense about this therapeutic. It’s an “ingested, transient, space occupying device for weight management and/or weight loss.” Pretty grand words for wood pulp. Plenity is cellulose, the indigestible fiber part of trees and other plants. How did sawdust, long used as a cheaper-than-flour additive to bread, get to be a medical device?

And how does fiber – a component of food, get listed as a medical device instead of a food or dietary supplement?  Is Metamucil (psyllium husk) a medical device? Is Raisin Bran a medical device? Fiber, whether insoluble (wheat bran) or soluble (psyllium husk, oats), is a natural constituent of grains, fruits and vegetables. Fiber isn’t absorbed by the body; insoluble fiber holds water like a sponge, while soluble fiber forms a gel. Both suck up many times their weight in water, and help produce regular, easy-to-pass bowel movements. Plenity is wood pulp, an insoluble fiber that somehow was “cleared” by the Food and Drug Administration (FDA), as a low-risk medical device. FDA clearance is a much less rigorous process than FDA approval.

“FDA cleared”, of course, looks good on ads. Plenity’s “who said” campaign – who said losing weight has to be miserable – sells a concept of weight loss without deprivation. That’s certainly an appealing message to the 70% of Americans who struggle with excess weight. But, of course, there’s no such thing as a free lunch.

The carefree tone of the campaign may give the impression of pounds falling away while eating whatever you want, but Plenity  ads don’t ever say it’s for weight loss. They can’t, because it’s not effective alone for weight loss. Instead, it’s modestly effective as an aid to weight management. Plenity only works in conjunction with diet and exercise. The clinical studies prescribed a reduced calorie diet and instructed all subjects to exercise daily, along with the pills.

Even as an aid to weight management, Plenity is not impressive. Sure, it met a primary endpoint of 35% of subjects losing at least 5% of total body weight; 59% of the treatment group did, but so did 42% of the placebo group. That’s after about 25% dropped out of the study, although there don’t seem to have been major adverse effects.

Overall, Plenity subjects lost about 6% of total body weight, compared to 4% for those on placebo. For the average subject, who weighed 220 pounds, that’s comparing a loss of 13 pounds to 9 pounds over six months. The Plenity claim that “59% lost an average of 22 pounds”  - that may be true but ignores the whopping 41% of subjects that took Plenity and saw no appreciable weight loss. Leaving out 41% of your subjects is a surefire way to make your numbers look good.

Plenity has carved itself a unique niche. Since it requires a prescription, it is set apart from the wall of over-the-counter dietary supplements. Yet with an indication that includes overweight adults, it’s more broadly available than most prescription weight loss drugs. For that reason, it’s not likely covered by insurance, but priced at $98/month, it’s not out of reach for many people. And there’s no need to convince your doctor to prescribe it. Most sales occur during free online visits with Gelesis’s tele-health partner Ro. Gelesis describes it as “clinically proven healthcare with the convenience you expect from e-commerce.”

Gelesis acknowledges that Plenity is modeled on eating vegetables, noting that the approach was “inspired by the composition and mechanical properties of vegetables that makes adults feel fuller faster with smaller portions.” Gelesis projects Plenity will bring in $58 million in 2022. Of course, actually eating vegetables would be less expensive and more nutritious. Who said chowing down burgers and cupcakes with a side of sawdust is really more attractive? 

Judy Butler is a research fellow at PharmedOut.

June 2022: Quivering with Quviviq: New sleep drug uses the same old marketing playbook

By Judy Butler

“Trouble sleeping? Let’s talk.” That’s a message on Seize the Day & Night, an unbranded website featuring Jennifer Aniston encouraging anyone with sleep struggles to talk to their doctor. Brought to you by Idorsia Pharmaceuticals, the website is part of the company’s efforts to launch its insomnia drug Quviviq (daridorexant). With its sights on a potential $1 billion in sales to 25 million people who have trouble sleeping, the marketing campaign for Quviviq draws on every strategy in the pharma playbook – except for coming up with a name that people can actually pronounce.

Approved in January, Quviviq reached the market in May after being classified as a schedule 4 controlled substance. “Scheduled” drugs are addictive drugs, but Schedule 4 drugs are in the least addictive category, including for example Valium (diazepam) and Xanax (alprazolam). An unbranded campaign seeding the drug’s marketing messages began as early as December with the creation of The Alliance for Sleep, a group of Idorsia-funded physicians and healthcare experts. Unbranded websites for consumers and health care providers soon followed. A Harris Poll generated opinion data from patients and doctors that was then promoted on the Wake Up America website. Continuing medical education, underwritten by Idorsia and featuring many of the Alliance members, also highlight marketing messages. So does a documentary narrated by Octavia Spencer, The Quest for Sleep, with more than half a million viewings to date.

Idorsia’s sleep campaign marketing messages will be recognizable to anyone familiar with opioid marketing for chronic pain. Insomnia (or pain) is a common, undertreated chronic disease. The disease  has significant health risks. Patients are desperate for a treatment. The disease is a medical condition that is not the patient’s fault but there’s a stigma associated with prescription treatment. It’s the same old playbook for elevating a common symptom into a disease that needs a newly available prescription drug.

There are many drugs for insomnia, so the makers of Quviviq  have come up with what they may think is a unique positioning message: insomnia is a day and night problem.

It’s both an obvious and clever message. The “day and night” message reminds people that if you don’t get sleep at night you don’t function well during the day. It also alludes obliquely to the fact that sleeping aids can cause sleepiness. So can Quviviq, but the brand positions itself as the brand that has few residual (morning) effects.

Quviviq is a dual orexin receptor antagonist, similar to Belsomra (suvorexant) and Dayvigo (lemborexant); all of these related drugs can cause daytime sleepiness, fatigue, cataplexy (a sudden loss of muscular control that sometimes causes falls), and other adverse effects.

For now, at least, any messages on insomnia that highlight the “day and night” problem are probably unbranded promotions for Quviviq.

The branded campaign is just getting off the ground. A team of 500 sales reps will target doctors, largely focusing on primary care. The branded website features actor Taye Diggs as a Quviviq patient, gives patients a doctor discussion guide to bring to an appointment, and offers prescription savings cards that will reduce the $450 monthly cost to under $25. Additional direct- to-consumer marketing, including online media, will surely follow.  

Idorsia isn’t shy about sharing its marketing strategy with trade publications. Idorsia U.S. president and general manager reports Quviviq is positioned as a “consumer-oriented brand that needs a physician’s prescription” and aimed to “meet patients where they are” in large part through digital and social platforms.

Marketing messages often have a grain of truth about a condition, but they create a perception that expands the bounds of that condition – and the market for their drug. At least one researcher, Kenneth Lichstein, warns that identifying as an insomniac may be more damaging than being one, and that “there is a cost to pathologizing sleep.” Some people who claim to be insomniac actually sleep fine, but those who claim an insomnia identity have a higher risk of  depression, anxiety, fatigue, and other ills.

The effectiveness of Quiviviq is based on clinical trials with very narrowly defined patient populations. For Quviviq, patients had to meet criteria for significant sleep impairment for at least 3 nights a week for 3 months in addition to taking a sleep test. There was a placebo run-in to the trial, meaning that anyone who responded to a week of placebo treatment was thrown out of the study. More than 1,000 of approximately 2,000 participants improved with placebo during the run-in and were dropped from the trial. Eliminating placebo responders always makes a drug look better, but even after that, Quviviq was still unimpressive. The clinical data did demonstrate statistically significant improvement, but treated patients at the highest dose only got about 20 minutes more sleep a night than those on placebo. Is a third of an hour extra sleep meaningful to patients? Time will tell.  

Despite Quviviq’s claims for improved “days,” the drug carries a warning of decreased awareness and alertness, informing patients that their ability to drive safely and think clearly may be decreased, possibly for days. The drug can also cause headache, fatigue, cataplexy, and sleep paralysis, which is the inability to move or speak right before falling asleep or after waking up.

It remains to be seen if Quviviq will capture the market. Online chatter among its sales reps suggests not, but there’s also online talk of patients wanting to try it. Whatever the outcome, the marketing behind Quviviq offers an example of almost every play in the pharmaceutical marketing book.

Judy Butler is a research fellow at PharmedOut.

May 2022: McKinsey & Company: Double Agent for Purdue and FDA

By Judy Butler

The latest revelation of the efforts of opioid companies to influence regulation and protect sales highlights a familiar opioid marketing strategy – undisclosed industry funding. For more than a decade, consultants from McKinsey and Co. advised the Food and Drug Administration on management issues, including drug safety, while they were also working for multiple opioid companies.

A report from the House Committee on Oversight and Reform revealed that at least 37 FDA contracts were staffed by at least one consultant who simultaneously or previously worked for Purdue Pharma.  

McKinsey’s links to Purdue were first revealed when Massachusetts’s legal filings against Purdue were unredacted in 2019. Some of the referenced internal documents, including one that proposed banding together with other companies to jointly strategize how to deal with the FDA to minimize the potential impact of safety regulations, were made public in 2020. McKinsey never disclosed its opioid clients to the FDA and the FDA did not conduct contract reviews or reach out to McKinsey after these relationships were made public.

Testifying before the Oversight Committee, McKinsey continued to maintain there was no conflict of interest. Yet the House Oversight report details multiple examples of McKinsey touting its government experience for industry contracts. A 2009 draft presentation pitching McKinsey to lead a working group of opioid manufacturers in developing an FDA safety plan noted that the firm had supported regulatory bodies and “developed insights into the perspectives of regulators themselves.” A 2011 overview of McKinsey support for Purdue highlights that they “improved Purdue’s ability to influence regulatory environment” and “challenged perimeter of REMS [FDA’s safety plan] to minimize risks.” By 2014 McKinsey boasted of “unequaled capability based on who we know and what we know” and cited its five years of support for FDA in an email to Purdue’s CEO soliciting work.

McKinsey decided it had no conflicts of interest to disclose, but as Representative Katie Porter asserted at the hearing, it was FDA, not McKinsey, that needed to determine if there was a conflict. In an op-ed, former FDA principal deputy commissioner Joshua Sharfstein agrees, noting that “the firm’s work on the FDA’s structure and management processes could have indirectly affected many regulatory actions.”

Industry relationships, particularly those involving money, necessarily create a potential conflict. Moreover, hidden money flowing to key opinion leaders, researchers, medical societies, and patient advocacy groups to name a few, allow these allies to promote industry messages with an appearance of independence. It’s only through legal and legislative action that the consequences are brought to light. 

McKinsey’s work is also a reminder that prescription opioids continue to be marketed. The company worked for Purdue through 2019 and consultants that had worked on Purdue contracts served on FDA contracts as recently as 2021. Because McKinsey has not fully complied with the Committee’s requests, information about consultants working for both FDA and pharmaceutical companies other than Purdue remains undisclosed. Until McKinsey turns over additional documents to the committee, the question of a similar relationship with other opioid companies remains outstanding. During the hearing, several representatives argued that there was no need to address the “history” of prescription opioids when the real problem was fentanyl at the border. Unfortunately, the problem of prescription opioids is not history yet.

Judy Butler is a research fellow at PharmedOut.

April 2022: 

The Alliance for Aging Research: Fronting for Pharma

By Judy Butler

The Alliance for Aging Research hit PharmedOut’s radar because of their vigorous campaigning on behalf of Biogen’s Aduhelm, an ineffective and dangerous Alzheimer’s drug. On the surface, the decades-old patient advocacy group appears to be objective and professional. But it doesn’t take much digging before it becomes clear that appearances are misleading. 

The Alliance bills itself as “the leading nonprofit organization dedicated to accelerating the pace of scientific discoveries and their application to vastly improve the universal human experience of aging and health.” Sounds good, right? Who wouldn’t want to age well — or support scientific discoveries?

When you realize the organization’s primary “alliance” is with pharma, that self-description takes a different cast. All 50 funders, are pharmaceutical companies or related businesses. As are the affiliations of the entire board of directors. With almost half of the organization’s $5 million budget in 2020 going towards program advertising and marketing, that leaves a lot of room for influence.

The Alliance’s steps to “safeguard independence” offer little reassurance. The organization asserts it has editorial control and makes independent policy decisions, but materials are only independently reviewed “whenever possible.” Promises to prohibit brand affiliations have little meaning when “disease awareness” campaigns are more effective than advertising. And, the conflict of interest determination for board members rests in the hands of fellow board members.

The Alliance’s 2020 Impact Report touts its many achievements -- all of which benefit drug companies. Here’s a small sampling:

• Project LOOP may try to “lower out of pocket” costs for Medicare recipients, but lowering actual drug prices is not part of the campaign. Not surprising, given that Project LOOP is funded by AbbVie, Astellas, and Eli Lilly.

• ACT-AD (Accelerate Cures/Treatments for All Dementias), a coalition chaired by the Alliance that seeks “to accelerate development of potential cures and treatments for Alzheimer’s disease (AD) and all dementias” is sponsored by Acadia, Avanir, Biogen, Cerevel, Lilly, Genentech, Green Valley, Lundbeck, Merck, and Otsuka.

• Aging in Motion, a sarcopenia disease awareness campaign advocating for research and innovation in treatment presses “for greater levels of research and innovation to develop treatments in the area of sarcopenia and age-related functional decline.” And aims “to overcome obstacles that impede the development and evaluation of promising treatments for sarcopenia and associated functional decline in people as they age.” AIM counts Abbott, Astellas, and Pfizer among its sponsors. Sarcopenia, normal age-associated loss of muscle, is not a disease.

• The Heart Valve Disease Policy Task Force claimed success in expanding Medicare beneficiary coverage for transcatheter edge-to-edge repair (TEER). The only US-approved TEER is owned by Abbott, a Task Force sponsor.

• Project PAUSE (Psychoactive Appropriate Use for Safety and Effectiveness) supports treatment for neuropsychiatric symptoms in dementia patients in long-term care to address the “large unmet medical need in long-term care settings for the diagnosis and management of NPS in dementia, including: psychosis, wandering, sleep issues, agitation, depression, apathy, and aggression.” Eighty three percent of Medicare claims for antipsychotics in long-term care are for non-FDA approved conditions, and antipsychotics increase mortality in elders. Pushing back on the Biden Administration’s efforts to rein in antipsychotic use in nursing homes, the Alliance argued for a focus on ensuring their appropriate use. Project PAUSE is funded by Acadia, Avanir, Lundbeck, Merck, and Otsuka. 

Since 2016, the Alliance has been training patients and caregivers to engage in research and development with funding from the Patient-Centered Outcomes Research Institute (PCORI). It’s the pharma-dominated Advisory Council, however, that “is responsible for sculpting the training program, engaging directly with network participants, and ultimately amplifying the Alliance's overall impact.”

Two training alums have been active participants in the Alliance’s efforts to challenge the Centers for Medicare and Medicaid Services’ proposal to restrict coverage for Aduhelm to clinical trial participants.

Pharma contributions to organizations like the Alliance are business decisions made with an eye to return on investment. Appearing independent, these organizations’ advocacy efforts support pharma’s primary interest – expanding market share. Close ties to industry means an organization is unlikely to support effective generic drugs, nonpharmacologic treatments, lifestyle changes, or preventive medicine. Pharma-funded groups advocate against public health. Perhaps nowhere is this easier to see than with the Alliance for Aging Research.

Judy Butler is a research fellow at PharmedOut.

March 2022: 

Let's lose the term "legitimate pain patient"

By Judy Butler

The frame of good versus bad opioid users, seen over and over, again made recent news. This month the Supreme Court heard arguments addressing a “good faith” defense in criminal cases involving the prescribing of opioids. Under the Controlled Substances Act (CSA), an authorized prescriber can dispense these drugs “for a legitimate medical purpose“ when “acting in the usual course of his professional practice.” Pain patient advocates argue that prescribers should not be criminally liable unless they intend to prescribe without a legitimate medical purpose. They reason that fear of criminal prosecution deters prescribers from using their best medical judgment to treat pain. With opioids, of course.

This case comes on the heels of the release of the CDC’s draft Clinical Practice Guideline for Prescribing Opioids, which updates and expands upon their 2016 Guideline. Most notably, the new recommendations no longer include suggested limits on the dose and duration of opioid prescriptions. Predictably, pain patient advocates framed the revisions as a win because

the opioids-for-pain advocates push back on any and all measures to curtail opioid overprescribing. The unstated message is that any “legitimate pain patient” may benefit from opioid treatment. They argue that because “legitimate pain patients” don’t divert drugs, and, somehow, are magically protected from misuse, their unimpeded access to opioids must be protected.

This decades-old delineation between “legitimate pain patients” and abusers is a marketing message, created by Purdue Pharma in response the worrisome rise in opioid addiction seen after the introduction of OxyContin. As Richard Sackler put it  – “we have to hammer on the abusers in every way possible. They are the culprits and the problem.”

Arguing that opioid prescribing decisions should be left to the best medical judgment of doctors with good intentions sounds deceptively reasonable, but it won’t address the complex problems resulting from decades of overprescribing. In fact, it will make them worse. Aggressive opioid promotion has long-lasting effects that are difficult to reverse. Opioid prescribing rates remain significantly higher than before the opioid crisis, and industry payments to doctors continue to be associated with increased prescribing. Industry-aligned groups continue to challenge effective public health measures aimed at reining in overprescribing.

Perhaps most significantly, a generation of patients have been prescribed long-term opioids for chronic pain – in the absence of any evidence that it works. In fact, in recent years, it has become clear that opioids are ineffective for chronic pain, can even worsen pain, and are dangerous to use long-term. The treatment of pain patients dependent on opioids, including opioid tapering, is a long-term, complicated process. Only a reduction in overprescribing will save a new generation from the same fate.

Patients on long-term opioids absolutely deserve care, and that care includes continuing opioids at least temporarily. Care also means medical support for tapers (when appropriate, which it usually is), advocating for coverage of effective non-opioid treatments, and support for research on pain that is not funded by pharmaceutical companies. Unrestrained access to opioids is not good medical care.

Opioid manufacturers told physicians that opioids were good for arthritis, low back pain, and headaches: conditions that opioids should never be used for. Corporate “educational” efforts over decades may have persuaded many physicians that opioids are reasonable treatments for ordinary pain syndromes, but believing doesn’t make it so. Pain doesn’t protect patients from opioid use disorder and addiction, which can wreck lives and kill people.

There’s a reason opioids are controlled substances: they’re addictive. Prescribers with good intentions to treat pain got a pass when they were duped by industry misinformation about addiction that influenced medical practice. Giving a pass to prescribers who intend to treat chronic pain with opioids means giving a pass for overprescribing. Restrictions on opioid prescribing save lives.  

Judy Butler is a research fellow at PharmedOut.

February 2022:

"It's a trap!" A doctor and a patient duped by Pharma speak out

By Judy Butler

Recognizing you’ve been duped and admitting it is unusual. Rarer still is making the story public. So it was unusual that two firsthand stories of getting sucked in by the opioid industry and regretting it were released last month.

It’s easy to be taken in by opioid marketing efforts when you’re trying to help people in pain – industry tactics aren’t obvious. Chronic pain patient advocate Cynthia Toussaint describes how gratifying it felt in 2003 to get recognition and support from Purdue Pharma for her fledgling organization. Enjoying the perks, platform, and connections made available to her, she didn’t question the motivations of the company. An “aha” moment came at a media training when Purdue’s consultant advised the “up-and-coming pain star” that when asked about treatment for her condition “the correct response is to take OxyContin.” Ms. Toussaint recognized “Purdue was actively grooming me to be their #1 patient sales person.”

Still, she continued her relationship with the company. Toussaint flew in on Purdue’s dime to meet with a national organization of female state legislators. But a request for a prominent link on her organization’s website to OxyContin’s marketing page finally prompted her to end her relationship. She announced “I won’t be a whore for a pharmaceutical company.”

It’s not the branded marketing, however, that really drives opioid companies to fund nonprofits. It’s the unbranded marketing messages that supposedly independent organizations can deliver – to legislators, the media, and health care professionals – that are really important. These organizations appear to be objective, independent, and trustworthy voices, and often don’t disclose ties to opioid companies. That’s what was happening when Purdue brought Ms. Toussaint to interact with state legislators.

The second insider account shows the impact of those stealth messages. In 2003, a Veterans Affairs (VA) doctor led a workshop for medical residents designed to increase their willingness to prescribe opioids for chronic pain. He developed his “evidence-based” training relying on consensus guidelines from the American Academy of Pain Medicine and the American Pain Society. Neither the organizations nor individual authors of those guidelines disclosed their industry ties. As a result, residents were taught about “pseudo-addiction” (a term invented to reassure prescribers that typical addictive behavior did not really indicate addiction) and other industry marketing messages as if they were evidence-based medical knowledge.

The four-hour workshop succeeded. Residents’ concerns about addiction, abuse, and harms associated with opioids significantly decreased while their beliefs about the safety and efficacy of opioids for chronic pain – as well as their comfort with prescribing opioids – increased. The VA doctor had no ties to industry, yet he perpetuated industry marketing simply by using consensus guidelines from legitimate-sounding medical societies. The result? A new generation of doctors overprescribing opioids.

These stories may have been from 2003, but no doubt similar stories could be written today. Opioid companies still support organizations that incorporate marketing messages into their materials and public statements, and many are duped because of it. We need more people to recognize, reject, and call out industry marketing. Kudos to those who have done so.

Judy Butler is a research fellow at PharmedOut.

2021

November 2021:

Sales of Some Opioids Lift Sales of All Opioids

By Judy Butler

When physicians accept food – and a sales pitch – related to patented opioids, not only do they prescribe more patented opioids, they also prescribe more generic opioids. What’s more, the spillover effect on generics lasts for years.

Researchers matched physicians’ Open Payments data on food and beverage gifts related to patented opioids to their Medicare Part D opioid prescribing claims from 2014-17 in findings published in Health Economics in September. Food and beverage gifts are a proxy for drug rep visits or promotional meetings. Almost 50,000 physicians, about 7.3% of Medicare providers, accepted at least one food and beverage gift over the duration of the study.

Promotion works. Physicians receiving the average number of yearly promotional visits increased patented opioid prescribing by 13.3% and generic prescribing by 3.6%. Although promotional visits result in a higher percentage increase in patented opioid prescriptions, they actually result in a higher number of generic prescriptions. Generics account for the overwhelming majority of opioid prescriptions, so a small percentage increase in prescribing translates to tens of thousands of additional prescriptions. This spillover effect on generics outlasts the effect on patented opioids; two years following promotional visits, there is no longer an effect on patented prescribing while a robust increase in generic prescribing persists. So, in addition to profits from sales of patented opioids, opioid companies gain the added benefit of normalized opioid prescribing from increased generic prescriptions.

Sales potential also related to who received promotions. Doctors who saw more patients and wrote more prescriptions, for both generic and patented opioids as well as non-opioids, were more likely to have industry relationships. Primary care physicians, including internists and family physicians, are more likely to be seen by the average patient – and are more responsive to increasing opioid prescriptions in response to opioid promotion than specialists.

Another group that showed higher effects of promotion were doctors new to opioid marketing. Physicians who received payments in 2016-17, but not in 2014-15, prescribed more opioids than doctors with pre-established opioid industry relationships.

The data show increased claims for Medicare recipients (people over 65 and the disabled), a vulnerable population in whom opioid prescribing is already unacceptably high. Addiction rates are growing among older adults, who also are experiencing increases in mortality and hospitalization due to prescription opioid misuse. Older adults with opioid use disorder may be at a higher risk of death compared to younger adults.

Although these data are from 2014-17, there is no doubt that opioid promotion still successfully increases sales – of profitable patented opioids as well as generic opioids – and challenge efforts to reduce overprescribing. In light of their findings, the researchers suggest banning direct-to-physician opioid marketing to reduce opioid prescribing. We couldn’t agree more.

Judy Butler is a research fellow at PharmedOut.

October 2021:

The FDA Should Mandate Industry-free CME

By Judy Butler

The Food and Drug Administration (FDA) is considering mandatory education for opioid prescribers. As an initial step, the agency will hold a public workshop, “Reconsidering Mandatory Opioid Prescriber Education Through a Risk Evaluation and Mitigation Strategy (REMS) in an Evolving Opioid Crisis,” on October 13 and 14.

In 2009, with growing concern over the opioid crisis and the dangers of OxyContin and other extended-release, long-acting (ER/LA) opioids, the FDA required ER/LA opioid manufacturers to establish a REMS. One of the strategies approved by FDA was the development of manufacturer-funded continuing medical education (CME) for health care professionals, which it launched in 2013. In 2018 the REMS was expanded to include immediate release (IR) opioids. FDA opted not to mandate CME on the grounds that doing so would result in a restricted distribution system for opioids. Given current e-prescribing options, the FDA believes this may be no longer be an obstacle to mandatory education.

There is no evidence that the current opioid REMS has done anything to mitigate opioid harms. Little wonder; these industry-funded activities are designed to allay prescriber concerns about opioids. Our recent study of 2018 ER/LA REMS CME identified 10 marketing messages that appeared consistently, including demonstrably false information that opioids were effective for chronic pain, and that addiction and other adverse effects affect only those who misuse or abuse opioids. One case study, for example, said that it was fine to prescribe opioids to a pack-a-day smoker with an alcohol use disorder, whose mother died from alcoholic cirrhosis. Rather than discourage prescribing, these modules framed prescribing opioids for chronic pain as safe, effective, and appropriate for any patient with monitoring. A look at a current, expanded REMS activity suggests that these marketing messages are still present.

Although opioid prescribing has declined, the FDA recognizes that rates are still too high, including overprescribing following surgery and prescribing to vulnerable populations (e.g., children and adolescents following common dental and minor surgical procedures). The FDA also expresses continued concern with overdose deaths. They correctly note that many illicit opioids users are initially exposed to opioids through non-medical use of prescription opioids and that more than 16,000 fatal overdoses in 2020 involved prescription opioids – higher than the number seen at the peak of opioid prescribing in 2012.

So, will mandating prescriber education make a difference? Certainly not, if the FDA mandates manufacturer-funded CME.

If the FDA wants to mitigate the risks of opioids through mandated CME, the first step is to remove industry from any involvement. Currently, in addition to providing undisclosed funding and selecting recipients for “independent educational grants,” industry participated in developing the “blueprint” for the content of the CME. It shows.

The second step is to contract an independent organization or institution – one that takes no money from manufacturers of drugs, devices, biologics, or diagnostics – to develop an unbiased, evidence-based CME. While industry-generated REMS CME are plentiful and feature a raft of industry-funded speakers, one comprehensive CME activity could easily educate prescribers – objectively – about opioid prescribing.

Without industry influence, mandated REMS CME for opioid prescribing could actually mitigate the harms of opioids. The FDA has a chance to act and help to redeem their tarnished history involving opioids. We should all encourage them to do so. In addition to the public workshop, FDA is accepting comments through December 3. Tell the FDA to mandate only industry-free CME!

Judy Butler is a research fellow at PharmedOut.

September 2021:

Manufacturing Doubt and Evading Responsibility

By Judy Butler

In the bankruptcy proceedings for Purdue Pharma, the Sackler family fought hard to win personal release from liability for harm caused by OxyContin and other opioids. That’s not usual – after all, it’s the company that filed for bankruptcy, not the family. With a paltry $4.3 billion personal contribution to the settlement – paid over the course of a decade – the family resolves potentially trillions of dollars in claims, admits no wrongdoing, and remains one of the wealthiest families in the world.

One reason immunity may be so important to the Sacklers is that the settlement will make public tens of millions of internal documents. With a delivery date of January 1, 2025, it will be a long wait, but the public will eventually learn what happened behind closed doors. And the odds are good that what’s disclosed will personally implicate the Sacklers.

The core of claims against opioid companies and their allies is that they knowingly created misperceptions about the safety and efficacy of opioids in order to promote sales. Deliberate efforts to manipulate information associated with a product, however, is a strategy that cuts across industries. The science of spin, a recent multi-industry analysis that did not examine opioids, identifies 28 unique tactics used to manufacture doubt. Ideally, these messages are amplified by perpetuators of doubt – journalists, bloggers, citizen scientists, and lay-people – who, without direct funding, disseminate and spread pro-industry spin.

Even before we see incriminating internal documents, it’s easy to see that the opioid industry relies on these tactics. Obscuring involvement is a tactic, and a well-hidden financial paper trail may make it hard to distinguish whether pro-industry actors are manufacturers or perpetuators. In either case, however, industry still benefits.

Consider the attacks on the pending update of the CDC’s Guideline for Prescribing Opioids for Chronic Pain. As with the original evidence-based document, industry-backed efforts focus on discrediting its scientific integrity. Let’s examine a sampling of tactics to manufacture doubt:

Attack study design: The industry-funded US Pain Foundation claims bias in selection of evidence used in the guidelines.

Gain support from reputable individuals: The American Medical Association (AMA) labels the CDC dose threshold recommendations as “arbitrary” and suggests patients need to be treated as individuals. Julia Lurie exposed the AMA’s long-time relationship with Purdue Pharma that “has made it virtually impossible to discern where public health guidance ends and industry interests begin.”

Contribute misleading literature: A review article written by outspoken critics of the CDC guidelines analyzed cherry-picked studies to challenge guideline conclusions. In an article on the website of the pro-industry American Council on Science and Health (ACSH), an author links to the review and then comments that the draft guideline is “simply wrong on fundamental science.”

Pose as a defender of health or truth: In arguing that “patients with pain continue to suffer from the undertreatment of pain and the stigma of having pain” in its criticism of the guidelines, the AMA again illustrates a tactic of manufactured doubt.

The seemingly discrete examples above actually interconnect. For example, in reaching out to its constituency, the US Pain Foundation cites the AMA as a “respected medical authority” that supports individualized pain treatment. Similarly, the ASCH article refers to “no less an authority than the American Medical Association.”

One thing there’s no doubt about – the opioid industry manufactures doubt.

Judy Butler is a research fellow at PharmedOut.

July 2021:

What Does a "Human Rights" Frame for Pain Advocacy Look Like?

By Judy Butler

The National Pain Advocacy Center (NPAC) formally launched in March to “advocate for smarter solutions to pain and the overdose crisis.” They state that “As an organization, we pledge to not accept funds from pharmaceutical companies or others that may create actual or perceived conflicts of interest.” While they disclose no information about current funding, they report that initial grants came from the Open Society Foundations, a funder of human rights activities.

Not surprisingly, NPAC describes itself as “advancing the health and human rights of patients in pain” – a human rights frame. Here’s how:

At NPAC, we work to change the mindsets and policies that shape the care people with pain receive. How we think about pain affects our willingness to invest in its treatment. Laws, guidelines, and payer policies often determine quality of care. Rather than represent individuals, we seek to eliminate common barriers to health care.

NPAC identifies many issues impacting pain and its treatment that fit within a human rights frame including structural issues, opioids, Covid-19, and equity and disparity.

With such a broad approach to pain care, it may be surprising to see that their advocacy centers on increasing access to opioids. It turns out that for NPAC, a human rights frame on pain looks remarkably similar to an opioid industry frame. It starts with the assumption that opioids are necessary for many types of pain, with an emphasis on chronic pain.

NPAC uses the analogy that the pendulum has swung too far when it comes to opioids. In their view, the pendulum swung wide in one direction when the risks of opioids were “understated” in the 1990s. In the 2000s, efforts to encourage cautious prescribing caused the pendulum to swing wide in the opposite direction, overcorrecting and limiting access for those with “legitimate” needs. NPAC’s language very carefully frames misuse as the sole driver of opioid addiction and overdose, echoing the industry message that abusers are “the culprits and the problem.”

Describing “the problem with pain today,” NPAC states: “Our current policy approach to addressing opioid addiction in 2.5 million Americans is hurting the 50 million in serious pain.” Their fact section backs up this distinction between addicts and patients, stating “addiction and overdose risks among pain patients are smaller than what is conventionally believed.”

Actually, some might find those risks strikingly large, were they to do the math. For example, NPAC cites that the risk of addiction to people who are prescribed opioids varies from “0.6% to less than 8%.” NPAC’s numbers are low, but even using their own numbers, with 8 to 13 million Americans taking opioids regularly for pain, according to NPAC, 18,000 to a million patients prescribed opioids would become addicted. Or, using NPAC’s too-low risk of less than 0.022% for overdose death: that works out to 1,760 to 2,860 dead patients.

Framing the problem as “legitimate” pain patients losing access to opioids leads to the industry-friendly solution of unrestricted prescribing. It’s fitting that the only advocacy efforts taken by NPAC are to encourage a government agency or legislature to make opioids more accessible. For example, NPAC sought to remove a three-day limit on opioid prescribing for acute pain in a federal bill. Characterizing it as an “arbitrary” limit and a “sweeping restriction”, they argued it would have negative implications for chronic pain patients. Along with the Drug Policy Alliance and the American Medical Association, NPAC’s lobbying efforts succeeded in eliminating the bill’s “restrictions on opioid prescribing.”

NPAC also opposed an evidence-based UK guideline on treatment of primary chronic pain. The guideline recommended against initiating opioids for chronic pain because they provided no benefit but could cause harm. In comments, NPAC argued that “Long-term opioid use for chronic pain is controversial, but not always unwarranted. Even in a system with limited resources, treatments that benefit only a few should still be offered to those few, if more conservative and less expensive treatments have failed those individuals.” In this instance,  NPAC was not successful; the final guideline, published in April 2021, retained its recommendation not to initiate opioids for chronic primary pain.

A human rights frame for pain advocacy could focus on the exact opposite argument – it’s a human right to be protected from starting a treatment that has substantial risk but no evidence of benefit. That, of course, applies only to initiating opioids and not to pain patients already being treated with opioids. The issues related to patients on long-term opioid treatment are complex must be addressed, but not by simply supporting policies that favor unrestricted access to opioids. Providing appropriate treatment to dependent patients makes sense; creating more dependent users does not make sense.

The fact that NPAC uses human rights arguments that mirror industry arguments is not a coincidence. Although the organization states that it takes no pharmaceutical money, there are no restrictions on staff, advisory council members, or members of the community leadership council taking pharma money. Two thirds (10 of 15) of advisory council members lack an MD, so the amount of money they are paid is not publicly available on the Open Payments website. The organization acknowledges that there are conflicts of interest without actually disclosing what they are with the statement, “Our team has submitted disclosures, and we have a recusal process.”

An organizational pledge not to take money from pharma means little when the organization’s leaders and advisors may be taking money. NPAC should publish all disclosures. And in any case, an industry argument is an industry argument, no matter who mouths the words. 

Judy Butler is a research fellow at PharmedOut.

May/June 2021:

Another Key Player in Purdue's Opioid Marketing Strategy

By Judy Butler

There’s yet another behind-the-scenes player in opioid marketing – Publicis Health. The marketing and communications firm worked to increase sales of Purdue Pharma’s opioids, collecting more than $50 million over ten years. The lucrative contracts ended when Purdue filed for bankruptcy in 2019. Using sealed documents filed as part of Purdue’s guilty plea to felonies and a settlement of civil claims with the Department of Justice in 2020, the Massachusetts Attorney General uncovered enough wrongdoing to bring suit against Publicis in May.

Publicis’ eagerness to increase Purdue’s sales jumps from the page of the complaint. They estimated the return on investment (ROI) for each patient based on dose and length of treatment. Publicis understood ROI was what mattered to Purdue: “Do we know how the client envisions success? Successful ROI on the program.” What was good for Purdue was good for Publicis; in an email Publicis “bragged that it ‘manage[d]’ Purdue’s business ‘like it’s our own.’” And, just like Purdue, internal documents show that Publicis knew the dangerous consequences of the opioids they were promoting.

Publicis developed marketing campaigns that maximized ROI by encouraging longer prescribing at higher doses – the most profitable – aimed at health care providers and patients. Their marketing messages were communicated through websites, emails, online ads tied to search terms, and targeted ads on electronic health records, as well as by trained sales reps.

Publicis did its homework, relying on data analysis to know how to frame its marketing messages. They went as far as recording conversations in examining rooms to hear how pain patients interact with doctors, nurse practitioners, and physician assistants. What they heard was that patients were concerned about addiction. To sidestep any mention of addiction – both in the examining room and in their marketing – Publicis recommended: “In materials to physicians, help them proactively address patient pushback against opioids by instructing them to educate and reassure patients on the importance of balance in pain management and the physician’s role in it.”

Integral to all of Publicis’ work for Purdue was responding to the public health efforts to combat the opioid epidemic, simply because, as the complaint alleges, “they threatened OxyContin sales and Purdue’s bottom line.” The CDC’s 2016 Guideline for Prescribing Opioids for Chronic Pain was perhaps the biggest threat. If doctors followed the recommendations, Purdue calculated it could lose millions of dollars in profits – $23,964,122 every year in Massachusetts alone.

Publicis analyzed each of CDC’s recommendations within the framework of “threats” to opioid sales. CDC recommendations were of particular concern to Purdue because almost half of all OxyContin prescriptions exceeded the maximum threshold in the guideline. In contrast, the “opportunities” identified by Publicis were the marketing strategies to counter the threats and still increase sales. The CDC’s guidance advised using the lowest effective dose and carefully monitoring patients. Publicis saw an opportunity in this, and told Purdue that the CDC’s “‘start low, go slow’ mentality may fit with Butrans [Purdue’s extended-release buprenorphine] prescribing messages.” Where the CDC recommended  evaluating the benefits and harms of opioids, Publicis wrote “Reassessing patients’ therapy frequently aligns with OXC previous campaign and promotional narrative.” And where the CDC recommended reviewing a patient’s history on the state prescription drug monitoring program, Publicis recommended balancing that information with whether the “[the] patient is legitimately in pain.”

In other words, Purdue should pretend to be agreeing with parts of the CDC guideline. Publicis argued that this marketing approach would actually increase sales: “By aligning this content with the CDC Guideline, and visualizing the patient journey for maximum clarity, we can drive a perception of transparency and simplicity-which, in turn, can make physicians feel more comfortable prescribing OxyContin.”

Later that year, Publicis proposed strategies for addressing the opioid crisis. Among them – “get every patient off Purdue’s medications” and “fully embrace a deeper-held responsibility for progress in pain and keeping people safe.” Too bad Purdue didn’t go with that one.

Judy Butler is a research fellow at PharmedOut. 

April 2021:

New and Convenient Does Not Equal Better and Safe

By Judy Butler

“Tongue and Done” proclaims advertising for Dsuvia, an opioid that’s five to ten times more potent than fentanyl and dosed under the tongue. “False and misleading” responded the Food and Drug Administration (FDA), flagging the marketing as illegal in their February warning letter to manufacturer AcelRx. The FDA may pursue regulatory action if AcelRx’s response and required plan to correct the misstatements are not considered sufficient.

In three words, the Dsuvia marketing message implies so much – ease, simplicity, speed, safety, automation – all benefits for busy staff. In fact, Dsuvia’s risks are so great, the FDA requires additional safety precautions over other opioids, including a multi-step dosing process. Its use is limited to certified medically-supervised healthcare settings where patients can receive the necessary monitoring and an overdose can be managed.

It may seem surprising that in 2021, opioids are still marketed with false statements. But given that sales are the road to profits, and the costs for illegal marketing have been relatively low, maybe it shouldn’t be. If the goal is to get a profitable drug on the market, then the process is designed to lead in that direction – that’s a business approach. What this approach inevitably forgoes, however, is consideration of public health. With opioids, the most important public health consideration is whether there’s a need for new opioids.

Dsuvia offers a clear example of a single-minded pursuit of creating a new opioid product rather than a broad-based approach to solving a problem. Dsuvia, so the story goes, began as an answer to reducing medical errors that result in overdoses of injectable opioids. AcelRx co-founder Pamela Palmer recounted, "It dawned on me — what if we could design an oral form of these drugs that worked as quickly as the liquid …you could have almost a fool-proof way of treating someone." AcelRx’s idea was to manufacture a fast-acting sufentanil tablet pre-packaged in a single-dose applicator for use under the tongue. But if medical errors are considered systems problems rather than drug development opportunities, the solutions become very different. Color-coded bottles or better labeling are low-cost answers offered by other doctors.

When Dr. Palmer connected with a military doctor seeking an alternative to injectable morphine for treating battlefield pain, she found a multi-million dollar revenue source. While AcelRx was developing Dsuvia with a $5.6 million Pentagon contract, the military moved away from injectable opioids for battlefield pain, instead recommending ketamine (a non-opioid drug that doesn’t slow breathing or reduce blood pressure) for soldiers with significant blood loss or fentanyl “lollipops” for those not in shock. According to media reports, military committees requested comparison studies of Dsuvia with these alternatives – but they were not conducted. Another opportunity to assess the need for a new opioid went unanswered, and the following year AcelRx received a $17 million Defense Department contract.

The prioritization of business over public health was evident again in the data presented to the FDA for Dsuvia’s approval. Studies demonstrated that Dsuvia outperformed placebo for reduced pain intensity over 12 hours, but no comparisons were made to ibuprofen, acetaminophen, aspirin, or morphine. Additionally, the “fast-acting” Dsuvia took 54 minutes to offer patients “meaningful relief,” the measure considered most clinically relevant by the FDA. The time to meaningful relief was not significantly different from the 84 minutes recorded by the placebo group. Whether the response time for alternative painkillers would be significantly different remains unanswered. How a drug – even an opioid – compares to existing treatments is not the basis of FDA's approval process; assessments are made only of safety and efficacy. In a defense of Dsuvia’s approval, the then-FDA Commissioner noted the drug was a priority for the Pentagon, and that FDA would re-evaluate the process by which future opioids are approved. To date, however, no changes have been made.

As sales of Dsuvia grow, AcelRx is projected to see profits by 2022. The company’s January 2021 overview for investors highlights initial stocking orders for the military, which are expected to grow to $30 million, and a distribution and promotion agreement for dental and oral surgery. Priority sales targets are hospitals and ambulatory surgery centers.

One Dsuvia sales pitch is that it saves money, in large part from reducing the time patients spend in post-op care. The bulk of the “savings” comes from recouping $15/minute from potential surgeries limited by slow turnover in post-op beds. AcelRx’s emphasis on getting all patients moved along quickly makes it easy to see why Dsuvia was promoted as “Tongue and Done.”

Businesses seek to make profits and have a responsibility to their shareholders. Someone else needs to be responsible for public health. How about the FDA? As an added benefit, they might save themselves the need to issue warning letters for illegal promotion of unnecessary drugs. 

Judy Butler is a research fellow at PharmedOut. 

March 2021:

Opioid Marketing Tactics: The Old and the New 

By Judy Butler

This column on industry marketing on opioids is in its third year, and, unfortunately, is in no danger of running out of material. Given the public awareness of the opioid epidemic, hundreds of lawsuits against manufacturers, and “remorse” shown by companies, some think that opioid marketing is a thing of the past. Not true: Purdue Pharma may no longer be sending sales reps to doctors’ offices, but companies are still using the opioid marketing playbook—and adding new pages.

Our challenge in identifying marketing strategies is that the industry works hard to hide its fingerprints. (And when it doesn’t, odds are it’s a public relations move to make the company look good.) This article reviews recent industry marketing strategies that support the false message that long-term opioid treatment is safe, effective, and necessary. Whether they are implemented with tactics that are old, new, or evolving, all of these strategies are used to sell opioids.

Opioid manufacturers:

• Support organizations willing to spread industry messages

A 2020 Senate Finance Committee report exposing the tens of millions of dollars opioid manufacturers paid to tax-exempt organizations succinctly explained the reasoning behind the funding: “to help seed the market for their products by shaping the views of patients, doctors, and policymakers.” Recent examples illustrate how this strategy impacts policy recommendations, efforts to challenge evidence-based government guidelines, testimony before Congress, and support of industry-friendly government reports.

• Mobilize pain patients

Chronic pain patients on long-term opioids evoke sympathy when advocating for unrestricted access to what they believe is a necessary treatment. The opioid industry and advocacy groups it funds have long provided resources and opportunities to encourage these patients to speak out. In 2020, pain patients sought to weaken state laws as well as government guidelines. Patients also now have a podcast to inspire them to “make noise.” Recognizing that trusted patient influencers with their own networks can sway their audiences in a manner that industry cannot, hiring or providing platforms for patient leaders as unbranded opinion leaders has become a multi-million dollar business.

• Reach out to doctors

The tried and true tactic of marketing directly to doctors still offers opioid manufacturers a robust return on their investment. An even better investment was Purdue’s tactic of manipulating an electronic health record, a tactic still in use in 2019. Undoubtedly effective, the tactic was also illegal and they got caught, but the case illustrates the fact that opioid marketers are still coming up with creative ways to sell opioids.

• Control media messaging

In 2018, Purdue Pharma bought full-page advertisements portraying itself as a good corporate citizen that wanted to be a partner in addressing the opioid epidemic. The ad, however, carefully positioned opioids as the gold standard, to be prescribed “when alternative treatments are inadequate.” Corporate fingerprints were missing when Purdue hired public relations firms to secure media opportunities for “experts” to espouse industry-friendly messages. These seemingly independent voices were never identified as having either individual or organizational financial ties to industry. And in the months ahead of a 2016 LA Times investigative series exposing internal Purdue documents, the company sought ways to lessen its impact. One recommendation was to buy ads linked to a Purdue site and headlined “Preventing Opioid Abuse” that would be generated by google searches for the articles.

Opioids remain a billion dollar industry, and to date the financial consequences of misleading marketing have been relatively low, so marketing continues. The highest profits come from the highest doses, which are frequently prescribed long term. Marketing strategies primarily focus on maintaining these sales both for current and future patients.

The false message that long-term opioid treatment for chronic pain is safe, effective and necessary invites the simple conclusion that unrestricted access to opioids needs to remain readily accessible. The damage done by the marketing of this false message, however, requires a more nuanced response. Opioid treatment should not be initiated in chronic pain patients, but for the millions of “legacy” patients who have been on opioids for years, compassionate, effective treatment must be part of the solution.

Judy Butler is a research fellow at PharmedOut. 

February 2021:

Why is the AMA Promoting Opioid Use?

By Judy Butler

The American Medical Association recently released policy recommendations to address opioid overdoses. Both an issue brief specifically related to the COVID pandemic and a policy roadmap addressing opioid use disorder more broadly were released in December. The AMA’s recommendations for greater access to treatments for opioid use disorder are fine, but industry-friendly messages on opioids permeate both documents.

Each document contains broad calls for removing “arbitrary” restrictions on opioids that the AMA considers to be barriers for patients with pain. For the duration of the COVID pandemic and “the opioid public emergencies,” the issue brief urges removing “arbitrary dose, quantity, and refill restrictions on controlled substances” for patients with pain. The roadmap recommends that unless “prescription opioid restriction policies” demonstrate improved patient outcomes, they be revised or rescinded.

Advocating increasing opioid prescriptions in a set of recommendations to reduce opioid overdoses seems both counterintuitive and counterproductive. Perhaps that’s why the AMA's policy roadmap press release emphasizes increasing access to medications to treat opioid use disorder, and never once mentions its recommendation to increase access to opioids, unless that’s encoded in the recommendation to “Enhance access to comprehensive pain care, including multidisciplinary, multimodal care for patients with pain.”

Most people would probably interpret that statement as openness to acupuncture or massage or spinal manipulative techniques. In fact, the policy roadmap itself argues “Attitudes and assumptions on the appropriate response for treatment of pain has focused on pharmaceutical options to the detriment of other treatments for far too long. This understanding must change in order to support both patients and physicians in creating pain management plans and treatment regimens that produce better outcomes for patients.” No argument with that.

Later, however, three pages are devoted to addressing the “aggressive action against the over-prescribing of opioids.” While acknowledging such policies reduced opioid prescriptions, the AMA questions whether they have resulted in reduced drug-related mortality and suggest that these policies have only harmed patients. The only metric the AMA uses for evaluating the beneficial impact of policies aimed at opioid overprescribing is deaths related to prescription opioids. No mention is made of whether these policies may have reduced any other opioid-related harms including opioid use disorder or harm related to street drugs that someone turned to after first becoming addicted to prescription drugs.

The AMA is certainly consistent in favoring unrestricted access to prescription opioids. Their June 2020 comments on updating the CDC’s Guideline for Prescribing Opioids for Chronic Pain blames the 2016 CDC guideline as the impetus behind “arbitrary” opioid policies and argues  that “a CDC Guideline only focused on ‘opioid prescribing’ will perpetuate the fallacy that by restricting access to opioid analgesics, the nation’s overdose and death epidemic will end.”

The AMA urges the CDC “to not only specifically address the fact that the CDC Guideline is not intended to restrict patients’ access to legitimate medical care—a point made in recent years by CDC officials elsewhere—but also to highlight the multifactorial nature of the epidemic.” The 17-page letter proposes revision after revision that both challenge the guideline’s evidence base and broaden and dilute the scope of the document.

The laudable CDC guideline, of course, evaluates the risks and benefits of opioids for chronic pain and provides clinicians with evidence-based prescribing recommendations. Expanding the scope of the guideline in any way would undermine its key strength: unequivocally stating that there is no evidence that opioids are effective in treating chronic pain while there is overwhelming evidence of harm.

The AMA calls for evidence-based treatment for opioid use disorder while discounting the CDC’s evidence-based recommendations for chronic pain. Their position on opioids for chronic pain, including the language of “legitimate” patients, stigmatization and unrestricted prescribing echoes that of opioid manufacturers and organizations receiving industry funding. 

The AMA Opioid Task Force, which informs AMA positions, includes the American Academy of Pain Medicine. The AAPM has long cultivated an influential role in shaping AMA policy, the successes of which were lauded by AAPM presidents in 2008 and 2017. In December 2020, the Senate Finance Committee released documentation showing that the AAPM received nearly $6 million from opioid manufacturers from 2012 to 2019. While $6 million may be significant to a non-profit, it’s a small fraction of what the pharmaceutical companies make from both opioid and opioid use disorder medications. 

Undermining policies that serve to reduce opioid overprescribing while calling for increased access to opioid use disorder treatment is exactly what the industry does, because they profit off both the problem and the solution. Why is it also the position of the AMA?

Judy Butler is a research fellow at PharmedOut. 

January 2021:

The House and the Senate Take on Opioid Marketing

By Judy Butler

With unusual bipartisan agreement, both houses of Congress took aim at opioid marketing in December 2020. The House Oversight Committee questioned Purdue Pharma’s CEO and two of its Sackler family owners while the Senate Finance Committee reported on opioid makers’ ties to tax-exempt groups. Opioid marketing matters to Congress because the government pays billions of dollars for opioids and treatment of opioid use disorders in Medicare alone.

Overprescription caused the opioid addiction epidemic. But what we are seeing is that industry has now switched to protecting the market for long-term opioid use. Marketing opioids today relies on a rhetorical framework established by opioid manufacturers that assumes that opioids are a safe and effective treatment for a wide range of pain, including chronic pain. Therefore, since the solution to the problem must stay within the framework, any action taken to mitigate the opioid epidemic must not limit access to prescribed opioids. The framework enables opioid manufacturers to occupy a neutral space far above any blame for the opioid addiction epidemic. They simply want to provide a beneficial treatment, while responsibility for addressing the problems of opioids lies firmly outside their domain.

That’s the frame Purdue consistently used in its interactions with the House Oversight Committee. Purdue repeatedly made a distinction between the use of OxyContin by individuals in pain and by those abusing or addicted to the drug. While no one expected the individuals  testifying to accept liability, it was somewhat remarkable how closely they held to the marketing script. David Sackler’s opening remarks set the tone:

On the one hand, many Americans suffer from terrible pain and need pain relief. On the other hand, the medications like opioids that treat this pain have a potential for abuse and addiction. The FDA and the medical establishment have always had to balance these medical problems. Prescription opioids are used successfully to treat millions of Americans every year. [David Sackler, hearing transcript]

In fact, opioids are an inappropriate treatment for most chronic pain. That’s why advocacy groups are needed to promote messages based on marketing rather than science. The Senate report analyzed confidential financial documents and exposed the fact that opioid manufacturers paid tens of millions of dollars to tax-exempt entities “to help seed the market for their products by shaping the views of patients, doctors and policymakers.” Opioid manufacturers poured money into organizations that would support industry positions and hobble efforts by regulators and legislators to set effective policies to manage overprescribing.

The Senators proposed two actions to counter industry influence. First, they called for transparency in these financial activities by including pharmaceutical industry payments to tax-exempt organizations in the Open Payments database. They also recommended conflict of interest disclosure standards for members of Federal task forces, research groups, and panels convened by Health and Human Services.

Both houses of Congress agree that opioid marketing must be addressed. Could 2021 be the year that happens?

Judy Butler is a research fellow at PharmedOut. 

2020

December 2020:

McKinsey Proposed What to Purdue?

By Judy Butler

The unfolding legal drama around Purdue Pharma’s bankruptcy settlement involves criminal charges, reporters’ filings for unsealing documents, and challenges to the basis of the settlement terms. It’s through this last action that a new trove of internal documents were released, revealing new details of the inner workings and motivations of the company.

These documents reveal that when confronted with strategies designed to prevent death and addiction from OxyContin, Purdue remained squarely focused on sales. Their greatest profits came from the highest – and deadliest – doses. Rather than lives, it was income that Purdue sought to protect.

The documents illustrate two strategies that show how drug marketing extends well beyond influencing doctors to prescribe. One set of documents reveals efforts to thwart regulation of OxyContin by the Food and Drug Administration (FDA). In light of reports of overdose, abuse, and addiction associated with OxyContin, in 2008, the FDA required Purdue to submit a plan for a Risk Evaluation and Mitigation Strategy (REMS). Specifically, the FDA required training and certification for both prescribing and dispensing OxyContin, as well as monitoring of each OxyContin patient who received the drug.

McKinsey, a consulting agency working for Purdue, quickly identified the impact of possible FDA actions on profitability and outlined strategic options to protect sales. One recommendation was to “band together” with other “pharmacos marketing or developing Class 2 opioid analgesics” to “formulate arguments to defend against strict treatment by the FDA.” Emails during this time described “lots of palpable concern over FDA threat to Oxy” and a need to “save the business.”

While the exact strategy taken does not appear in the internal documents, five months after Purdue received the FDA’s REMS request, the agency met with opioid manufacturers to discuss the requirement for a class-wide, shared-system REMS. The approved REMS had no requirement for certification or patient monitoring.

Fast forward nine years and McKinsey was again offering Purdue help to counter another threat to sales. In 2017, McKinsey presented Purdue with “High impact interventions to rapidly address market access challenges.” Among the strong “headwinds” identified was the skyrocketing increase in negative media, some of which implied that “OxyContin may have been a driver of the opioid crisis.” In this climate, decisionmakers that control the prescription formularies (drugs approved to be prescribed in health care systems and under insurance plans) suggested “excluding OxyContin may be the best thing we can do in current context,” and Cigna and BCBS of Florida had already done so.

In chart after chart, McKinsey analyzes the current business landscape to identify options that would ensure OxyContin remained an attractive drug in prescription formularies. Two strategies for potential contracts with payors and Pharmacy Benefit Managers (PBMs) addressed offsetting costs incurred by the payors/PBMs related to OxyContin.

The first focused on dosage levels. In its 2016 guidelines, the CDC advised against daily opioid doses greater than 90 morphine milligram equivalents (MME) per day.  As a result, Purdue was seeing a drop in its highest, most profitable doses of OxyContin. Even so, the average daily dose of OxyContin was 113 MME for the 1.9 million prescriptions written in 2017. Half (51% ) were at or above 90 MME and 6% were above 360 MME (at an estimated cost of almost $2000/prescription). These very high doses were not reserved for cancer pain: the dosing distribution was identical whether prescribed for cancer, back pain, or osteoarthritis. To keep OxyContin in the formularies and maintain these sales, McKinsey proposed that Purdue offer payors/PBMs rebates that increased by dosage level.

A second strategy focused on rebates related to “events,” meaning overdose (OD) or opioid use disorder (OUD). McKinsey estimated there would be 50 OxyContin-related events per million members based on a rate of 4% of opioid OD/OUDs involved OxyContin exposure. McKinsey calculated two recommendations for a meaningful rebate – $6,000 (for the cost of OxyContin) or $14,000 (for excess medical costs), the choice dependent upon which offered the best balance of “meaningfulness of rebate and financial protection.”Predicting that 8,306 OxyContin users would overdose or become addicted among Purdue’s top 7 commercial accounts in 2019, the high-end rebate would amount to payment of $123 million. If that’s the sum McKinsey proposed spending, one can only speculate the sum Purdue expected earning.

The internal documents provide stark evidence of how Purdue operated exclusively with respect to their bottom line. When faced with actions by government or private business to protect people from addiction and death, Purdue looked to McKinsey to advise them how to protect their profits. The lives shattered by their drug were reduced to “events” that stood in the way of earnings. It is not clear which McKinsey recommendations Purdue acted on. What is clear from these documents is, that McKinsey knew its recommendations were a legal liability. Upon learning that Massachusetts filed suit against members of Purdue’s board, one McKinsey employee wondered whether they should take additional defensive actions besides “eliminating all our documents and emails.” 

Judy Butler is a research fellow at PharmedOut. 

November 2020:

Purdue's Most Successful Strategy No One Is Talking About

By Judy Butler

One of Purdue Pharma’s most subversive — and most successful — strategies to increase prescriptions for OxyContin and other extended-release (ER) opioids barely made the news. The third charge in the plea agreement between Purdue and the Department of Justice (DOJ), announced in October, reveals a strategy that resulted in hundreds of thousands of prescriptions for ER opioids.

In essence, Purdue bought access directly to the exam room, by manipulating an electronic health record (EHR) system used by health care providers as they saw patients.

Purdue paid Practice Fusion a million dollars to increase sales of Purdue’s ER opioids. Practice Fusion is a technology company that provides EHR suffused with marketing messages free to health care providers. Purdue’s marketing team worked with Practice Fusion to create a clinical decision support (CDS) for pain in the EHR that launched in July 2016. The CDS remained active until 2019 (which should dispel any doubts about whether Purdue still markets opioids).

Certain patient information entered in the EHR would trigger a Pain CDS that guided the health care provider through a series of actions designed to promote prescription of ER opioids. The first alert prompted physicians to record a pain score on a scale of 0 to 10. For patients with chronic pain or reporting a rating of 4 or greater (moderate pain) at least twice over three months, an alert suggested doctors take a Brief Pain Inventory (BPI), which focused on pain symptoms and included questions about the severity and impact of the patient’s pain. The third alert (generated by a patient with chronic pain who had completed a BPI or a patient with a  pain score of 4 or greater over four months), indicated a follow-up plan should be created for treating the patient’s pain. The follow-up plan offered ten alphabetized treatment options including “opioid therapy (short-acting, long-acting/extended release).”

The Pain CDS was designed to emphasize pain and influence prescribers to convert patients from non-opioids and immediate-release opioids to ER opioids. Purdue knew that the BPI could increase use of ER opioids. Purdue also knew opioids did not belong on a list of treatment options for chronic pain. In fact, they created the list of therapies from a New England Journal of Medicine article on opioid abuse in chronic pain that addressed risks of opioid overdose and addiction and included a list of alternative, non-opioid treatments. Without regard to these concerns, Purdue added opioids to the list.

So perhaps it was what prescribers were not advised of that was most important for marketing. Among the missing pieces of information were that opioids are not recommended for chronic pain; opioid-naïve patients should not receive ER opioids; and that opioids carry risks for overdose and addiction.

CDS are intended to guide prescribers in making treatment decisions by providing unbiased information consistent with medical practice guidelines. Instead, Purdue designed a CDS which, according to the DOJ, “deviated from medically accepted standards, CDC guidelines, and FDA approved labels for Purdue’s EROs.”

Practice Fusion confirmed the marketing plan worked. In the first five months, the Pain CDS alerted during 21 million patient visits, involving 7.5 million patients and 97,000 health care providers. In that time there was a general shift from immediate-release opioids to ER opioids with the biggest shift seen in emergency medicine, orthopedics, and pain medicine.

Ironically, Practice Fusion data also showed that ER opioids were the least effective of all treatment options in lowering pain overall, and superior only to adjuvants in lowering pain for patients with chronic pain.   

Although Purdue had a one-year contract, the Pain CDS remained active on the Practice Fusion platform for almost two additional years. In that time, the Pain CDS was triggered on more than 230 million patient visits, after which prescribers wrote hundreds of thousands of ERO prescriptions.

Practice Fusion entered into an agreement with the Department of Justice in January 2020 to resolve its role in this marketing scheme. At that time its client was referred to only as Pharma Co X. Purdue’s agreement confirms they are Pharma Co X. Because they conspired together to increase sales of Purdue’s ER opioids, a portion of which would be purchased through federal health care programs, both companies were found to have violated the Federal Anti-Kickback Statute.

It’s easy to understand why the headlines emphasized the money involved in the plea agreement or that went to paying doctors to write prescriptions. Explaining marketing strategies that mislead by including opioids as an appropriate treatment and omitting significant facts is not simple. But it doesn’t make these marketing strategies a lesser contribution to the opioid epidemic. Patients and prescribers alike will surely be interested to know how drug companies can pull strings in the doctor’s office.

Judy Butler is a research fellow at PharmedOut. 

October 2020:

Industry's Influence on Pain Patients' Advocacy

By Judy Butler

Chronic pain patients are celebrating a New Hampshire law enacted in July that addresses opioid prescribing. A result of the efforts of a small group of chronic pain advocates, the law broadly defines chronic pain and prohibits limiting opioid prescriptions by dose. It protects practitioners who provide “objective evaluations” in “good faith” and with their “best judgment,” “notwithstanding any statute or rule to the contrary,” from disciplinary action. And it ensures patients are not “unduly denied the medications needed to treat their conditions.”

The chronic pain advocates who lobbied tirelessly for the law undoubtedly believe it is in the best interest of their cause. Although there is no evidence that the opioid industry provided direct financial support to this law, this strategy highly benefits the opioid industry and it is exactly what they want — real patients delivering industry messages to influence public opinion and public policy.

In fact, Purdue outlined this strategy in its 2001 Partners Against Pain Pain Control Advocacy Toolkit. The Toolkit, one of the many internal documents made available through recent litigation, is described as a “community service of Purdue Pharma,” offering “simple ways to prevent ‘suffering in silence’ [and] gain positive action and support for pain sufferers.” Purdue’s interest in training pain advocates is acknowledged in the Toolkit, which states that Purdue has a “business self-interest in promoting the use of its products” and can be viewed “as potentially biased when commenting on the need for its products.” Pain patients and allies, on the other hand, will evoke “sympathies” and be “most credible” because they have “no financial interest in seeing a medication used more widely and more frequently.” Pain patients will not be asked to work alone, however, Purdue commits “to do whatever it takes to assist you in accomplishing this task.”

Pain patients are the opioid industry’s best asset when it comes to promoting the use of their products. Surely, the New Hampshire law advocates were not working from a decades-old Purdue toolkit, but their efforts very much align with the industry’s interests. Looking back at Purdue’s toolkit, it instructs the use of the following messages, which do not directly mention opioids:

• Criminal and drug abusers are threatening to complicate or prevent legitimate access to the very medications that chronic pain sufferers need the most.

• These patients with chronic pain can no longer “suffer silently” and may be denied the medications and adequate dosing they require. They will vociferously make their case known by “suffering out loud.”

• We cannot allow drug abusers to dictate our public health policy [2001 Partners Against Pain Pain Control Advocacy Toolkit].

Fast forward twenty years and industry messages haven’t changed. Nor have the targets, which are the media and policymakers. Consider the New Hampshire Union Leader’s coverage of the bill in January: “Chronic pain patients say they have become silent victims of the drug crisis, as doctors and insurers decide to 'taper' the prescription pain medications they have relied on for years, or cut them off entirely. They point out the drug epidemic involves illegal street drugs, not the prescription medications they depend on."

How the problem is framed informs how it should be solved. Industry’s description of the problem implies, inaccurately, that opioids are safe and effective for chronic pain and that prescription opioids are unrelated to today’s opioid crisis. As a result, removing any prescribing restrictions for any and all patients becomes the solution. If the real problem is that patients who have been taking opioids are being abruptly tapered or withdrawn, the solution should apply only to those patients. It’s easy to see why removing all prescribing restrictions is in the industry’s interest but less obvious for the pain patients.

Perhaps the reason pain patients promote industry solutions is because resources targeted to them are seeded with industry messages. Pain patients justify their positions with information drawn from pain advocacy organizations, key opinion leaders, and researchers who receive industry funding. In this way, pain patients become one more piece of the industry’s overall marketing strategy.

In the end, even if today’s patients are not directly recruited by industry, the discussions and activities of countless pain patients are influenced by industry efforts. The result is legislation that fosters opioid prescribing. Just what industry would lobby for, but now it does not have to.

Judy Butler is a research fellow at PharmedOut.

September 2020:

The UK's Take on the Treatment of Chronic Primary Pain

By Judy Butler

The UK government’s draft of their clinical guideline for the treatment of chronic primary pain was recently made publicly available. Their recommendation is loud and clear: don’t prescribe opioids for chronic primary pain.

Rather than a symptom of an underlying condition or diagnosis, chronic primary pain is a condition in itself, characterized by emotional distress or functional disability and persists for longer than 3 months. The UK draft guideline recommends not only against using opioids for this condition, but also against using most other popular drugs, including non-steroidal anti-inflammatories (NSAIDs), paracetamol (acetaminophen), benzodiazepines, and gabapentinoids. The committee found little or no evidence that these drugs make any difference to patient quality of life, pain, or psychological distress while there was evidence they can cause harm. Recommended treatments included exercise, psychological therapy, acupuncture, and antidepressants. The August 2020 draft will be open for comments through September 14 and the final guideline is expected to be published in January 2021.

By providing solid evidence for the effectiveness of other treatments, the guideline looks to support healthcare practitioners in managing their patients’ – and their own – expectations. Nick Kosky, chair of the guideline committee, noted that the “mismatch between patient expectations and treatment outcomes can affect the relationship between healthcare professionals and patients, a possible consequence of which is the prescribing of ineffective but harmful drugs.”

The UK guideline is unequivocal in its recommendation against opioids, simply including them in the list of drugs which are not to be offered by any route to people aged 16 years or over to manage chronic primary pain. The current review of the effectiveness of treatments for chronic primary pain followed a 2019 review of prescription drug dependence which found that 13% (5.6 million) of adults in England in 2017 to 2018 had one or more prescriptions for opioids. About half of those receiving a prescription in March 2018 had been receiving a prescription continuously for at least 12 months.

Recent data from the Office of Inspector General indicates that opioid prescriptions are even higher in the US. Opioids were prescribed to more than 1 in 4 — 13 million — of the 48 million beneficiaries in Medicare Part D in 2019, according to an August 2020 report; similar to the UK, patients received multiple prescriptions. Part D paid for 67 million opioid prescriptions, an average of 5.3 prescriptions per beneficiary, at a cost of $2.8 billion. Nearly 270,000 beneficiaries received high doses for at least 3 months, with almost 34,000 at serious risk of opioid misuse or overdose. Because Medicare Part D beneficiaries are almost all over age 65, these data do not include prescriptions for younger Americans.

While these numbers are staggering, they have dropped steadily since the release of the 2016 CDC Guideline for Prescribing Opioids for Chronic Pain. Like the UK’s guideline, the CDC found no evidence of benefit but evidence of harm and therefore recommended against opioid treatment for chronic pain.

Because the CDC guideline specifically focuses on opioid prescribing rather than the treatment of chronic pain in general, it contains guidance for health care providers who do decide to prescribe opioids for chronic pain. An important suggestion is that holding doses below 50 morphine milligram equivalents (MME) will likely reduce fatal overdoses (even though there is no dose threshold that would eliminate overdose risk).

Pain advocacy groups and pain patients challenged the guideline and continue to push back on recommendations against opioid treatment for chronic pain as the CDC looks to update the guideline. With millions of Americans receiving opioids for chronic pain – and the billions of dollars opioid manufacturers make from those chronic pain patients – there will always be opposition to restrictions on opioids for chronic pain. We hope that with the strong support of the UK’s clearcut, evidence-based position against opioid treatment for primary chronic pain, the CDC will stand its ground and continue to offer scientifically objective analyses of treatment outcomes in its guideline update.

Judy Butler is a research fellow at PharmedOut.

August 2020:

Yet Another Industry-Friendly Platform for Opioid Promotion

By Judy Butler

Pain Politics, a well-produced podcast from the Center for Effective Regulatory Policy and Safe Access (CERPSA), launched in June with an introductory episode encouraging “people living in pain to make noise and be heard.” CERPSA defines their central mission as “the reduction of unnecessary human suffering by improving the way pain is treated and legal drugs are controlled.” In other words, maintain access to opioids for chronic pain.

Their mission is not a surprise given the team that leads CERPSA; of the five leaders, two maintain long-standing financial ties to opioid manufacturers. Lynn Webster is a prominent and well-compensated industry key opinion leader and Bob Twillman is the former executive director of the Academy for Integrative Pain Management (AIPM), formerly the American Academy of Pain Management. A 2018 Senate report revealed that AIPM had received $1.25 million from opioid makers between 2012 and 2017, and when the industry subsequently discontinued its funding, AIPM ceased operations in 2019.

Webster, Twillman, and CERPSA’s director, Stephen Ziegler, share a connection to the Mayday Fund. In different years each was selected to be a Mayday Fellow, completing a public engagement and leadership training program for pain experts. The Mayday Fellowship Advisory Committee was chaired by Russell Portenoy, a highly influential key opinion leader funded by Purdue Pharma. Several advisory committee members also had deep industry ties. Portenoy also co-chaired a special committee, again with industry-funded members, convened by the Mayday Fund in 2009. Their report, still available on their website, advocates for “access to medications required for legitimate pain management.” More recently, the Mayday Fund was among a group of organizations allied with Purdue that influenced the World Health Organization to adopt an industry-friendly position in its pain management guidelines, according to a 2019 congressional report.

It is unclear how CERPSA is funded. Currently it is a project under the Colorado Nonprofit Development Center (CNDC) which acts as a non-profit umbrella to selected applicants, most of which have not yet received non-profit status. CERPSA’s convoluted donation and sponsorship policy makes weak statements about independence while seeming to invite corporate sponsorship from opioid manufacturers. Bizarrely, they invoke the FDA Risk Evaluation and Mitigation Strategy for opioids as an excuse for taking industry funds. (The FDA, in a particularly misguided move, required opioid manufacturers to fund continuing medical education on opioid safety. The predictable result was industry biased CME.)

At least the FDA requires every REMS educational program to disclose their opioid manufacturer funding. In contrast, CERPSA’s funding is unnamed. Considering that their positions align with those of industry, and their leadership has industry ties, if they don’t have industry funding now, they are certainly auditioning for the role of the opioid lobby’s best friend.

Every Pain Politics podcast episode includes the message that for some patients, opioids are necessary for the treatment of chronic pain, and that access to opioids is being unjustly limited or denied. They draw on common industry arguments that opioids prescribed to “legitimate” patients are not an addiction risk and therefore do not contribute to the opioid epidemic. Personal stories introduce patients who unsuccessfully sought pain relief for years and, although they were reluctant to take opioids, finally found a doctor who understood them and successfully managed their pain with opioids. Their fear of losing access to opioids is palpable. Guests with industry ties include Cindy Steinberg, who works for the industry-supported US Pain Foundation, and Jeffrey Fudin, a pharmacist who has served on advisory boards and speaker bureaus of opioid manufacturers.

CERPSA undeniably promotes industry messages. They dispute the established fact that there is no evidence that opioids are effective for chronic pain, with the argument that absence of evidence is not evidence of absence and they minimize the risk of addiction among pain patients. With multiple avenues to reach large audiences, Pain Politics is just another industry-friendly platform to promote opioids. Policy, however, should be informed by scientific evidence, not pain patients armed with industry mistruths.

Judy Butler is a research fellow at PharmedOut.

July 2020:

Will the CDC Opioid Guideline Update be Informed by Scientific Evidence or Narrative?

By Judy Butler

The Centers for Disease Control and Prevention are working towards updating their 2016 Guideline for Prescribing Opioids for Chronic Pain. The 2016 Guideline, which recommends against prescribing opioids as a first line or routine therapy for chronic pain, was met with a vigorous attack from pain advocacy groups.

The update is bound to receive a similar response. In April, the CDC solicited comments on pain and pain management from stakeholders – patients with acute or chronic pain, patients’ family members and caregivers, and healthcare providers. More than 5000 comments were submitted during the two month comment period that ended mid-June. A casual review of comments suggests a prevalence of complaints that the guideline reduced access to opioids.

Patients contend that opioids are the only way to manage their severe, chronic pain and share stories of involuntary rapid tapers or doctors’ refusal to continue prescribing opioids. They argue they are being mislabeled as addicts when they need opioids to treat their pain.

The many comments received by the CDC are from pain patients on opioids and reflects their active online community. Many patients connect through Facebook and other social media. Several websites provide information related to pain and an opportunity for patients to post comments. For example, the Pain News Network (PNN) reaches almost 2 million readers, almost all of whom are in the US and two-thirds of whom take opioid medication. In addition,  there are other organizations, many of which receive corporate support from pharmaceutical companies, that focus on chronic pain. For example, Johnson and Johnson, which owns opioid manufacturer Janssen Pharmaceuticals, is a member of the US Pain Foundation’s corporate council.

Both PNN and the US Pain Foundation encouraged patients to submit comments to the CDC. While both of these organizations include information about non-opioid pain treatment on their websites, they have also been outspoken critics of the 2016 CDC guideline, disparaging it in part for lack of inclusion of patient input.

Thousands of pain patients advocating for opioid treatment for chronic pain submitting comments to the CDC says more about effective mobilization than science. Hundreds of patients were also mobilized to comment on the benefits of marijuana and kratom. On the other hand, patients who have benefited from stopping opioid treatment for chronic pain are not an organized constituency. And people who have died from direct or indirect effects of prescription opioids cannot testify.

A countervailing comment supporting the 2016 guideline, however, was submitted by Physicians for Responsible Opioid Prescribing (PROP), which also appealed to its membership to write individual letters. PROP addressed both the need to meet the legitimate concerns of pain patients currently on opioids for chronic pain and the need for the CDC to maintain the scientific integrity of the guideline.

In addition to gathering stakeholder input, the CDC is also establishing an expert workgroup and funding systematic reviews of pain treatment. Three reviews, on opioid treatments for chronic pain, nonopioid pharmacologic treatments for chronic pain, and noninvasive nonpharmacological treatment for chronic pain, were published in April. Consistent with the 2016 guideline, the opioid review found evidence of increased, dose-dependent risk of serious harms and very limited evidence on long-term effectiveness of opioids.

The opioid industry spent hundreds of millions of dollars to misinform physicians and patients that opioids are a safe and effective treatment for chronic pain. Part of that legacy is a generation of patients who believe that opioids are the only answer. The patient stories are passionate and heart-breaking. No one wants to be in – or watch someone they love in – uncontrolled pain. Research is urgently needed to identify appropriate, effective, and accessible treatments for chronic pain. Guidelines for treatment, however, must be informed by science, not patient narratives or industry marketing.

Judy Butler is a research fellow at PharmedOut.

June 2020:

Asking About Pain Tolerance Could Lead to Fewer Opioid Prescriptions

By Judy Butler

Could four words potentially reduce unnecessary opioid prescribing? As it turns out, asking a patient “is your pain tolerable?” could have physicians rethinking whether a treatment, including opioids is necessary.

In a 2020 study led by John Markman, MD, almost 4 out of 5 patients rating chronic pain as moderate reported it tolerable, while as many as 40% of those with severe chronic pain found it tolerable. "Knowing that patients consider their pain to be tolerable, physicians wouldn't necessarily prescribe a medication with serious risks or expose them to surgery," said Markman.

Overtreatment of pain with opioids resulted, in part, from industry efforts to change cultural norms around pain. One promotional initiative successfully established pain as the “5th vital sign,” equating it with heart rate, respiration, blood pressure, and temperature. The patient-reported numeric rating scale (NRS) for pain intensity became accepted as a quantitative measure of a subjective experience. With the NRS, patients rated their pain from 0 (no pain) to 10 (worst possible pain). As a result, this scale shifted control to the patient and implied that being pain free is an attainable treatment goal. Instead of being unavoidable, pain became unacceptable. At the same time, opioids moved from a treatment option to the perceived gold standard for pain control.

Used tens of millions times a day in the US healthcare system, the 0-10 pain scale influences health payment systems in hospitals and outpatient clinics; approval and regulation of pain treatments by the Food and Drug Administration (FDA); and pain studies conducted by the National Institutes of Health (NIH). It is also important to note that hospital policy decisions may be based on “acceptable” pain ratings, which are often less than 4 on the scale.

The NRS has been called into question as the best metric for chronic pain, which, unlike acute pain, is complex. There is no evidence that long-term opioid treatment is effective or that increasing opioid doses improves NRS scores for chronic pain patients. In a recent retrospective study of veterans receiving opioid treatment, increases in opioid doses were not associated with lower NRS scores when compared with stable doses.

When physicians were required to disrupt their routine by writing “triplicate prescriptions”—with copies of every opioid prescription kept at pharmacies and state regulatory agencies– physicians wrote fewer prescriptions for opioids. Perhaps asking about pain tolerability instead of solely relying on the pain scale could do the same. 

Judy Butler is a research fellow at PharmedOut. 

May 2020:

Triplicate States and Opioid Prescribing

By Judy Butler

After the launch of Purdue Pharma’s OxyContin in 1996, five states had 50% lower distribution of the drug than any other states. These five states then saw a substantially lower growth in overdose deaths, which continued even 20 years after the drug’s introduction. The data analysis, published in a working paper from the National Bureau of Economic Research (NBER), tells a story of how a simple, low-cost, state-led policy had a long-term impact on public health.

The five states – California, Idaho, Illinois, New York, and Texas – all had active triplicate programs (also called “Multiple Copy Prescriptions or “Trip Scrips”) at the time of OxyContin’s launch in 1996. These programs required physicians to use state-issued triplicate prescription forms when prescribing Schedule II controlled substances, including many opioids. Besides the prescription given to the patient, one copy was kept by the pharmacy, and another was kept by a state agency. Monitoring prescriptions resulted in lower prescribing rates for those drugs.

The reluctance of physicians to prescribe opioids in these “triplicate states” was not lost on Purdue Pharma. Purdue’s internal marketing research, unsealed in court cases and obtained by the researchers of the NBER paper, found that doctors in triplicate states were unlikely to adopt OxyContin. Instead, they would “try to follow alternative protocols” to avoid the extra effort of triplicate prescriptions. The marketing recommendation, therefore, was that “the product [OxyContin] should only be positioned to physicians in non-triplicate states” because “our research suggests the absolute number of prescriptions they [physicians in triplicate states] would write each year is very small, and probably would not be sufficient to justify any separate marketing effort.”

As a result, NBER researchers found that triplicate states adopted OxyContin at a much lower rate and had a low overdose death growth compared to non-triplicate states, differences that have remained consistent throughout the most recent years of data. 

By 2000, non-triplicate states had two and a half times more exposure to OxyContin. Quantities of Oxycontin and other forms of oxycodone, were also higher in non-triplicate states in amounts that could not be attributed to OxyContin alone. NBER researchers suggest that Purdue’s marketing increased the use of other oxycodone products, which was consistent with an unusual strategy that Purdue used to expand the opioid market in general for chronic pain. 

Misuse data follow the same pattern; non-triplicate states have about twice as much OxyContin misuse as non-triplicate states. Strikingly, all states showed similar misuse of pain relievers other than OxyContin. These data remain steady through the most recent years.

Similarly, non-triplicate states evidenced a more rapid increase in drug overdose deaths than triplicate states. This difference remained even when the cause of these deaths transitioned from prescription opioids to heroin and fentanyl, leading the researchers to conclude that “states less exposed to OxyContin’s introduction were also less affected by these transitions.”  That backs what we have been saying for years: that many users of street drugs started off with prescription drugs. Reducing opioid prescriptions can be expected to decrease deaths from street drugs.

Neither variations due to prescribing culture, adoption of other opioid policies, misuse of other opioid drugs nor economic shocks explain the data differences between triplicate and non-triplicate states. Even the demand-side factors – those attributed to deaths of despair –  do not account for the supply-side differences between the two categories of states. The fact that suicides (excluding overdoses) and alcohol-related liver deaths are not impacted by triplicate status suggests “that the differential supply and access to opioids played a crucial independent role in the opioid crisis.” 

A simple triplicate prescription pad inoculated five states from the serial marketing of OxyContin and its long-term consequences. In non-triplicate states, including those that had eliminated their triplicate program two years prior to OxyContin’s launch, Purdue’s marketing led to higher prescribing.

NBER’s research paper is just one example of what happens when insightful researchers gain access to industry documents. The true cost of marketing is revealed.     

Judy Butler is a research fellow at PharmedOut.

April 2020:

Fact or Fiction? How Opioid Misinformation Continues Online

By Judy Butler

“Don’t be concerned about addiction risks” was the message delivered – both to doctors and directly to patients – that launched blockbuster sales of OxyContin. This claim contributed to a felony charge of “misbranding” OxyContin and, eventually, the company’s bankruptcy filing. Nonetheless, this message persists, and remains a consistent argument for dismissing concerns about prescribing opioids to chronic pain patients. 

Julie Roy, whose son died of a heroin overdose, took action when she saw such a message on Twitter – a claim that “in 99.5% of people opiates work fine without addiction potential.” She filed a complaint with North Carolina’s medical board, stating that Thomas Kline, the physician who authored the tweet “is giving out information regarding opioids that is not correct and could cause harm,” according to North Carolina Health News.

Dr. Kline’s practice included “pain refugees,” patients who have been turned down for pain treatment by at least 10 other doctors . Many of his patients came from out of state and received high-dose opioids.

Citing confidentiality, the medical board would not confirm an investigation against Kline, but the doctor acknowledged cooperating with an investigation and ultimately surrendering his DEA license and thereby his opioid prescribing privileges.

There’s not much mainstream media coverage of the loss of Dr. Kline’s license. Notably, the few stories online address neither the accuracy of the doctor’s claim that addiction is rare nor any possible issues with his prescribing practices. Instead, coverage has focused on the patients who will no longer have access to opioid prescriptions. 

Several articles appear on the Pain News Network (PNN) site, a source utilized by many chronic pain patients.  While Dr. Kline reports no involvement with industry, a PNN column in Dr. Kline’s defense was written by Lynn Webster, a physician with long-standing industry ties. Dr. Webster writes, “It is flawed thinking to lump prescription opioids together with illicit opioids such as heroin. Prescription opioids have a medical purpose, whereas illicit opioids do not.” This language echoes a Purdue pamphlet from the late 1990s – “Drug addiction means using a drug to get 'high' rather than to relieve pain. You are taking opioid pain medication for medical purposes. The medical purposes are clear and the effects are beneficial, not harmful." 

Distinguishing “abusers” and pain patients with respect to addiction is an industry strategy. In contrast, the Centers for Disease Control and Prevention state “anyone who takes prescription opioids can become addicted to them” and “as many as one in four patients receiving long-term opioid therapy in a primary care setting struggles with opioid addiction.”

Reaching out to pain patients directly, under the guise of empowerment, has also been a consistent industry strategy. Purdue Pharma’s internal documents from 1998 stated that a goal was to "convince patients and their families to actively pursue effective pain treatment. The importance of the patient assessing their own pain and communicating the status to the health care giver will be stressed."

Dr. Kline remains a passionate and vocal advocate for opioid use in chronic pain patients and uses Twitter and YouTube to argue against opioid “myths” that include addiction, deaths from respiratory depression, and overprescribing. 

It is a shame that this physician can be stopped from prescribing opioids but not from reaching more than 31,000 followers with marketing messages. 

March 2020:

We Know About Opioids, but Where Else Are Pharma Payments Going?

By Judy Butler

Follow the money. That’s the lesson from the latest research on the extent and influence of pharmaceutical payments on health care.

Industry spending on doctors has been well documented (see our November 2019 newsletter). Just having a pharmaceutical company cover lunch can influence prescribing, in part because meals create a subconscious obligation to sales representatives. A recent analysis of primary care physicians’ perceptions of messages presented by opioid sales reps during the height of opioid overprescribing found that reps emphasized benefits ---serious harms, on the other hand, were rarely mentioned. Furthermore, “doctors generally judged the information positively and stated their willingness to prescribe.”

Opioid prescribing is decreasing but amphetamines for children may be the next overprescription epidemic. While we don’t yet know what messages they are hearing, 1 in 18 physicians appear to have received marketing for stimulants from 2014 to 2018. Prescription stimulants doubled in use in the US from 2006 to 2016 and, as of 2013, accounted for more pharmaceutical expenditures for children than any other class of medications.

To promote opioids, stimulants and other drugs, pharmaceutical companies often turn to patient advocacy groups. Industry funding of patient groups is common, according to a systematic research review. Payments to these groups are not well-documented; while industry payments to physicians are now publicly available, payments to groups do not have to be disclosed either by companies or the groups themselves. Groups that often accept industry money often lack policy guidelines, let alone transparency. Additionally, while the recent study found that data was limited on funding and policy positions, what was there “suggests positions reflective of sponsors’ interests.”

Another target for industry payments are individuals providing public testimony before Food and Drug Administration Advisory Committees. Although not required to publicly disclose a conflict of interest (COI), speakers are asked about COIs prior to testifying. Of the individuals appearing before the Psychopharmacologic Drug Advisory Committee over 10 years, more than a third disclosed a COI and, of those, more than 80% provided positive testimony. These data align with similar findings for public testimony related to drugs for nervous system diseases, oncology, and anesthesiology and pain management.  One researcher explains “public comment periods are actually being leveraged to reinforce the sponsor's message under the guise of neutrality suggested by the word 'public.' "

Pharmaceutical companies are businesses, and businesses don’t make investments unless they see a return on those investments. The public health value of a drug should not be conflated with its business value. Individuals – and groups – that receive money from industry are participating in a business relationship that needs to be disclosed in all public interactions. Be it a doctor with a patient, a patient group with educational materials, an individual testifying or any one speaking to the media – industry relationships must be disclosed. The recipients of industry money may not think it undermines their integrity but that’s not their decision to make.

February 2020:

The Trouble with Tramadol

By Judy Butler

Most people would not guess that the second-most prescribed opioid in the US in the past five years is tramadol. One reason people might be surprised is because many patients – and, unfortunately, many physicians – don’t even know that tramadol is an opioid, or view it as a weak, harmless opioid. These perceptions are dangerous and untrue.

Tramadol is a synthetic opioid that is metabolized to a potent opioid. Tramadol is unusual because it is most potent when swallowed rather than injected, so it is not popular as an injected drug, either medically or recreationally. Furthermore, the opioid effect of tramadol varies widely among individuals. Some people lack the enzyme to transform tramadol, others have a little of the enzyme but are poor metabolizers, and up to 10% of people are rapid metabolizers. Those without the enzyme won’t get much effect from tramadol, but rapid metabolizers can experience an intense high. While tramadol shares all the harms of opioids, including addiction and respiratory depression, it is also associated with additional risks like seizures. Withdrawal from tramadol can cause symptoms common to opioids but also atypical symptoms including panic attacks, hallucinations, and paranoia. Bottom line: tramadol is an unpredictable drug, an unreliable pain killer, and potentially highly addictive.

So why don’t doctors know this? To understand how tramadol acquired its reputation as a weak opioid with little addiction potential, we need to look back to when the drug was approved by the FDA in 1995. The year tramadol was approved there was growing concern about the under-treatment of pain, thanks to public perception groundwork laid by the opioid industry,. OxyContin (oxycodone) pills had yet to saturate the country and opioid abuse was largely confined to intravenous use.

Ortho-McNeil Pharmaceutics convinced the FDA to allow them to market tramadol under the brand name Ultram as an “unscheduled” drug, meaning that it could be prescribed as liberally as an antibiotic with none of the restrictions required of all other opioids. A “scheduled” drug on the other hand would be categorized into one of five levels based on potential for abuse and addiction and have restrictions on prescribing. According to the Milwaukee Journal-Sentinel, the FDA based its decision on reports from Europe and research on injected tramadol, which acts differently from the drug taken orally. The Journal-Sentinel’s investigative reporting found that the agency had unpublished research showing that opioid abusers liked high doses of oral tramadol as much as oxycodone.

The FDA agreed to address concerns about potential abuse by having the manufacturer fund a post-marketing surveillance program developed and overseen by an “independent steering committee” that was to recommend scheduling if unexpectedly high levels of abuse were found. The committee was certainly independent from the FDA, but given Ortho-McNeil’s $15 million annual spending on the group’s work and members’ consulting fees, one could question the group’s independence from its corporate sponsor. Unsurprisingly, the committee did not recommend scheduling the drug.

Because tramadol was originally approved as an unscheduled drug, it’s an uphill battle to change it. In 2005, mounting evidence of tramadol’s dangers prompted the submission of five citizen petitions to the FDA requesting the scheduling of the drug. It wasn’t until 2014 that tramadol became a schedule IV drug, which is barely scheduled; most other opioids are in the more restrictive schedule II category. Public Citizen filed a petition for rescheduling tramadol to schedule II in November 2019.

Tramadol addiction is a major problem in India, Africa, and the Middle East. One reason could be that the World Health Organization (WHO), while noting reports of tramadol dependence, has declined to add international regulation. Grünenthal, the German company which held the now-expired patent on tramadol and continues to sell the drug, wants it to stay unregulated. One of their arguments? That the U.S. signaled tramadol was less risky by not including it in the same category of controlled substances as other opioids.

January 2020:

Story vs. Anti-Story in Opioid Marketing

By Judy Butler

More than twenty years after the launch of OxyContin, we’re still learning exactly how the opioid industry created and maintained the highly profitable opioid market by spreading misconceptions about opioids. Internal company documents unsealed in court cases in Kentucky and Ohio continue to offer evidence. Through its investigative reporting, however, ProPublica offers insight into how these misconceptions take hold. They piece together the public relations strategy – an “anti-story” – that still shapes media coverage.

The misrepresentation of the addictive potential of opioids comes not only from manufacturers but also from seemingly independent voices. Perhaps it’s no surprise that all is not as it seems. ProPublica’s investigative reporting outlines an “anti-story” campaign conducted by public relations firm Denzenhall Resources on behalf of Purdue. Public relations firms are an important part of creating narratives that compete with the truth. The anti-story both blames the patient addicted to opioids and substitutes a more sympathetic “real victim”—the pain patient who may lose a vitally important medication.

Getting marketing messages out through third-party organizations is key; Purdue funded the American Enterprise Institute (AEI) and also established a relationship with Sally Satel, a psychiatrist and resident scholar at AEI. ProPublica meticulously documents how Denzenhall and Purdue employees were involved in Satel’s prominently published, supposedly independent, opinion pieces promoting the anti-story, with not one of her Purdue links disclosed in her publications.

The narrative of chronic pain patients who can only be helped by opioids continues to run strong, and the millions of prescriptions written continue to generate profit. An audit of Purdue, made public in bankruptcy filings, tracks payments to the Sacklers of $10.7 billion from 2008 to 2017, the years following the company’s guilty plea to federal charges of falsely marketing OxyContin. The public has yet to see Purdue’s factual and legal defenses contained in a 580-page internal report filed with the court; whether it will be released remains in question. Hours after Purdue requested it be made public, they withdrew their motion without explanation.

Court cases against Purdue that precipitated bankruptcy filing are on hold during the proceedings and Purdue seeks to resolve U.S. Justice Department probes as part of the process as well. At least six drug companies, including Purdue, have received subpoenas from federal prosecutors suggesting a broad criminal investigation, according to the Washington Post.

Although the resolutions of court cases, federal probes, and Purdue’s bankruptcy await, efforts to both expose and redress industry harms continue. The Centers for Disease Control and Prevention (CDC) is in the early stages of updating its 2016 Guideline for Prescribing Opioids for Chronic Pain. The original guideline, whose authors had no industry conflicts, recommended against treating chronic pain with opioids. In so doing, they promoted different messages from the guidelines issued by professional organizations, which supported industry marketing messages but didn’t disclose industry ties. Not surprisingly, industry-allied organizations attacked the CDC guidelines and argued against potential additions to the update. The only media coverage of CDC’s plans shares this viewpoint.

Industry also sought to advance its interests through funding universities. In December, Tufts University became the first major university to publicly remove the Sackler name from its walls as a response to student concerns. Media coverage prompted the resignation of Richard Sackler from the medical school’s board in 2017, but the Massachusetts complaint against Purdue detailed the University’s extensive involvement with the company. Tufts commissioned an independent review of the Sackler relationship, which found that the university did not distance itself from the Sacklers until after extensive media attention. The Sacklers’ lawyer met Tufts removal of their name with a letter arguing it was a breach of binding commitments. Such a response not only makes it clear the Sacklers are willing to continue to fight all threats, but also sends a strong message to other Sackler-funded institutions.

The opioid “anti-story” continues to be voiced by the industry and allies whose industry ties are not always obvious. The details of how this false narrative that resulted in opioid overprescribing was created and perpetuated is steadily being revealed. As  the layers of the anti-story peel away, the more space there will be for the truth – that the risks of opioids outweigh benefit in the treatment of chronic pain. 

2019

December 2019: 

In Opioid Cases, Look to Tobacco Litigation for Guidance

By Adriane Fugh-Berman and Robert Weissman

Twenty years ago, a litigation breakthrough marked a vital pivot point in one of the greatest public health advances in American history. The settlement of state lawsuits against Big Tobacco ended key corporate strategies to hook young smokers, funded effective anti-smoking message campaigns and required the disclosure of millions of pages of documents that laid bare the industry’s deadly and deceptive stratagems.

Today, the country stands on the brink of another litigation breakthrough involving another public health scourge, the opioid addiction crisis. Lawsuits brought against opioid manufacturers and distributors by states and nearly 2,000 cities and counties may soon settle, according to news reports.

If the opioid cases are in fact settled, it is crucial that they draw on the experience of the tobacco litigation and ensure the full release of all documents provided in the discovery phase of the litigation.

The tobacco litigation eventually unearthed literally millions of documents that transformed the role of tobacco in American society and, to a lesser extent, around the world. The tobacco documents revealed how the industry built its business on deceiving new smokers as to the deadly health consequences of using its product, luring children to become new smokers, denying the effects of second-hand smoke and much more.

Those revelations weren’t just of historical interest. In revealing the industry’s studies, marketing and political playbook over the prior 50 years, they helped shape the policy agenda to counteract the industry’s damage. They also fundamentally and permanently changed the tobacco industry’s political standing and cultural attitudes toward smoking.

Documents from the opioid manufacturers and distributors are likely to be equally revelatory and important for public health. As with tobacco, the opioid addiction crisis is rooted in an inherently dangerous product that was marketed based on safety claims that the drug companies knew to be untrue.

Purdue Pharma stands at the heart of the litigation. This company, closely held by the Sackler family, spawned the opioid epidemic through their aggressive marketing of Oxycontin. Going back generations, Sackler family members have been, and remain, brilliant marketers. Arthur Sackler, a giant in medical advertising and promotion, pioneered drug marketing that doesn’t look like marketing. He also founded IMS, now renamed IQVIA, the first data-mining firm that tracked physician’s prescriptions and sold that information to pharmaceutical companies to help them tailor messages to targeted physicians based on detailed knowledge of their prescribing behavior.

Two of Arthur’s sons, Raymond and Mortimer, and grandson Richard, launched Oxycontin with a huge campaign based on Arthur Sackler’s groundbreaking work. Promotional tactics included extensive funding of medical education, the funding of professional and patient groups that focused on pain, and payments to Tufts, Massachusetts General, and other academic medical institutions to spread opioid-friendly messages far and wide. Opioids are appropriate for acute trauma, cancer-related pain, and end-of-life care. The cruel genius of Arthur Sackler’s descendants was to position Oxycontin for arthritis, low back pain, and other forms of chronic, everyday pain – conditions opioids should almost never be used for.

In settlement talks, Purdue Pharma is reportedly offering to hand its business over to a public trust, that would restrict sales and direct future profits to addiction treatment. In that instance, the company will have no ongoing proprietary interest and a litigation settlement should mandate that all its internal documents, except those implicating personal privacy or raising public health issues, be made public.

Purdue is only one of the defendants in the opioid litigation. Settlement agreements with the other companies should also require that all the documents they have produced in discovery be made public.

We’ve already gleaned a hint of the value of the discovery materials in the success of the Washington Post and Charleston Gazette-Mail in obtaining access to an eye-popping government-maintained database, made available in discovery, that tracks the distribution of every single pain pill sold in the United States. One finding: In one year, the companies shipped an unconscionable 306 pain pills for every person in one Virginia town at the center of the addiction epidemic.

There’s much more to come: Lessons about how the companies manipulated the science around opioid addiction, their marketing strategies, their use of patient and front groups to advance their deceptive marketing claims, and their political tactics. Those lessons will help us design policies to stem the damage they have inflicted on families and communities across the country.

But that’s not all. The companies’ internal communications are important for exposing and analyzing covert marketing techniques that are commonly used by many prescription drug manufacturers to exaggerate the benefits of drugs and to suppress perceptions of harm. The public needs to see the internal company documents so we can all help prevent the next industry-sponsored epidemic of harm from unethical promotion. 

November 2019:

When Sunshine Doesn't Cast Enough Light

By Judy Butler

It could be that sunshine (transparency and disclosure) is not a strong enough disinfectant for the drug and medical device industry. ProPublica analyzed the first full five years of federally-mandated public disclosure of payments to prescribers and found annual payments totaling between $2.1 billion and $2.2 billion. More than 56 million payments were made for speaking, consulting, meals, travel, and gifts; the analysis excludes research payments.

ProPublica offers several jaw-dropping breakdowns of the data, including millions of dollars spent on blockbuster drugs and total payments of at least half a million dollars apiece to more than 2,500 physicians over five years. But perhaps most concerning is the sheer volume of prescribers reached in five years – “1 million doctors, dentists, optometrists, chiropractors, and podiatrists received at least one payment, most often a meal” and almost one-third of those received a payment in each of the five years analyzed.

One concern about these payments is that they influence prescribing practices. Physicians understand the implicit conflict of interest yet take exception at the idea that they are being manipulated. But what industry would spend $2.2 billion without a return on its investment? Study after study link drug-related payments with increased prescribing of targeted drugs including drugs used in oncology, cardiology, gastroenterology, psychiatry, and neurology. Limiting relationships with industry helps: some academic medical centers restricting pharmaceutical representative sales visits saw reductions in prescribing of promoted drugs.

Several recent studies focus on the influence of payments on the overprescribing of opioids, which are heavily promoted with devastating consequences. One study found opioid-related payments associated with both increased prescribing and a shift to more expensive opioids in a manner that increased with payments. Another study linked opioid-specific payments to increased prescribing of the specific opioid. Again, payments had a dose-related effect: each 1% increase in payment was associated with an increase of 50 daily doses of prescribed opioids. A different study showed that lunch matters—each meal received in 2014 was associated with increased numbers of opioid claims in 2015. Finally, one study identified an association of opioid marketing with deaths from opioid overdoses. The number of marketing interactions was more strongly associated with death rates than the dollar value of marketing.

While prescribers receiving relatively small consistent payments may change their own prescribing behavior, those receiving large payments are often those who impact the broader environment in which decisions about drugs or devices are made. This strategy of handsomely paid key opinion leaders (KOLs) promoting opioids and influencing discourse and policy is well-documented. KOLs are used to promote opioids and across the industry to promote many different drugs and medical devices.

3D mammography is a good example of overpromotion of a medical device. An investigation by Kaiser Health News of the marketing behind 3D mammography, shows how paying doctors, combined with marketing to consumers, lobbying state lawmakers, and funding experts and advocates, resulted in exponential growth in the use of the new technology, even though its superiority over conventional mammography isn’t established. It is, however, superior in terms of radiation dose; 3D mammograms expose women to far more cancer-causing radiation than conventional mammograms. Paid doctors speak out in the media, write research papers, and lobby for laws benefiting 3D mammography, often without disclosing their industry relationships.

This one-two punch from the industry – leveraging small and large payments to influence prescribing – has served them well. So far, the reporting of these expenses hasn’t actually lowered spending. Turns out sunshine isn’t quite enough to affect irrational prescribing, and we need something stronger to disinfect industry’s influence on medicine. 

October 2019: 

Disinfecting Pharma with Sunshine: The Case for Bringing Documents to Light

By Judy Butler

In 2016, the LA Times published a groundbreaking series on Purdue Pharma’s marketing of OxyContin based on thousands of pages of confidential Purdue documents and other records. Purdue responded with their digital support team recommending a strategy to divert online traffic away from the 2016 articles and to PurduePharmaFacts.com, according to documents disclosed by counties suing the drug company in federal court.

From those same court documents, the Washington Post pieced together how drug companies were able to limit the powers of the Drug Enforcement Agency. A legal challenge from the Washington Post and the Charleston Gazette-Mail then brought the documents to light.

More documents will be forthcoming, thanks to legal victories by other media outlets. Health news website STAT won release of court records sealed in 2015 as part of a $24 million settlement between Purdue Pharma and the state of Kentucky. Although a deposition of Richard Sackler is now public, it is unclear when the 17 million pages of documents will be available. Similarly, after a request from CBS News, internal documents from Teva Pharmaceutical filed in Oklahoma were ordered unsealed.  

The outcome of settlement talks in the multidistrict litigation (MDL) in federal court and the subsequent bankruptcy filing by Purdue Pharma is any legal scholar’s guess. One thing we do know is that the opioid manufacturers will do everything in their power to keep their internal documents secret. 

Fortunately, many of the state Attorneys General refuse to back down and their efforts have already provided some stunning disclosures. In an effort to gain permanent access to all the industry documents in the MDL, a group of historians petitioned the court for both the release of the documents and funding for public access to them. 

The deceptive marketing of opioids has had an extraordinarily tragic outcome, but the marketing strategies that caused the opioid epidemic continue to be used for countless drugs, including opioids, to the detriment of public good. In fact, medical advertising, the use of physician education, and other marketing tactics predated Purdue’s Oxycontin, if not the Sacklers behind Purdue. Arthur Sackler pioneered these strategies in the promotion of antibiotics in the 1950s, contributing to a nearly 5-fold increase in antibiotic consumption in that decade. One needn’t look too far to see the parallel consequences resulting from the overuse of antibiotics and opioids, respectively.

In 2016, marketing expenditures for prescription drugs and disease awareness campaigns reached $26.9 billion in the US. Marketing works, and recently-released opioid documents provide glimpses of internal marketing strategies that can help researchers and regulators battle other manifestations of unethical drug marketing. The power of the industry’s own words in exposing how pharma companies influence prescribing by manipulating the medical, regulatory, and social environment can be used to counter that influence. Current litigation must make sure that internal documents are disclosed to the public. It’s time to disinfect pharma with some sunshine.

August/September 2019: 

Highlights from the Johnson & Johnson Opioids Verdict

By Judy Butler

The Oklahoma verdict against Johnson & Johnson was headline news, but it lacked the punch it deserved. The good news is that once the evidence presented at trial is released, journalists will have the internal documents to bring the verdict alive.

 J&J knew the dangers – addiction and death – of its opioids and still waged a widespread marketing campaign using both branded and unbranded strategies. The company knew their marketing was based on studies that were “incomplete, unsound, or fraught with misrepresentations,” yet continued the campaign for years.

 The judge’s findings of fact against J&J outlined the many ways they knowingly created a false narrative around opioids that resulted in a cultural shift in the acceptance of opioids. Their campaign not only targeted doctors but patients, government officials, and the media. Consider these highlights [reference citations omitted for clarity, emphases mine]

Defendants… disseminate[d] the messages that pain was being undertreated and “there was a low risk of abuse and a low danger" of prescribing opioids to treat chronic, non-malignant pain and overstat[ed] the efficacy of opioids as a class of drug.

 Defendants' marketing and promotional efforts were designed to reach Oklahoma doctors through multiple means… includ[ing], among other things, “education" from Defendants’ representatives, literature funded by Defendants in medical journals and publications, materials from professional societies/patient advocacy groups, continuing medical education funded by Defendants unbranded marketing materials, and Defendants paid speakers... All of these many different efforts were intended to influence the prescribing behavior of physicians and thus, increase Defendants' profits from opioids.

A key element in Defendants' opioid marketing strategy to overcome barriers to liberal opioid prescribing was its promotion of the concept that chronic pain was undertreated (creating a problem) and increased opioid prescribing was the solution. For example, Defendants' unbranded marketing campaigns frequently focused on “[h]eightening awareness of the under treatment of pain and its consequences”… and the use of “emotional selling” for opioids by convincing physicians that undertreated pain was harming patients.

Another unbranded marketing message Defendants used to accomplish the “[b]ehavior [c]hange” of “increase[d] opioid use" was that undertreated acute pain inevitably would turn into chronic pain… [to promote] opioids generally as a class of drug.

Defendants ran a website called Prescribe Responsibly as a form of unbranded marketing. Information on the Prescribe Responsibly website promoted Defendants' messaging that the solution to “pseudoaddiction" was “to prescribe more opioids.”

Defendants employed strategies to influence a wide range of governmental agencies, through messages aimed at optimizing the benefits of prescription opioids for pain management [and] minimizing their risks, including the risk of addiction, abuse and diversion.

Defendants training of their sales representatives in Oklahoma included teaching sales representatives to avoid the so-called “addiction ditch” – i.e., to avoid the negatives (addiction) and emphasize the positives (supposed efficacy) in sales calls – and to use a study from Dr. Portenoy “to create dialogue about Opiophobia as a barrier.”

As part of this training, Defendants trained their sales representatives that there was a 2.6 % or lower risk of addiction when using opioids prescribed by a doctor. As part of this same training, Defendants trained sales representatives to establish that moderate to severe acute pain continues to be undertreated.

Part of Defendants' marketing strategy included… the creation and funding of a group known as “NPEC” (National Pain Education Council) whose purposes was to provide Continuing Medical Education (“CME”) related to pain and opioids. The target audience for Defendants NPEC initiative included primary care physicians, pain specialists, oncologists, residents, nurses and pharmacists. CME materials for Defendants NPEC program in 2002 disseminated false and misleading statements regarding opioids and pain management.

In 2001 Defendants were advised by Defendants' own hired scientific advisory board that many of the primary marketing messages Defendants used to promote opioids in general, and Duragesic specifically, were misleading and should not be disseminated... Defendants were advised that no data existed that could support these claims that the data Defendants pointed to (DAWN data) was incapable of supporting these claims, that aggressively marketing OxyContin on this same basis was what had gotten Purdue in trouble, that minimizing the risk of abuse of Duragesic was “dangerous” due to its lethal nature, and that an increase of Duragesic sales would surely cause an increase in abuse of and addiction to the drug. The “Conclusion: Do not include the abuse message. Do not sell opioids on the abuse issue.”

Without the actual evidence, it’s easy to lose sight of the gravity of J&J’s actions. They knew what they were doing and we’re still suffering the consequences of addiction and death. For such a large company, the eventual release of internal documents could be more of a punishment than a $500 million fine. Wait for it.

May 2019

Preventing a new generation of opioid “legacy patients”

By Judy Butler

April was a big month for communications from the federal government about long-term opioid treatment.

First, the FDA announced it would update opioid prescribing information to warn about the risks of rapid discontinuation and provide guidance on tapering.

Then, two letters from the CDC addressed concerns raised by its 2016 Guideline for Prescribing Opioids for Chronic Pain. One answered a letter written by three cancer groups (the National Comprehensive Cancer Network, the American Society of Clinical Oncology, and the American Society of Hematology) that complained that although the Guideline was not written for cancer patients, it was being applied to some cancer patients. The CDC clarified that opioids could be effective for successfully treated cancer patients who continue to have chronic pain and directed prescribers to relevant guidelines. The other, a response to a letter signed by a group of health professionals, related to patients who may be unintentionally harmed by misinterpretation of the Guideline.

Each of these responses address “legacy patients”, or chronic pain patients who have been on opioids for years, perhaps receiving their initial prescriptions at the height of opioid overprescription. Additionally, many legacy patients receive opioid dosages that exceed the CDC Guideline’s upper limit recommendation for initiating high-dose prescribing.

A new generation of legacy patients is exactly what the CDC Guideline seeks to prevent from occurring again. Aimed at primary care physicians, the CDC Guideline raises cautions about the initial prescription of opioids for chronic pain, and recommends regular assessment of benefits and risks when opioids are prescribed.

No one wants to see legacy patients abruptly withdrawn from opioids; anyone going off of opioids should be appropriately tapered. That doesn’t mean, however, that maintaining patients on high doses of opioids forever is appropriate.

Yet this is the solution consistently proposed by chronic pain patients and opioid industry allies, which not only impacts current patients but future patients as well. If legacy patients need to stay on opioids, that must mean opioids are an effective treatment for their chronic pain. Therefore, long term opioid treatment must also be effective for new chronic pain patients.

Perpetuating the use of opioids for chronic pain maintains the opioid industry’s profitable user base. A study of trends in opioid use through 2016 found that the bulk of opioids were dispensed for long term use: “62% of opioids dispensed to commercial beneficiaries were part of a long term episode, 70% for aged Medicare beneficiaries, and 89% for disabled Medicare beneficiaries.”

Providing compassionate, effective medical treatment to legacy patients is not simple. Oregon, a leader in addressing opioid overprescribing, offers resources for treating legacy patients. The overview explains why these resources are necessary: “Prescribers are also asking whether or not tapering is necessary if the patient is stable and compliant on their current dose. Yet, overdose rates continue to be high compared to historical standard and it is well established that patients on high doses of opioids are at increased risk for a variety of side effects, serious morbidities, and death. Quality of life may be adversely affected, despite the fact that the patient perceives benefit in terms of pain relief.” 

The CDC Guideline states that “in some cases, where the risks are minimal and the patient appears to be doing well, continued opioid therapy may be justified,” but recommends a systematic assessment of the risks and benefits of continued opioid treatment and provides tools for both assessment and tapering.

Continued prescribing of opioids to all legacy patients may be the easy answer, but it isn’t the right answer, and arguments in support of continued prescribing are misleading. As with so many problems, it’s much harder to correct them than it was to create them. Unless we take this more difficult path, however, both the health of current legacy patients and the health of a new generation of legacy patients is at stake.

April 2019

Who's Really Advocating for Pain Patients?

By Judy Butler

Last month we looked at the testimony of the U.S. Pain Foundation’s Cindy Steinberg before a Senate health committee. She asserted that there was no overlap between two sets of opioid users: those with chronic pain and those with opioid use disorder. This is a consistent, long-standing industry message confirmed by internal documents; not only is it untrue, but documents disclosed in litigation confirm that the industry knew it to be untrue.

Based on the marketing message that chronic pain patients are somehow exempt from opioid risks, there is no reason to restrict or reduce opioid treatment for these patients. Instead, the only relevant “risk” is the undertreatment of pain and lack of access to opioids.

Ms. Steinberg used this argument to malign the CDC Guideline for Prescribing Opioids for Chronic Pain saying that the guidelines should be rewritten and adding "people think that those [guidelines] are based on strong science and they're not."

In contrast, she endorsed the Draft Report on Pain Management Best Practices: Updates, Gaps, Inconsistencies, and Recommendations issued by the Congressionally-mandated Pain Management Best Practices Inter-Agency Task Force of which she is a member. 

It’s easy to see why one document aligns with an industry message while the other does not. First, compare their methodologies (emphases mine):

• • The CDC guideline is based on “a clinical systematic review of the scientific evidence to identify the effectiveness, benefits, and harms of long-term opioid therapy for chronic pain, consistent with the GRADE approach.” 

  • The draft report of the Task Force “reviewed extensive public comments, patient testimonials, and existing best practices; considered relevant medical and scientific literature; and requested information from government and nongovernment experts in pain management and related disciplines.” 

Then compare the authors (emphases mine):

• • The CDC guideline involved experts without “conflicts that might have a direct and predictable effect on the recommendations. CDC excluded experts who had a financial or promotional relationship with a company that makes a product that might be affected by the guideline.”

  • The Task Force membership was defined by the Comprehensive Addiction and Recovery Act of 2016 (CARA) with no consideration of possible conflict of interest. Members were appointed by the Health and Human Services Department.

See the difference?

Many of the 29 Task Force members had financial conflicts. Of the 15 Task Force members subject to Open Payments reporting, 10 have received payments from pharmaceutical companies and medical device manufacturers, according to Senator Wyden. Other Task Force members may have undisclosed conflicts of interest. In addition, Ms. Steinberg’s organization receives industry funding.

It is no coincidence that the documents differ dramatically.

The CDC’s rigorous, evidence-based approach, purposefully conducted without conflicts of interest, resulted in a guideline with recommendations to treat chronic pain with “nonpharmacological therapy and nonopioid pharmacological therapy” and to limit opioid doses to decrease harms. These highly reasonable guidelines state:

“When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing opioids at any dosage, should carefully reassess evidence of individual benefits and risks when increasing dosage to ≥50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to ≥90 MME/day or carefully justify a decision to titrate dosage to ≥90 MME/day.”

The draft report of the Task Force rejects the CDC’s rational prescribing recommendations, arguing that “[clinical practice guidelines] that only promote and prioritize minimizing opioid administration run the risk of undertreating pain, especially when the cause of the pain is uncertain or cannot be reduced by nonopioid approaches.”

And it’s not only the Task Force and Ms. Steinberg who are raising the rallying cry of undertreatment of pain: This message is a favorite when it comes to countering evidence-based efforts to address the opioid-crisis. Yet this argument only makes sense if opioid risks are reduced when used for chronic pain (they aren’t) and if opioids were actually effective for treating chronic pain (no evidence supports that).

We do know that there are effective non-opioid treatments for chronic pain that are offered to children (see February newsletter). Why not offer those treatments to adults?

Chronic pain sufferers on high doses of opioids are being done a double disservice by the industry and its allies. Not only were these patients given increasing doses of opioid drugs that have no evidence of efficacy for their condition, but they are getting no support in getting access to safer alternatives with more evidence of efficacy. Maintaining chronic pain patients on high-dose opioids benefits opioid manufacturers. Any benefits to patients are far less clear.

March 2019

Industry's Voice, Pain Patient's Face

By Judy Butler

In February, chronic pain patient and advocate Cindy Steinberg testified at a Senate Health Committee hearing, “Managing Pain During the Opioid Crisis”. Steinberg, National Director of Policy and Advocacy for the U.S. Pain Foundation, presented herself as the voice of unheard chronic pain patients; what she didn’t mention was the financial support her national organization receives from opioid manufacturers.

Pain advocacy organizations argue that corporate funding does not influence their positions. If that’s true, why would Ms. Steinberg’s testimony so closely parallel the marketing messages of industry? We know about these messages from internal company documents excerpted in a legal complaint filed by the Massachusetts Attorney General against Purdue Pharma.

The parallels between Purdue’s messaging and Ms. Steinberg’s statements before the Senate committee are striking. Examples of specific messages follow (all emphases are mine).

Pain patients are not addicts and they need continued, unchallenged access to opioids:

Massachusetts complaint: In May [2008], staff sent the Sacklers more ideas about ways to promote Purdue’s opioids… deflect blame from Purdue’s addictive drugs by stigmatizing people who become addicted. “KEY MESSAGES THAT WORK” included this dangerous lie: “It’s not addiction, it’s abuse. It’s about personal responsibility.”        

Steinberg written testimony: A critical misunderstanding that pervades media coverage of opioids and pain is the conflation of two largely distinct populations—those with the disease of chronic pain and those with the disease of opioid use disorder.

Massachusetts complaint: [CEO] Stewart also planned for Purdue to continue to push under-treatment of pain as a major message. Finally, the plan highlighted that sales could be increased by falsely convincing doctors that they could and should prescribe more to patients deemed to have low risk of addiction and that patients who were at risk of addiction were really just illegal drug users

Steinberg written testimony: As a result of well-intentioned measures to contain the opioid crisis, such as restricting the supply of prescription opioids, intense regulatory scrutiny of physicians, the establishment of ceiling doses and day limits on the number of opioids that can be prescribed, legitimate chronic pain patients are being made to feel like criminals simply for seeking relief—many of whom have been on long-term stable doses of their medication for years.

The concept that chronic pain patients are somehow protected against addiction to opioids is simply not true, and the Massachusetts complaint alleges that the industry was well aware of this. An internal Purdue document states about addiction:

"This can happen to any-one – from a 50 year old woman with chronic lower back pain to an 18 year old boy with a sports injury, from the very wealthy to the very poor." [text box from internal Purdue document]

The truth is that anyone can become addicted, and long-term use has demonstrable negative adverse outcomes with little if any improvement in function. But you certainly won’t hear that from Ms. Steinberg, or the industry messages she promotes.

February 2019

What Really Helps Chronic Pain Patients?

By Judy Butler

The New York Times recently ran an article called Helping Children Conquer Chronic Pain; not exactly breaking news, just a look at kids and chronic pain, but this article has important implications for the opioid epidemic. With proper treatment, “the majority of children are significantly helped with pain problems, and for many the pain disappears completely,” said Dr. Neil Schechter, the director of the chronic pain clinic at Boston Children’s Hospital.

Proper treatment, it turns out, is not opioids, but instead getting back to normal activities, using non-opioid medications that treat the nervous system, cognitive behavioral therapy, and mind-body techniques. Reassuring patients that their pain is real and that it’s not a message that “something dangerous or threatening is happening” also helps. Dr. Schechter notes that chronic pain “is hurtful but not harmful.”

Psychologist Rachel Coakley explains, “There is really strong evidence supporting the psychological treatment for chronic pain, and that doesn’t imply that the pain itself is a psychological problem.” Patients can learn to reduce the sensitivity of the nervous system and “disrupt the habit cycles and behavior patterns that have built up around chronic pain.”

If this works for kids with chronic pain, what about adults? Turns out it works for them too.

So why isn’t this the way adults with chronic pain are treated?

With a no-holds barred pursuit of billions of dollars in profits, the Sackler family, owners of Purdue Pharma, knowingly (and illegally) marketed Oxycontin, its highly addictive opioid, as a treatment for chronic pain. So alleges January’s court complaint by the Massachusetts Attorney General expanding its June 2018 filing against the company, its individual owners, and corporate leaders.

Purdue’s corporate misdeeds have been documented before and the company even entered a guilty plea in a 2007 case: “Beginning on or about December 12, 1995, and continuing until on or about June 30, 2000, certain Purdue supervisors and employees, with the intent to defraud or mislead, marketed and promoted OxyContin as less addictive, less subject to abuse and diversion, and less likely to cause tolerance and withdrawal than other pain medications.” A corporate integrity agreement and consent judgment ordering Purdue to “not make any written or oral claim that is false, misleading, or deceptive” in the promotion or marketing of OxyContin should have ended these practices.

Instead, the Massachusetts filing offers example after example from internal documents of continued practices from 2007 to 2018 of aggressive sales tactics to physicians to get more people on Oxycontin for longer periods at higher doses and to keep patients away from safer alternatives.

In addition, Massachusetts alleges Purdue used its money to influence the way its drugs were perceived generally, including among policymakers. When making the case to continue funding for the Massachusetts General Hospital Purdue Pharma Pain Program, staff told the board that it gave Purdue name recognition among medical students, residents, and the public, as well as political protection against efforts to address the opioid crisis. Similar activities were pursued with Tufts University.

Opioid money saturates the medical, political, and academic environment to support falsehoods about the efficacy and dangers of these addictive drugs, which trickles all the way into the conventions around individual patient care. Unethical companies have been able to resolve the consequences of illegal marketing with a tiny fraction of their profits. Until that changes, there’s little hope that evidence-based treatments for chronic pain will dislodge opioids as the gold-standard, despite viable alternatives, like the one outlined for children in the New York Times.

2018

December 2018

An opioid treatment for depression nixed by FDA advisory committee

By Ben Goodwin

In November, an FDA advisory committee convened to hear the merits of an opioid drug as an adjunctive to treat major depressive disorder (MDD). On one side of the room sat the best bench scientists, doctors, biostatisticians, and executives that Alkermes, a Dublin based pharmaceutical company, could muster. Along the other wall sat FDA officials, and in the neutral middle was the advisory committee, which included psychiatrists, researchers, and pharmacists.

Buprenorphine/sampidorphan (BUP/SAM) combines an opioid (buprenorphine) with an opioid antagonist (sampidorphan). Buprenorphine is a widely used treatment for opioid use disorder; its long duration of action and its partial activation of opioid receptors make it well suited for keeping withdrawal symptoms at bay without sedation or euphoria. In non-opioid users, however, buprenorphine can cause euphoria, which is the opposite of depression—not an effect we aspire to in depression treatment.   

An abusable drug, buprenorphine is usually combined with naloxone, an opioid antagonist that reverses buprenorphine’s effects when used intravenously.  Sampidorphan, an opioid antagonist, serves the same purpose as naloxone, although less effectively.

BUP/SAM’s usefulness for treating major depressive disorder is unclear, and its potential risks are concerning. The efficacy and safety trials for BUP/SAM that have been performed so far suffer from the same fundamental problem as many other opioid trials: they are short term trials for drugs that may be prescribed for years. There is no way to assess the real long-term benefits and harms of a drug other than with longer, more robust trials. This may be especially important with opioids as dependence and addiction can develop quickly. 

The antidepressant market is one of the biggest cash cows the pharmaceutical industry has: nearly 13% of individuals older than 12 took an antidepressant between 2011 and 2014, and a quarter of people who took an antidepressant had done so for a decade or longer. A new, branded antidepressant would be a huge moneymaker for Alkermes.

Opioids may temporarily improve mood but they are not an appropriate treatment for depression. As was pointed out by guest speaker Mark D. Sullivan MD PhD, depression, chronic pain, and substance abuse disorders are in many cases inextricably linked. Depression does not protect patients from addiction, respiratory depression and all of the other adverse effects of opioids. As useful as buprenorphine is in medication-assisted treatment for opioid use disorder, it’s an inappropriate drug for treating depression.

Psychiatric disorders are so complex and multifaceted that to place all of one’s hope on a single pill is reductive, especially with a disorder so over-diagnosed. The medicalization of depression as simply a chemical imbalance has done less for the stigma and the symptoms patients are suffering from, and more for the bottom line of companies peddling antidepressants. Serious research into novel non-pharmacological interventions for treatment-resistant depression remains lacking.

The advisory committee ultimately voted 21 to 2 against the approval of BUP/SAM. The FDA, almost always follows the opinion of the advisory committee; with such a resounding rejection, BUP/SAM won’t be approved this round.  The company could try again, however, and could argue that more safety and efficacy data will be gathered from “real-world” patients.  If BUP/SAM gets pushed through on the back of a promise that more safety and efficacy data will be gathered from “real-world” patients, it will be a case of Alkermes using unknowing patients as guinea pigs.

November 2018

Make Punishment Personal

By Judy Butler

October’s pharmaceutical industry news included the following:

• • GlaxoSmithKline will resume payments to physicians to promote their products; the company had stopped the practice after a 2012 $3 billion settlement for illegally promoting medicines, and withholding safety data. The only company that ceased such payments, GSK now argues that their “educational programs have not been as widely available, or seen as compelling to HCPs.” In other words, it’s costing them sales.

  • Pfizer settled with New York State following an investigation into deceptive advertising of its “pay no more than” drug copayment coupon card which, in fact, had limits on total savings that resulted in costs “more than” they claimed. The drug maker will pay $500,000 to the state and $200,000 in restitution to consumers, but did not admit to any wrongdoing.

  • More expensive, brand-name drugs tend to be prescribed in urban areas, particularly between New York and Washington, DC, even when the drugs have not demonstrated higher effectiveness, according to a study in Nature Communications.

  • Five doctors, a nurse practitioner, and a pharmacist face charges from the Manhattan U.S. Attorney for illegally distributing millions of oxycodone pills.

  • Purdue Pharma continues to run full page ads in the Washington Post and other papers touting its participation in addressing the opioid crisis... with no mention of its role in the creation of the crisis.

Collectively, this reporting underscores facts that we’ve seen before: that paying trusted professionals to promote drugs works, pharmaceutical companies have deep pockets to pay for settlements, expensive drugs continue to be prescribed irrationally, and doctors continue to write millions of prescriptions.

What could counter this system of pharmaceutical marketing that undermines rational prescribing? Perhaps going to the very root of the problem and holding industry executives personally liable—that’s what Massachusetts is doing with a suit against executives and owners of opioid manufacturer Purdue Pharma. Drawing from more than a million pages of evidence, the legal complaint describes how these individuals oversaw a range of deceptive marketing practices intended to maximize profits by increasing the number of opioid prescriptions, fostering higher doses, and encouraging longer duration of use.

The industry’s efforts to shield its executives from criminal liability underscore the potential impact of such action. In 2007, after high-powered industry legal teams met with top officials at the Justice Department, three Purdue Pharma executives pled guilty to a misdemeanor that did not accuse them of wrongdoing. The negotiation also resulted in Purdue’s parent company being charged with a felony for falsely marketing OxyContin and levied a $630 million fine, allowing Purdue Pharma to remain free of restraints on the sale of a drug that come with a criminal conviction. 

More recently, the Washington Legal Foundation petitioned the Supreme Court to consider a case that would weaken the Responsible Corporate Officer doctrine, which allows federal prosecutors to hold executives liable. According to the Intercept, Purdue Pharma was one of several donors supporting the effort.

The Sackler family, sole owners of Purdue Pharma which generated $3 billion in US sales in 2016, of which $700 million went to its owners, are estimated to have a net worth of $13 billion according to Forbes. The Massachusetts complaint documents board reports from 2007 to 2013 that show “the directors and CEO knew about, allowed, and directed Purdue’s deception” including management of sales reps, hiring top prescribers to promote opioids, and efforts to get more patients on higher doses of opioids for longer periods… all to increase sales and revenue with no regard for the public health crisis it engendered.

With deep pockets and political connections, the Sacklers have remained free to donate lavishly to Sackler galleries, wings, and centers at museums and Sackler institutes, facilities, and endowed professorships around the globe. If Massachusetts succeeds in holding the family accountable for its actions, the family’s public image will change dramatically, and other drug companies will understand that deceptive marketing has consequences.

These firms know that if they can shield their officers from liability, the potential fines and settlements resulting from unethical marketing practices are simply the cost of doing business.  Take away that protection and the cost of losing personal reputations — and the possibility of jail time — may finally be too high.

October 2018

Greater Decline in Opioid Prescribing After CDC Guidelines Released

By Judy Butler

What happens when a government agency uses an unbiased, evidence-based approach to examine opioids for chronic pain? It finds no evidence of long-term benefits and extensive evidence of possible harms of opioids, recommends nonpharmacological and nonopioid pharmacological therapy for treatment of chronic pain, withstands an industry-funded assault, and reduces opioid prescribing.

That, in a nutshell, is the story of CDC’s Guideline for Prescribing Opioids for Chronic Pain, released in March 2016.

The Centers for Disease Control and Prevention (CDC), did not include any industry-funded participants in the process of drafting its guidelines. This stands in contrast to other federally-funded efforts addressing chronic pain and opioids: the National Institutes of Health, the Food and Drug Administration, and the Institute of Medicine all included industry-funded participants in their efforts. 

It’s no surprise that the draft CDC guideline was met unfavorably by the opioid industry, which remained behind the scenes. Working through surrogates with undisclosed funding, the industry mobilized forces against the publication of the guidelines. As reported by the Associated Press, many of those attacking the CDC guideline belong to the Pain Care Forum (PCF), a group founded by the chief lobbyist of OxyContin-maker Purdue Pharma and comprised primarily of drugmaker-funded members. For example, a letter from the Washington Legal Foundation (WLF) argued that the CDC broke the law by not disclosing its advisers’ identities and should redo the guidelines. Ironically, the WLF did not disclose that it received funds from Purdue.

The American Academy of Pain Management (now the Academy of Integrative Pain Management), another Purdue-funded PCF member, called for Congress to investigate the CDC. Pain patients mobilized to oppose the guidelines included representatives from the Interstitial Cystitis Association and other consumer advocacy group members of PCF, and also Purdue-funded groups including the Power of Pain Foundation (now iPain).

Although the CDC opened the guideline for comments and delayed its release to maximize public participation, the opioid industry failed to invalidate its conclusions. The CDC compiled and responded to all the comments derived from a constituent webinar and public comment, and stood behind the strength of its evidence-based guideline. The CDC's steadfastness paid off in public health benefits.

A recent study in the Annals of Internal Medicine demonstrates the substantial impact of the guideline on opioid prescribing rates. The study compared monthly opioid prescribing data prior to guideline release (January 2012 - February 2016) to post release (March 2016 - December 2017). The monthly drop in overall opioid prescribing rates increased from 23.48 per 100,000 to 56.74 per 100,000. For prescriptions higher than the upper limit of 90 morphine milligram equivalents (MME) per day recommended by the CDC, the monthly decline increased from 3.56 per 100,000 persons to 8 per 100,000.

The CDC guideline has also played an interesting role in opioid litigation. As part of a 2017 settlement with Santa Clara County, California, Pfizer agreed not to make any claims that conflicted with the CDC guideline nor support organizations and individuals that make such claims. Pain News Network (PNN) reported it will no longer receive Pfizer’s $10,000 annual grant for sponsorship of its newsletter. However, it’s unlikely that other opioid manufacturers would take similar steps, unless required to by litigation.

This is a success story that we should recognize and encourage. One can only imagine the impact that the federal government could have on opioid prescribing—and rational prescribing of other drugs—if all Federal actions had more evidence and fewer conflicts.

August 2018

A Million Ways to Market A Pill

By Judy Butler

Consumers may believe that doctors are taught to choose treatments based on the best-available evidence and for which benefits outweigh harms. That’s the definition of rational prescribing. Yet rational prescribing is not a given because of something not covered in medical training—pharmaceutical company influence. Pharmaceutical companies profit through the sale of new, patented drugs, so they spend millions on marketing to shape the environment in which doctors write prescriptions.  

Take, for example, opioids. In 1990, the president of the industry-supported American Pain Society (APS) called for a new approach to pain, including expanded therapeutic opioid use; the APS argued that such use rarely results in addiction. APS went on to produce guidelines encouraging expanded opioid use and trumpet their slogan “Pain: The 5th Vital Sign”, adding the highly subjective concept to the four objectively quantifiable measures of temperature, blood pressure, respiration, and pulse. 

Policy changes followed: in 1998 the Federation of State Medical Boards issued a policy that physicians would not face regulatory action for prescribing large amounts of opioids; the same year, the Veterans Health Administration required all clinicians to ask about patients’ pain at each visit; and in 2001 the Joint Commission (JCAHO) issued management standards requiring its accredited health care facilities to measure pain and prioritize its treatment. One need only to look at Purdue Pharma’s 2001 OxyContin marketing report to confirm industry involvement in these policies: “corporate initiatives and partnering efforts were very successful with the Veterans Administration, American Pain Society, and JCAHO in an effort to make Pain: The 5th Vital Sign. This ‘call to action’ was an important promotional initiative for Purdue. In addition to building sales for OxyContin Tablets, it also positioned Purdue as the leader in pain management education.”  

By 2006, the government implemented a patient survey that would determine hospital reimbursement rates. Patients were asked, "How often did the hospital staff do everything they could to help with your pain?" thus leaving patients to assess their own treatment with possibly unrealistic expectations and without regard for rational prescribing.

These policy changes occurred alongside an unprecedented effort by Purdue Pharma to market OxyContin (oxycodone), introduced in 1996. Hundreds of highly incentivized sales reps wooed doctors based on prescribing patterns discovered with sophisticated marketing data. The company funded and trained a speakers’ bureau for medical conferences and other events, treated doctors to pain symposia at resorts, ran ads in medical journals, sponsored web sites about chronic pain, and produced promotional videos. All these efforts were backed up with commercially-influenced medical literature citing physicians and research funded with undisclosed support from Purdue. The too-good-to-be-true message behind the marketing—here’s a safe, effective, “‘virtually’ non-addicting” drug that can treat long-lasting pain.

The consequences of the opioid industry misdeeds continue. Consider a July 2018 study finding that of opioid-naive patients reporting to an emergency room for an ankle sprain, 25% were prescribed opioids from 2011 to 2015. Rational prescribing? Definitely not—inexpensive NSAIDs treat ankle sprains most effectively and opioids are unlikely to have any clinical benefit. The researchers estimate that “more than 140,000 opioid tablets could have been prevented from entering the community if opioids had not been prescribed for our study sample.” Because large numbers of tablets are commonly left over after acute pain prescriptions and are poorly secured, it’s unclear how many of these tablets may have been diverted.

The study also found that while less than 5% of prescriptions were written above 225 morphine milligram equivalents (MMEs) per day, patients with these prescriptions were nearly five times more likely to transition to prolonged use than those with lesser dose prescriptions. The study authors note that without specificity about how many tablets and MMEs constitute a day’s supply, common 5- to 7-day supply limit policies aimed at safer opioid prescribing could be above 225 MMEs per day. 

It’s easy to see problems with misprescribing opioids and even easier to blame doctors for writing these prescriptions. It’s important to realize, however, the context in which these doctors’ decisions are made. The opioid industry flooded the environment with misinformation and distorted evidence reaping billions of dollars of profits along the way. These tactics continue, and not just with opioids. Is it any wonder doctors have difficulty with rational prescribing?

July 2018

Subsys Sales, from Salacious to Scammy

By Judy Butler

Just what would a drug company do to make millions? Take doctors to strip clubs and shooting ranges? Direct sales reps to “behave more sexually”? Create a workaround to bilk Medicare of millions of dollars? All of the above. In recent months, we’ve seen evidence of the outrageous and the sly from Insys, maker of Subsys, a fentanyl drug that is sprayed under the tongue.

A synthetic opioid 100 times more potent than morphine, fentanyl is highly addictive and dangerous; “transmucosal immediate-release formulations” (TIRFs) are very rapid-acting and considered more addictive than pills or patches. Approved by the FDA only for breakthrough cancer pain (i.e., for cancer patients whose pain “breaks through” scheduled opioid doses), the intended market for Subsys is well-defined and limited. Even with its four-figure price, selling Subsys just to this narrow group would never produce explosive revenue. Instead, Insys allegedly lured doctors to prescribe Subsys off-label to patients without cancer and created a mechanism to secure insurance coverage for those uses. By 2016, just four years after its launch, Subsys owned 42% of a TIRF market that had a total of $710 million in US sales.

Although details of Insys’ egregious sales practices have been emerging for several years, they prove to be just the tip of the iceberg. Whistleblower complaints filed by former Insys sales representatives and reported by Julia Lurie in Mother Jones cite egregious allegations:

• • In 2015, a sales rep was advised to “behave more sexually toward pain management physicians, to stroke their hands while literally begging for prescriptions,” and to ask for the prescriptions as a “favor.”

  • In 2013, Insys executives took Dr. Gatz, a pain specialist, to a strip club, subsequently receiving a text from him stating “Thanks for the best weekend in years! ! !” The same doctor also received lavish meals and at least one trip to a shooting range. “Since 2012, Medicare has paid over $3.3 million for Subsys that was prescribed by Dr. Gatz.”

  • In 2012 Insys hired an employee with no pharmaceutical sales experience “to have sexual relations with doctors in exchange for SUBSYS prescriptions.” A sales manager described her as “dumb as rocks, but she was sleeping with another doctor and getting a lot of prescriptions out of him.”

  • When recruiting doctors for a lucrative speaker’s bureau sales reps were told, “They don’t need to be good speakers, they need to write a lot of Subsys.”

These sales strategies resulted in an estimated 80 to 90 percent of Subsys being prescribed for off-label use. Outrageous as these practices are, Insys’ biggest scam might be their manipulation of Medicare to cover Subsys. But getting doctors to prescribe Subsys off-label only pays off if insurers cover it.

Even with insurance coverage, because copay cost may be prohibitive for some patients, many pharmaceutical companies provide copay assistance programs, but only for commercially insured or cash-paying patients. Medicare will not accept pharmaceutical coupons or copay vouchers under the anti-kickback statute, that is, the payment may serve to persuade the patient to purchase something Medicare must pay for. Medicare will allow patients to get copay assistance from copay charities.

So who helps Medicare patients with copays for Subsys? The short answer: Insys. Senator McCaskill’s 2017 report on the pharmaceutical industry’s funding of pain advocacy groups revealed that Insys provided $2.5 million in payments to the U.S. Pain Foundation for it Gain Against Pain copay assistance program. In response to the report, the U.S. Pain Foundation posted a letter on its website stating that the copay assistance program is for “cancer patients dealing with pain” and “helps to cover the high costs of treatment; assistance is not limited to any specific type or brand of pain medication.”  

PharmedOut interns dug deeper and published an article revealing that the only drugs covered by Gain Against Pain are “analgesic medications that are prescribed for breakthrough cancer pain.” That is, TIRFs, with the market leader being Subsys. Since Gain Against Pain is a copay charity, it is not excluded from providing money to Medicare recipients. By funneling money through the U.S. Pain Foundation, Insys could again cover copay costs for its users.

Weeks after our article was published, the founder and CEO of the U.S. Pain Foundation resigned at the request of the Board of Directors. And the Gain Against Pain webpage states the program is not accepting new applicants; the website states that “programs open and close depending on funding”. Let’s continue to make pushing highly-addictive drugs to patients they weren’t intended for a liability!

June 2018

Behind the Purdue Curtain

By Judy Butler

Purdue Pharma spent millions on ads featuring words it wants the public to hear—assertions that the company is working to address the opioid crisis. But it spends many millions more trying to protect the words it doesn’t want seen—its marketing strategies for OxyContin and the early awareness that OxyContin was highly addictive.

In May, the world got a glimpse of Purdue’s secrets in a New York Times article revealing the contents of a confidential Justice Department report. For four years, prosecutors built a case against Purdue for aggressive marketing of OxyContin despite knowledge of its widespread abuse. Although prosecutors recommended felony indictments, including conspiracy to defraud the United States, following meetings in 2006 with a high-powered team of attorneys representing Purdue, the Criminal Division decided not to pursue indictments and negotiated a plea deal.

As part of the deal, federal prosecutors did not produce evidence that showed Purdue officials were aware of wrongdoing, and they narrowly avoided a prison sentence. Without a trial, the incriminating company documents and grand jury testimony from sales reps never went public. 

A Kentucky lawsuit against Purdue filed in 2007 concluded with a $24 million settlement and the sealing of court documents. That was the end of that… until STAT News filed a lawsuit to compel the court to release the records. Purdue appealed a circuit court decision to unseal the records, which include a deposition of Richard Sackler, a member of the family that owns Purdue, as well as documents related to OxyContin marketing practices. A decision has not yet been made.

Perhaps the growing number of lawsuits filed against Purdue, will eventually lead to a trial and more internal documents will see the light of day. In the meantime, Purdue will continue to deny its role in the opioid crisis, as they did in response to the New York Times article: “Suggesting activities that last occurred more than 16 years ago, [for] which the company accepted responsibility, are contributing to today’s complex and multi-faceted opioid crisis is deeply flawed.” We won’t hold our breath for Purdue to accept responsibility for its role in the crisis. 

May 2018

Pharma and the NIH: Innocence By Association?

By Judy Butler and Dr. Adriane Fugh-Berman

In April, the National Institutes of Health (NIH) announced that it would not accept cash contributions from opioid manufacturers in its efforts to address the national opioid crisis. Credit to NIH for this decision, but it doesn’t negate the industry’s influence. As long as NIH allows industry “engagement” through a public-private partnership, it cedes control of the agenda.

The problem with these public-private partnerships is that an industry agenda is not a public health agenda. Pharmaceutical companies are legally bound to represent the best interests of their stockholders; NIH, in contrast, should represent the best interests of the public.

To see the industry’s influence to date, consider NIH’s intention to “advance focused medication development for addiction and pain.” Prioritizing new medications for pain and addiction is a marketing tactic derived from industry. While new nonopioid analgesics would be welcome, we already have effective, nonaddictive, and underutilized medications for pain including ibuprofen, naproxen, acetaminophen, diclofenac, ketorolac, lidocaine, capsaicin, gabapentin, low-dose antidepressants and many others. Four out of five people with opioid use disorder are not on medication-assisted therapy. A focus on new medication diverts NIH’s resources away from research on more cost-effective strategies including utilizing existing therapies, effective social and behavioral approaches to pain and addiction, and on cannabinoids, non-pharmacologic approaches, and complementary and alternative therapies. It is vital for NIH to support research that the industry won’t fund.

The impeccable scientific integrity of NIH makes a public-private partnership the best marketing strategy industry could have. The industry gains credibility and advances its agenda with taxpayer dollars while compromising NIH’s integrity.

Industry has no intention of letting the opportunity slip away. A spokeswoman for PhRMA, the drug industry trade group, told STAT that they are “working to identify in-kind contributions that will help improve our approach to pain management, while minimizing the risk for addiction and better treating overdose,” as if in-kind contributions were washed clean of conflicts of interest.

Look to the recent revelations about the alcohol industry’s influence on NIH. In 2015, the director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) summoned to his office—and yelled at—agency-funded researchers who were examining the association between alcohol advertising and underage drinking. NIAAA pulled back from their research. Three years later, the reason for the change in agenda was revealed—NIAAA had been negotiating with the alcohol industry to fund a large-scale study on the benefits of daily alcohol intake.

Beyond the ethical questions raised by industry support for a study aimed at examining the benefits of alcohol, the sponsorship undermined the integrity of NIAAA funding decisions. It’s hardly a coincidence that research threatening to alcohol companies’ bottom line would be suppressed. Is there any reason to think the opioid industry would be any different?

NIH should refuse to be a pawn. Pharma is seeking innocence by association.

April 2018

Purdue's Latest PR Move

By Judy Butler

Opioid manufacturers rely on a well-honed playbook to protect their profits. One popular play in recent months? The good corporate citizen. Consider these two examples.

In February, with a simple two-sentence announcement that its sales representatives will no longer promote OxyContin to prescribers, Purdue Pharma generated a media buzz. Judging the headlines trumpeting Purdue’s move, one could believe the company acted in the public interest. Digging deeper, some press coverage cited the growing number of lawsuits against the company as a likely contributing factor to Purdue’s decision. Even harder to find was the fact that although an “authorized” generic form of Oxycontin, manufactured under paid license, is available, competing generic drugs will soon be able to enter the market in light of Purdue’s legal loss to protect its patent. Pharmaceutical companies often stop promoting a drug when generic competitors come on the market. By announcing what would have been a standard business practice, Purdue seeks to present themselves as a responsible corporation—without a negative impact on its bottom line.

As Purdue stops its sales reps hitting doctors’ offices, it’s ramping up a new strategy of positioning itself as a partner in the fight against the opioid epidemic. Ever the good corporate citizen, Purdue launched a campaign in December with full page ads in major newspapers featuring an open letter with the bold headline, “We manufacture prescription opioids. How could we not help fight the prescription and illicit opioid abuse crisis?” 

Glaringly absent from the text is Purdue’s role in creating and maintaining the crisis. Beginning with knowingly misleading doctors regarding the addictive potential of OxyContin and continuing with its overpromotion of “abuse-deterrent” opioids, Purdue’s top priority is its bottom line. 

So what would really make a difference? Imagine Purdue fighting the prescription and illicit opioid abuse crisis by acknowledging that there is no evidence that opioids effectively treat chronic pain. Or by stopping appeals to prevent the unsealing of 17 million pages of discovery documents in a Kentucky suit against Purdue alleging illegal promotion of OxyContin, settled in 2015.

These actions would impact the supply side of the equation and thus cut into profits, which is not in Purdue’s interest. What is in Purdue’s interest? A standard practice—scaling down promotional activities upon the loss of a drug patent—turned brilliant PR strategy that paints the picture of the corporation with a heart of gold… and not a dollar lost.

March 2018

Rx Files: No Medication is Benign, Part 2

By Andrea Sikora Newsome, PharmD

Residency is a grind and Stacy is a hard-ass; she's the perfect foil for a jaded and exhausted resident like myself, especially if that resident adds the word “just” before the name of a medication, as if to downplay its importance when discussing a patient.

I began a game where I tried to rile her up by using the word “just.” I was going to find a medication that didn’t have a side effect, one that truly was benign, even if it was just one medication in one patient. I would prescribe what I thought I could get away with and see if she could find it during our review of the patients that afternoon. I’d be secretly prepared to defend the medication despite its lack of or minimal indication.

Why I thought the student could beat the master is beyond me.

“It’s just a stool softener,” I’d say in mock surprise as she asked why the patient needed it.

“Unnecessary laxatives can cause diarrhea which can lead to electrolyte imbalances, dehydration, and also acute kidney injury.”

“It’s just albuterol.”

“Albuterol has no data in patients without asthma. It can cause tachycardia and atrial fibrillation and next thing you know we are treating acute Afib with three other drugs.”

“Just ipratropium?”

“Just because it’s as needed and not scheduled doesn’t mean it won’t get given. You know medications aren’t free? This patient does not have COPD. Plus, you can get an infection manipulating the ventilation masks.”

“Just Fred Flintstones Multivitamins?”

“They can cause constipation. And you know constipation can prolong your time on the ventilator. And it can clog the G-tube, which means you have to subject the patient to another procedure.”

“What about chlorhexidine?” You can never go wrong with chlorhexidine, right?

“You know that they’ve seen some reports of it increasing resistance of bacteria.” (No, I didn’t know that).

One day a medical resident asked us a question about amoxicillin. Stacy replied with a recommendation, but the resident shrugged and did not plan on taking her recommendation to discontinue the medication. By way of explanation the resident said, “I mean, it’s just amoxicillin.”

I cringed on behalf of the resident.

“It is not just amoxicillin,” she retorted, and then lectured the resident as only a mother of three could do, “You are prescribing a medication to a patient. A patient. A medication.” She repeated for emphasis. “No medication is benign. It’s not just amoxicillin. If you think they have an indication, then that’s fine. But if you don’t, then don’t give it.”

Take it from me (and that traumatized medical resident): you should never use the word “just” about a medication. 

February 2018

Rx Files: No Medication is Benign, Part 1

By Andrea Sikora Newsome, PharmD

“What about these iron tablets?” Stacy, my program director, asks me.

“The iron tablets?” My voice is incredulous.

She stares at me waiting for an explanation.

“Um…”

It is my second day in the medical intensive care unit (MICU) during my critical care residency. This patient is probably the most complicated patient in the entire unit. He is on four pressors and five antibiotics. Another five medications take care of his ICU prophylaxis measures. He is intubated and sedated (another three medications) and fighting for his life. He has nearly thirty medications prescribed and we are thinking of adding some more. And me? I’m just grappling for even a basic understanding of this patient. He feels infinitely complex to me. I feel like I can barely get my mind around all of his medical problems.

And now, she is asking me about an iron tablet? An over-the-counter (OTC) medication?

“I think it’s a—“

She cuts me off, “A home med? Home med is not an indication.” Continuing a medication because it is listed as a “home med” (an over-the-counter medication that the patient has chosen to take) is considered a cop-out to most clinical pharmacists. Patients go on and off medications all the time. They are frequently prescribed inappropriate medications as well. Most self-respecting pharmacists want to understand exactly why a patient is taking a particular medication, ideally with a patient or family interview to corroborate their discussion with the outpatient pharmacy and review of the medical record. So I admit it: she’s got me there. I have been worrying about other things, and it had slipped lower on my priority list, I mean, it’s not that big of a—

“You probably think it’s not that big of a deal.”

Either I have a terrible poker face or she has given this speech before. With her 25 years of experience in the MICU, I’m hoping it’s the latter.

“You’re probably thinking it’s just an iron tablet. But you know, no medication is benign.”

Stacy is one of the most practical, no-nonsense people I have ever met, and she is rarely someone I have known to become emotional or to wax philosophical, but the next thirty minutes amazed me that an iron tablet could draw such ire and bring on a lecture reminiscent of a dissertation. Iron, it turns out, can cause nausea, vomiting, and gastrointestinal pain (which sound like minor side effects in most drug commercials but can cause an entire litany of unnecessary work-up tests and procedures when a patient is in a hospital), has drug-drug interactions inhibiting the absorption of many other medications, and while rare, iron poisoning can be lethal. “You’re adding another unnecessary variable to an already complex equation with no real benefit.”

Stacy’s lecture was as close to an ethos as one can get.

The key points felt like a simple mathematical derivation.

One. The first dictum of medicine is “Primum non nocere” or “First, do no harm.”

Two. All medications have side effects.

Three. Therefore, no medication is benign.

Four. As a result, every time you prescribe a medication, you are inherently violating “First, do no harm.”

Five. The only way to justify prescribing a medication is that the benefit from treating the condition outweighs the inherent harm of that medication.

Six. Therefore, all medications must have a specific purpose.

Corollary. A medication without a specific purpose is harming the patient. (Whether or not you know it yet).

So despite everything else that was going on with that patient, I interviewed the family and found out that the patient had been recommended iron for anemia but that his last set of bloodwork had been normal. So, while iron was listed on his home medication list, he wasn’t actually taking it. Iron had been ordered by the admitting team under the auspices of being “a home med.” We discontinued the tablet at my recommendation.

Because no medication is benign. 

2017

December 2017

Final Nail in the Addyi Coffin?

By Alycia Hogenmiller

In June, PharmedOut wrote about the death of Even the Score, a fake advocacy group created to sell Addyi. Now a beautiful song to our ears: Valeant has given Addyi back to Sprout Pharmaceuticals. While this deal is not surprising to people who have been following the story, the details of the arrangement are strange.

Valeant is not selling Addyi back to Sprout, instead they are giving the drug back for free and providing Sprout a $25 million loan to cover "initial operating expenses." In return for this deal, Sprout investors will end a lawsuit against Valeant alleging that the company did not adequately promote Addyi.

This deal must be a relief for Valeant, a company shrouded in scandal and financial upheaval since 2015. A Bloomberg article characterized the initial $1 billion buyout of Sprout in not-so-kind words:

"Setting that $1 billion on fire back in 2015 would have been more constructive for Valeant than buying Addyi; at least it would have generated warmth."

With Even the Score gone and Addyi back in the hands of its original owners, will this be it for the famed 'Female Viagra'? For the sake of tired feminist activists, let us hope so. But there is a twitch of movement for this drug. Months ago, Valeant sponsored 'Find My Spark,' an educational campaign created by the American Sexual Health Association to help women take charge of their sex life. The site features Drs. Sheryl Kingsberg and Michael Krychan, both consultants to Sprout and characters familiar to anyone who tracked Even the Score. It doesn't seem as if the website has been catching traction, since prescription sales for Addyi haven't picked up. I suspect I am the only one regularly checking findmyspark.com.

Maybe Valeant realized what we had known all along: there was no market for Addyi. If Valeant had perused the great materials available on PharmedOut, we could have saved them the $1 billion and lawsuit headache. Let us all pray that this is the last we hear of Addyi and we can finally lay this drug to rest.

Alycia Hogenmiller is the project manager of PharmedOut and a law student at American University Washington College of Law.

November 2017

Live from Capitol Hill: McCaskill Investigates Insys Marketing Practices

By Alycia Hogenmiller

On September 12, Senator Claire McCaskill (D-MO) convened a Homeland Security and Governmental Affairs Committee roundtable to examine the marketing practices of opioid manufacturers, focusing on the illegal marketing practices of Insys Therapeutics, the maker of Subsys (fentanyl sublingual spray). Senators Harris (D-CA), Hassan (D-NH), and Heitkamp (D-ND) were also present during the hearing.

The previous week, Senator McCaskill released her first report on her investigation of opioid manufacturers, "Fueling an Epidemic: Insys Therapeutics and the Systematic Manipulation of Prior Authorization." The report focuses on how Insys manipulated the prior authorization process: Insys representatives, posing as staff from a doctor's office, would call insurance companies to obtain approval for patients to use fentanyl off-label. Senator McCaskill's staff uncovered a phone call between an insurance company and an Insys represenative where the employee implied that a patient had cancer, even though she did not, to obtain authorization for fentanyl.

Testifying at the roundtable were Deborah Fuller, mother of Sarah Fuller who passed away from an alleged Subsys overdose; Jeffrey Buchalter, who became addicted to fentanyl after being prescribed extremely high doses of Subsys; Dr. David Fleming, professor at the University of Missouri School of Medicine; and Dr. Fugh-Berman. 

Mrs. Fuller spoke about the devastating loss of her daughter and described the role that Insys played in the death of her daughter. Mrs. Fuller said that the cause of death on her daughter's death certificate should have been "corporate greed". Mr. Buchalter spoke about how he was prescribed high doses of opioids by his physician, who was paid by Insys. Dr. Fleming testified that physicians need better education on opioid prescribing and non-pharmacologic modalities to treat pain.

Dr. Fugh-Berman at the Homeland Security and Governmental Affairs roundtable on Opioids Sales and Marketing.

Dr. Fugh-Berman testified how industry influenced community norms on prescribing opioids through industry-funded continuing education, ghost-written articles, gifts to physicians, and sham advocacy groups. "Industry does not [educate] against its interests. Industry-funded education of physicians is what created this problem in the first place. As long as prescribers are being educated by companies that market drugs fueling the problem, the body count will continue to rise."

The hearing ended with recommendations from the panel on how Congress can help to combat the opioid epidemic. We thank Senator McCaskill for holding this roundtable on an important and pressing issue.

To watch the full hearing, click here. Photos from the roundtable are available here. 

Alycia Hogenmiller is the Project Manager of PharmedOut.

September 2017

RxFiles: Drugs as Innocent Bystanders

By Andrea Sikora Newsome, PharmD

“The patient is thrombocytopenic at 134, so I think we should switch off the Pepcid to a PPI,” the resident says to the team.

A wince briefly passes over my face. The attending catches my expression knowingly, and when the resident finishes, he speaks. “What are this patient’s risk factors for thrombocytopenia? Why don’t we have the students go around in a circle until we can’t anymore.”

Sepsis.

Critical illness.

Infection.

Fungal infections.

HIT.

CRRT.

Cardiac bypass.

Hemodilution. 

Liver disease.

The students are able to go around three times before they start grasping at straws and this was a question just focused on this one patient. If the question had been opened up to any risk factor or cause, we may have been there all morning. Patients in the intensive care unit (ICU) have multiple risk factors for thrombocytopenia and this patient was no exception.

This is an example of what I have started calling the “drugs as innocent bystanders” phenomenon that can occur in the intensive care unit. This is where we blame a drug for something that it probably has nothing to do with and then switch to a less optimal therapy to avoid this purported interaction.

Thrombocytopenia is one of the most common laboratory abnormalities observed in the ICU; by some estimates, more than half of patients are thrombocytopenic at some point in their ICU stay. Indeed, it is so common that once, as a resident, a pharmacist asked me what a “normal” platelet count was. I guessed, “Over 100?” They chuckled at my answer, “I guess for the ICU that is normal.”

Thrombocytopenia is generally defined as a platelet count less than 150 x 103 /µL. Critically ill patients will frequently dip below 100 x 103 /µL. Severe thrombocytopenia, less than 50 x 103 /µL, occurs in about 5-20% of patients; at that level, many surgeries are deferred and thromboprophylaxis with heparin is withheld. Histamine-2 blockers – especially cimetidine – have been associated with thrombocytopenia. However, the numbers are extremely low and most reports are individual case reports in which patients had multiple other risk factors in addition to drug therapy.

Thus, we are faced with a risk-benefit analysis. Should we switch from famotidine, a H2 blocker, to pantoprazole, a proton pump inhibitor (PPI)? Stress ulcer prophylaxis (SUP), previously discussed in this column, is such a rich example of evidence-based medicine (or lack thereof) it is worth revisiting. PPIs have demonstrated superiority in the treatment of gastrointestinal bleeding due to their superior acid inhibition properties; however, this benefit has not translated to SUP in the unit. When it comes to SUP, there is a goldilocks effect. Too little acid suppression (as with antacids) is not as effective in prevention of bleeding. However, too much acid suppression (as with PPIs) is associated with increased infection because the stomach can no longer neutralize bacterial threats.

H2 blockers seem to have the “just right” amount of acid suppression that minimizes bleeding but causes fewer infections. However, an aggressive marketing campaign, among other factors, has led many prescribers to believe that PPIs are superior - despite increased adverse effects and higher costs. As a result, everyone looks for a reason not to use famotidine and thrombocytopenia is an easy target. Ironically, PPIs also have thrombocytopenia listed as an adverse effect but somehow have avoided this bad rap.

“So tell me why you’re making our pharmacist make that face?” The attending jokes with the resident. He has heard my speech on this before and takes the lead.

“Because it is probably all those things and not the famotidine?” The resident replies.

“Exactly,” I say, “famotidine is probably just an innocent bystander in all this.”

Andrea Sikora Newsome, PharmD, is a Clinical Faculty Member at the University of Georgia in Augusta, Georgia

August 2017

RxFiles: When it comes to drug allergies: Is the allergy real?

By Andrea Sikora Newsome, PharmD

“The patient has a reported penicillin allergy, so we put them on aztreonam,” the resident says proudly, content with his knowledge of the patient’s history and aztreonam’s pharmacology.

The patient is floridly septic, and the cultures coming back are reporting gram-negative rods. My mind immediately panics. The patient has been on this drug since late last night. GNR sepsis can kill in hours, and there is a real possibility this patient is not on appropriate therapy.

“Is the allergy real?” I ask bluntly (I admit the coffee has not kicked in yet).

“What do you mean is it real?” The resident asks, a little put out. Sensing my distaste for the antibiotic choice, the resident defends the choice, “It covers Pseudomonas.”

“So about 10% of all patients we see will say they have a penicillin allergy. But only 10% of those reported allergies turn out to be true allergic reactions. And the chances that this patient will have a cross-reactivity reaction to a fourth generation cephalosporin is really small. We don’t have good empiric sensitivities for aztreonam here. So I’m recommending we go to a fourth generation cephalosporin or a carbapenem or we add an aminoglycoside until that culture speciates.”

Aztreonam is a unique antibiotic. The website proudly cites “the structural difference” and shows a picture of the medication’s molecular structure. As the only monobactam, it has markedly less cross-reactivity potential than occurs between penicillins and cephalosporins, or other beta-lactam antiobiotics. From an institutional perspective, however, we face two large problems. First and foremost, its activity against resistant gram-negatives does not stack up against piperacillin-tazobactam, cefepime, or meropenem. At this institution, Pseudomonas sensitivities are approximately 70% to aztreonam compared to 85% and 90% with cefepime and meropenem, respectively. Piperacillin-tazobactam has 96% sensitivity.

The science and statistics of cross-reactivity of antibiotics in the clinical setting is well beyond the scope of this column, but the most important aspect is to realize that a reported allergy is very different than a true Type 1 allergic reaction. Indeed, some reports have studied skin testing those patients with reported penicillin allergies and have found that up to 90% of those patients did not react, or were negative for penicillin allergy.

Thus, we are faced with the common occurrence wherein a more expensive, potentially less effective drug is being utilized because everyone is aware of the factoid about its unique structure but not the institutional antibiogram.

A healthy dose of cynicism in addition to a thorough patient allergy history can ferret out many of these allergies. If I have had the following conversation once, I have had it a hundred times.

“Hi, I hear you have an allergy to penicillin? I was curious what happened.”

“Oh, yes, I’m very allergic to penicillin. When I take it, I get really nauseous.”

Nausea is an intolerance to a medication but is not an allergy and certainly not a reason to avoid using a first-line agent when the patient really needs it. In such cases, it is optimal to perform penicillin skin testing, which has been shown to reduce the inappropriate use of aztreonam and other broad-spectrum agents. This, of course, takes time: time to interview the patient, perform the skin testing, and review the institutions antiobgram. It can be much easier to just pick “that drug penicillin-allergic people can take” but what’s easy is not always what’s right.

When making an evidence-based choice regarding an antibiotic in the situation of a reported allergy, the first question to ask yourself is this: “Is the allergy real?” 

Andrea Sikora Newsome, PharmD, is a Critical Care Pharmacy Specialist at Georgia Regents University, North Augusta, South Carolina.

June 2017

RxFiles: When it comes to drug allergies: Time is money

By Andrea Sikora Newsome, PharmD

“So guess which $5,000 drug we gave to our patient last night that they didn’t need?” The second-year critical care pharmacy resident asks me one morning. He doesn’t wait for me to guess.

“We gave the guy ethacrynic acid.

IV.

For a sulfa allergy.

He takes Bumex at home.

He is taking PO.”

His staccato style of speech emphasizes his frustration.

Ethacrynic acid (Edacrin) is a potent loop diuretic, similar to furosemide (Lasix) or bumetanide (Bumex). It has the unique feature of being just about the only diuretic that does not contain a sulfa moiety. Furosemide, bumetanide, torsemide, hydrochlorothiazide, chlorothiazide, and metolazone all contain sulfa moieties.

The resident’s frustration is two-fold. First, the patient did not need this agent because they tolerate another, far less expensive, agent. Second, IV ethacrynic acid is about 100 times more expensive than oral, and the oral product has excellent bioavailability. Thus, if it really was deemed necessary, we could have used the oral version instead of the intravenous version and saved a considerable amount of money (both for the institution and the patient) with minimal effect on efficacy.

A good allergy history can be very difficult to tease out. First, a great many patients misconstrue an intolerance or a side effect for an allergy. For example, a patient may have an upset stomach with amoxicillin: this is not an allergy. Another patient may report vivid dreams when taking voriconazole: this is not an allergy. A simple conversation with the patient filters out a number of “allergies.” The next step is understanding the type of allergy. Was this a Type I anaphylactic reaction or Stevens Johnsons Syndrome? Was this some kind of rash? Did you have shortness of breath? Have you ever taken a medication with sulfa in it since then?

In speaking with the patient that morning, he did confirm a rash with furosemide but said that he had been taking bumetanide for years with no issues. He has no memory of any antibiotic-related allergies. The entire exchange took less than five minutes.

In this setting, we have driven up medication costs by using a branded medication with a four-figure price tag instead of utilizing a drug that costs less than a dollar – a choice that would have been clear if someone had taken time to speak with the patient. This is not a rare event. Advertising touts Edacrin as an alternative for sulfa-allergic patients, but fails to mention the myriad of recent literature indicating that despite theoretical concerns, rates of cross-reactivity among sulfa drugs appear so low as to be negligible in a vast majority of cases.

This type of cost-saving intervention does require knowledge of pharmacokinetics (to understand that in this particular patient, the difference between IV and PO is a wash) and the pharmacological potential for cross-reactivity of non-antibiotic sulfa drugs (which the latest literature says is very low). But more so than knowledge, this intervention required time and willingness to speak with the patient in person to clarify something reported in the chart. Time certainly is valuable. In this case, five minutes could have saved us $5,000.

Andrea Sikora Newsome, PharmD, is a Critical Care Pharmacy Specialist at Georgia Regents University, North Augusta, South Carolina.

April 2017 

Orphan Drugs: Pharma's New Favorite Child

By Alycia Hogenmiller

In March, the Government Accountability Office (GAO) announced that they will launch a full scope investigation in the Orphan Drug Program at the request of three U.S. Senators (Orrin Hatch R-Utah, Chuck Grassley R-Iowa, and Tom Cotton R-Ark). The Orphan Drug Program was created after the Orphan Drug Act was signed in 1983 by President Reagan. The program was created to incentivize companies to create drugs for orphan diseases (diseases that affect fewer than 200,000 patients). When a drug is approved through the program, the company receives seven years of market exclusivity for the drug.

Since the act was signed, 200 companies have introduced 450 orphans drugs into the market. The value of the program has been called into question after a Kaiser Health News investigation revealed that companies have been exploiting loopholes in the program to "evergreen" their blockbuster products. Many of the drugs that have gone into the orphan drug program have already been on the market. For example, top-selling drugs for non-rare diseases like Crestor (rosuvastatin, a cholesterol drug), Abilify (aripiprazole, an anti-psychotic), and Humira (adalimumab, a rheumatoid arthritis drug) have all received an orphan drug designation. The investigation found that a third of orphan approvals by the FDA have been either repurposed mass market drugs or drugs that received multiple orphan approvals.

PharmedOut applauds Kaiser Health News for their extensive investigation, and Senators Hatch, Grassley, and Cotton for looking into this program. Consumers suffer when companies exploit government programs, preventing generic equivalents from being approved and introduced into the market. This exploitation also hurts patients with rare diseases, as companies need not innovate, instead disguising aging blockbusters as orphan drugs. We look forward to seeing the outcome of this report and hope the program can be overhauled into a truly innovative system to incentivize research into orphan diseases.

Alycia Hogenmiller is the Project Manager of PharmedOut.

March 2017

RxFiles: Should Device Reps Be Involved in Anticoagulant Decisions? Part 2

By Andrea Sikora, PharmD

It is a Friday afternoon, and I am getting ready to go home when I get a call from a nurse in the cardiac intensive care unit (CICU). The conversation was so unintelligible, I cannot even pretend to do it justice. 

Nurse: “I can’t back-calculate this patient’s argatroban dose because it runs through the pump.” 

Me: “Huh?”

Nurse: “Like the pump changes the rate based on its needs, so it’s really hard to know how much he is getting, so I can’t titrate it.”

Me: “What?”

Nurse: “His ACT is really high, and I think I need to come down, but I don’t know how.” (ACT or activated clotting time is a measure of anticoagulation. High means the patient is at risk for bleeding).

Upon entry to the CICU, the nurse shows me the patient’s ventricular assist device (VAD) and explains that this particular device requires a continuous infusion in order to prevent it from clotting. Usually, this infusion is D20W with heparin. The device then decides, based on resistance, how much of this infusion it needs and automatically adjusts flow. Overall, it is a neat device that is life-sustaining for patients in refractory cardiac shock before they can undergo more definitive treatment. Due to a concern about heparin-induced thrombocytopenia (HIT), the patient is receiving argatroban, another anticoagulant, in D20W through the device.

This raises many questions:

1. Is there data for using argatroban with this device? (Answer: no)

2. Is there compatibility data for mixing argatroban with D20W? (Answer: no)

3. Does the patient actually have HIT? (Devices of any kind, especially those that involve a motor, can cause thrombocytopenia.) (Answer: ultimately, no)

4. Can the device be run without an anticoagulant in the infusion? (Answer: potentially, yes)

So I am faced with a situation where there is a mixture of unknown stability providing anticoagulation of unknown efficacy for a device that if it were to abruptly stop would likely cause the patient to go back into cardiac arrest. The ACT is elevated and wet bandages and pink-tinged chest tubes output provide more evidence that the patient is over-anticoagulated, but the nurse and I have no way of controlling how much anticoagulant he is receiving because the pump is in control.

How did we get here? It turns out that because this device has never been studied without an anticoagulant (read: heparin) in the solution, the device representative could not recommend the use of the device without any anticoagulant. Despite an extremely low probability score for HIT, and published evidence describing an extremely low incidence of HIT in patients with ventricular assist devices (thrombocytopenia occurs, but it is not usually heparin-related), the medical team was nonetheless concerned the patient may have HIT. The options would be to go directly against the device representative’s recommendations or ignore clinical suspicion.

Also, through a strange series of events, it turns out that this patient was rushed from another hospital two hours away in an ambulance that broke down not once but twice on the way. In the back was one EMS personnel, one nurse, and the device representative. Together, they kept this critically ill patient alive long enough to reach the hospital. Someone told me that the device representative practically had “God status” after this happened.

Why didn’t anyone call the pharmacist? Healthcare providers dealing with dangerous narrow therapeutic index medications in a critical environment with a patient fighting for his life should not be relying on device reps. Non-standard concentrations are tricky and in this case trickier because a drug with unknown stability and unknown efficacy was used. Argatroban and heparin are both anticoagulant infusions commonly used in the ICU. However, heparin was the only medication studied with this device. There was a very real risk of this patient having a bleed with no way to stop it.

A device rep with no training in patient care may have expertise in how a device works, and a background in business sales, but a rep has no reason to ponder the lack of stability data for argatroban in concentrated dextrose. Stability in solution means you have a clear solution, one that it is safe to give intravenously. When something does not have stability, it precipitates. Or degrades the integrity of the active drug. Instability means either that one is shooting crystals into someone’s vasculature (which can cause cardiac arrest or stroke depending on where they lodge) or simply administering an inert product.

Only pharmacists spend their formative healthcare years thumbing through dusty textbooks reading about what precipitates in solution and what does not. Much of the healthcare system is designed around the first very simple point: first, do no harm. Patient safety is the reason why multi-disciplinary teams exist and why approval bodies within institutions exist. We had once again circumvented this process, which the patient bearing this risk.

When I explained my concerns to the team, they were shocked at the implications. We ultimately decided on a different regimen for the patient. Fortunately, the next time a similar situation came up, they called, “Hey, got a question about heparin?” I said, “Hit me.”

Andrea Sikora Newsome, PharmD, is a Critical Care Pharmacy Specialist at Georgia Regents University, North Augusta, South Carolina.

February 2017

Rx Files: Should Device Reps Be Involved in Anticoagulant Decisions? Part 1

By Andrea Sikora Newsome, PharmD

“This is the wrong heparin drip!” A nurse from interventional radiology (IR) berates one of the surgical ICU nurses. “You shouldn’t let pharmacy change it. They don’t know what they’re doing!”

As the surgical ICU pharmacist, I come over to see about the commotion. The IR nurse proceeds to explain that “pharmacy” has changed the heparin to the “wrong” concentration (the change was to the standard concentration for the institution). She hands the pre-printed orderset to me, and it is one I have never seen before. She proudly explains that she and a medical device sales representative devised it. The device in question is a novel device used with the anticoagulant heparin to aid with catheter -directed thrombolysis for various types of clots including deep venous thrombosis, arterial thrombosis, and pulmonary embolism. It is a great advancement in technology for a specific patient group, and medical literature supports its use.

“The bottom line is that pharmacy didn’t use this orderset,” she says to me.

“May I have a copy of this?” I ask. “Any pre-printed orderset requires pharmacy review and committee approval to make sure it complies with our safety standards.”

It has not gone through any such approval process. This violates our institutional policy regarding safe medication practices. Every protocol, guideline, and orderset undergoes committee approval specific to the content (i.e., an antibiotic orderset would undergo Infections Disease Committee review). Prior to this process, the document is vetted by multiple pharmacists and physicians and reviewed by the policy pharmacist to ensure accuracy, safety, and best practice.

Medical device sales representatives can be valuable sources of information about devices, but they are not health care providers and their role should be informational. It remains the responsibility of the healthcare team to interpret the medical literature and evaluate practices.

When I contacted the company about the issue, the device rep noted that he had been involved with the case on both days due to the machine malfunctioning and in that time made recommendations regarding heparin concentrations and flow rates as part of the troubleshooting process.

Quite simply, non-medically trained salespeople are recommending medication therapy without the medication expert (read: pharmacist) involved in the process. As device representatives, they have minimal pharmacy training, and as non-hospital personnel, they have limited institutional context to bring to these recommendations.

Heparin is a narrow therapeutic index drug with potentially lethal effects when misdosed. Dosed in units and often weight-based, it is ripe for medication error. Perhaps the most high profile case occurred in 2008 with Dennis Quaid’s premature twins, when a nurse delivered a 1,000 fold overdose as a result of mixing up two heparin products. It is an easy, albeit terrifying, mistake to make because most hospitals  carry varying concentrations that are easy to  confuse in a hurry. Although barcode scanning and other safety measures decrease errors, it is still relatively easy to incorrectly program a pump or create the wrong admixture. The Institute for Safe Medication Practices (ISMP) cites heparin as a high-alert medication and The Joint Commission ranks heparin among its National Patient Safety Goals for a reason: it’s dangerous. While it may seem overly cautious to only allow one heparin concentration in an entire institution, it reduces error in the preparation, dosing, and administration of the medication, and to deviate from a safe practice policy requires diligent thought (not to mention approval).

The general disregard for how the device and the heparin used with it affects the actual patient was frustrating, and the willingness to rely on a medical device salesperson’s opinion about a medication over a pharmacist’s opinion was worrisome. Layers of review are not silly bureaucratic hoops – they are part of a necessary safety process. It is a reminder that the bottom line should always be patient outcomes.

Andrea Sikora Newsome, PharmD, is a Critical Care Pharmacy Specialist at Georgia Regents University, North Augusta, South Carolina.

January 2017

Live at the FDA: Battling Off-Label Promotion

By Alycia Hogenmiller

On November 9 and 10, 2016, PharmedOut attended an FDA stakeholder meeting on "Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products" during which companies made the case that the FDA should permit companies to promote products off-label.* Dr. Fugh-Berman, Joy Eckert (DCRx project manager), and I testified on the second day. Dr. Fugh-Berman and my testimonies can be viewed here (starts at 1:55). Joy Eckert's testimony can be viewed here (starts at 33:00).

Dr. Robert Califf, the current FDA commissioner, provided opening remarks that cited cases where unapproved uses later proved dangerous (such as antipsychotics). In an unusual move, he attended much of the meeting, engaging with the speakers and asking tough questions on how to deal with harms that go along with off-label use and how the first amendment shapes the role of FDA policy.

In total, 60 people testified, with 30 advocating for allowing off-label promotion and 27 people testifying against. Three people’s testimonies were unclear on what position they took on off-label promotion.

People who supported off-label promotion were representated by pharmaceutical and device companies (including Medtronic, Pfizer, Merck, and Genentech), industry groups (including PhRMA, BIO, and the Medical Information Working Group), industry vendors (such as G&M Health, OneSource Regulatory), industry law firms (including the Washington Legal Foundation), and industry-funded patient groups (including the National Alliance on Mental Illness and the Lupus Foundation). Speakers cited “chilling of medical innovation”, “getting physicians and patients more information”, and the first amendment as reasons for the FDA to allow off-label communication. Industry had a consistent message that drugs were beneficial and that blocking off-label communication prevented patients from obtaining the full benefit of these drugs, and that busy physicians had few other avenues for accessing this information. Industry representatives did not address the harms of drugs and, when directly asked questions about harms, did not answer the question.

Two insurance companies (Anthem and Humana) testified that they do not support off-label promotion for physicians and patients, but wanted the FDA to allow off-label communication with payers so that they are able to plan their yearly budgets.

People who spoke about why off-label promotion should not be allowed were researchers from Yale Law School, GW Milken Institute School of Public Health, and Harvard Medical School, non-pharma-funded consumer advocacy groups (Public Citizen, National Women’s Health Network, Consumer Reports), and patients hurt by off-label use of medications. Patients spoke about how they or loved ones were hurt by an off-label use of a drug that they did not know was off-label. Consumer groups spoke about how off-label drug promotion harmed public health as it would disincentivize companies from doing research on the efficacy of their drugs or submitting a new drug application. PharmedOut spoke about how information from industry about off-label use is always misleading because companies are incentivized to promote the benefits of a drug and downplay harms or lack of efficacy.

On December 14th, the FDA announced that it would extend its public comment period to April 10, 2017. Comments can be submitted to www.regulations.gov with the docket number FDA-2016-N-1149.

*Drugs are approved for specific “labeled” indications (for a specific disease or condition). Physicians are allowed to prescribe drugs off-label – for something other than the approved indication – but it is currently illegal for companies to promote drugs off-label.

2016

December 2016

RxFiles: Staying Up to Date

By Andrea Sikora Newsome, PharmD

“Well, UpToDate says that PPIs are superior for stress ulcer prophylaxis.”

As a pharmacist, most sentences starting with “UpToDate says” do not bode well. UpToDate is one of several electronic tertiary resources that attempts to summarize a myriad of medical topics ranging from seasonal allergies to management of neuromuscular blockade in acute respiratory distress syndrome. Overall, these resources provide a wealth of information. The figures and flowcharts are top notch. Plus, it provides primary literature citations that links directly to Medline. The issue is user error, wherein a resident reads the one-liner on a topic and does not dig any deeper.

This particular resident was replying to my recommendation that we utilize famotidine over pantoprazole for stress ulcer prophylaxis (SUP). Although this is an area of some clinical controversy, many clinicians interpret the available literature as saying that famotidine and other histamine two (H2) receptor blockers provide similar stress ulcer protection to pantoprazole and other proton pump inhibitors (PPIs), and that H2 blockers may have a reduced incidence of infections like ventilator-associated pneumonia, Clostridium difficile infections, and other infections. The cost difference has historically been very significant as well (although as PPIs become generic, this difference has diminished). Thus, in the absence of a compelling indication for a PPI, H2 receptor blockers are generally considered the preferred agent for SUP.

About every eight weeks, a resident explains what UpToDate says to me about PPIs, so my answer is already prepared. “I know the line you’re talking about, but have you read the 2013 Critical Care Medicine meta-analysis it actually cites supporting that statement?”

So far, none of them have, which is really unfortunate. First and foremost, the information they have is incomplete, compromising the quality of patient care delivery. Secondly – perhaps more disheartening – it implies that residents do not appreciate how much of medicine is practiced where there are no absolute answers. Realizing how rarely one can assuredly cite a medical fact like “Smoking is globally detrimental for your health” is an important concept to appreciate. The line the residents were citing (“For critically ill patients who are able to receive enteral medications and in whom stress ulcer prophylaxis is indicated, an oral proton pump inhibitor (PPI) is preferred rather than an alternative prophylactic agent.”) sounds definitive but warrants further investigation.

If the resident had even just pulled up the abstract, they would have noted caveats. The abstract cautions, “The robustness of this conclusion is limited by the trial methodology, differences between lower and higher quality trials, sparse data, and possible publication bias.” If one went a step further to read the actual discussion of the article, the authors dedicate an entire paragraph to recommending “cautious interpretation of these results” due to trial quality (lack of blinding, poorly defined endpoints, etc.) and evidence of publication bias. 

This practice of just reading the one-liner appears disturbingly pervasive, especially when I see this cited in medical notes in the patient’s chart. Truly staying up to date requires a love of learning and playing devil’s advocate to what you read.

Andrea Sikora Newsome, PharmD, is a Critical Care Pharmacy Specialist at Georgia Regents University, North Augusta, South Carolina.

November 2016

RxFiles

By Andrea Sikora Newsome, PharmD

"Uh! Uh! Uh! Uh!" The nurse shouts sternly, as she runs over to stop the patient from pulling his IV out of his hand. The patient is a cantankerous man at baseline, had suffered a complicated hospital course and appeared to be floridly positive for ICU delirium. (An evidence-based screening tool for delirium is available at icudelirium.org. Of note, questions like "what is your name?" or "where are you right now?" are not validated as tests for delirium). We had started olanzapine, an atypical antipsychotic. It had shown little effect, but what else could we do?

Sitting at my rounding table, I watched as the physical therapist came into the room. She was a stocky, middle-aged woman with her dark hair pulled back in a tight bun, white streaks showing in some parts. It strikes me that she was the only African American staff in the unit and the patient was the only African American patient in the unit. More importantly, she seemed an equal match for his personality. The patient must have tried some funny business on her, because she immediately says to him in that strict-but-affectionate schoolteacher tone, "Oh honey, I know you didn’t just try that funny business on me." Duly reprimanded, he quiets down, and they get to work. She spends the next hour with him, berating him, albeit in an affectionate tone. "Oh, you’re a strong man, I know it, I can feel it, why are you stopping now? Don’t you slack off now." She does mobility exercises, strength exercises, occupational exercises. She asks him questions about his family. She leaves him with "Bye sugar."

Looking up from my computer, I see him sitting up high in bed, his cheeks flushed, a slight sheen of sweat on his forehead. We make eye contact and we nod at each other in mutual acknowledgment. His nurse comes by, and he politely requests some water. The nurse then tells me she plans to hold the olanzapine because he is so alert and calm, even oriented and pleasant. I agree and recommend this to the resident. The resident is amazed, but why?

We have taken this man from his home, opened his chest, isolated him from his family, and stuck him with at least a half dozen lines and tubes. He finally got an hour of what most every human being crave. We gave him one-on-one attention, a sense of purpose, conversation, and physical touch. We gave him physical activity. We stimulated his mind and his body, and he responded. Who wouldn’t feel better if they had enjoyed a stimulating conversation, an invigorating workout, and a relaxing massage? Sadly, PT positions are limited, while olanzapine is plentiful. Compared to the costs of a full-time staff position, olanzapine is a steal. The only problem is that it doesn’t really work. In comparison to the documented costs of delirium, maybe PT is the real steal here.

Andrea Sikora Newsome, PharmD, is a Critical Care Pharmacy Specialist at Georgia Regents University, North Augusta, South Carolina.

October 2016

FDA Caves to Patient Pressure

By Alycia Hogenmiller

On Monday, September 19, the FDA approved eteplirsen (Exondys 51). Produced by Sarepta Therapeutics, eteplirsen is a drug for Duchenne Muscular Dystrophy (DMD), a genetic disorder that is characterized by progressive muscular degeneration.

From the beginning, this approval has been mired in controversy. During the FDA advisory committee meeting to evaluate the drug, the FDA expanded the time for the open public hearing and moved the location to a larger room to accommodate all of the people signed up to speak. Testimony was given by children with DMD, their parents, and lawmakers urging the FDA to approve the drug. Of the 52 people that testified, only 1 person (from National Center for Health Research) spoke out against approval of the drug.

The evidence for this drug was based on an open-label 12 person study, with a post hoc comparison with untreated patients used as a historical control group. The study found that there was a 1% increase in dystrophin (a muscle protein). AFter debating whether this increase in dystrophin conferred a clinically meaningful benefit, the committee voted 7-3 against the approval of the drug, with 3 members abstaining. Documents for the advisory committee hearing can be accessed here.

Although the decision was scheduled to be announced on May 26, controversy raged inside the FDA as the decision was delayed for months. Janet Woodcock, Director of the Center for Drug Evaluation and Research, approved eteplirsen against the recommendation of the review team. In an unusual move, two FDA reviewers, Dr. Ellis Unger and Dr. Luciana Borio, wrote an appeal letter to Robert Califf, the FDA commissioner. Commissioner Califf deferred to Janet Woodcock's decision to approve the drug. In the same memo, however, Califf also stated that the only published study of eteplirsen's efficacy should be retracted. This brings up the question of what basis the FDA thad for approving an ineffective drug.