Monthly Newsletter Column
New and Convenient Does Not Equal Better and Safe
By Judy Butler
Opioid Marketing Tactics: The Old and the New
By Judy Butler
Why is the AMA Promoting Opioid Use?
By Judy Butler
The House and the Senate Take on Opioid Marketing
By Judy Butler
McKinsey Proposed What to Purdue?
By Judy Butler
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.
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.”
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 , 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.
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.
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.
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.
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.
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?
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!
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.
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.
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.
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 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.
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.
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.
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.
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.
Alycia Hogenmiller is the Project Manager of PharmedOut.
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.”
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
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.
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.
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.
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.
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.”
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.”
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:
Is there data for using argatroban with this device? (Answer: no)
Is there compatibility data for mixing argatroban with D20W? (Answer: no)
Does the patient actually have HIT? (Devices of any kind, especially those that involve a motor, can cause thrombocytopenia.) (Answer: ultimately, no)
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.
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.
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.
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.
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.
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.
This controversial approval will open the doors for Pharma to use patient advocacy groups to pressure the FDA to approve more ineffective – or dangerous – drugs. That hardly creates an incentive left for pharmaceutical companies to create drugs that work.
By Andrea Sikora Newsome, PharmD
“Don’t you put that damn thing on me again!” The patient hollers over the white noise of empty IV pump alerts and ventilator alarms. The nurse is trying to replace the patient’s condom catheter. At this point, other nurses are filing in, and the resident looks up and asks me what the dose is that I would recommend for quetiapine (Seroquel, an atypical antipsychotic, with some data supporting its use for ICU delirium, though this is an off-label use). The patient continues in a raised voice, “It hurts, and I’m plum sick of wetting all over myself.” His voice is angry, frustrated. This broad-shouldered, 6-foot man who works with his hands is now barefoot in an open-back gown in a room smaller than a prison cell, and the nurse wants to place a sticky plastic condom catheter on him. I shake my head at the resident, “Sounds like a pretty reasonable argument to me. He isn’t delirious. You think you’d want to wear one of those things?”
Delirium is a leading cause of agitation in the intensive care unit. Defined as a lack of attention, waxing and waning in nature, it makes people answer the question, “Does a stone float on water?” “Yes.” It is associated with increased length of hospital stays and mortality. But this wasn’t ICU delirium, this was a man giving a rational argument regarding his preferences. “I think the bigger question,” I continued, “is if we really need accurate ins and outs on him.” This sparked a conversation with the patient, and he ultimately agreed to measure his urine output for us.
“You know for being a pharmacist, you spend a lot of time telling us not to use drugs,” someone says. “Only the ones that won’t help,” I reply. The team laughs, but in some way, becoming an expert means not just knowing about our tools but knowing about their limitations, and knowing where there are gaps in our knowledge. Expertise is knowing enough to realize all that we do not know.
Delirium is deeply misunderstood by many practitioners. Many patients become disoriented, and we often don’t do the little things that make a difference - like turning the lights on in a patient’s room. Instead, we rely on pharmaceutical restraints. Vanderbilt’s ICU Delirium study group (icudelirium.org) has excellent resources on the topic and recommends that clinicians STOP and THINK. This approach recommends stopping offending agents and interventions that may be causing delirium and then thinking about and working up possible causes of delirium such as electrolyte imbalances or sepsis.
In this case, the patient just needed something stopped, not started.
Salespeople in the Surgical Suite
How does a surgeon choose which hip joint or other device is surgically implanted into your body? That may depend on which medical device representative (“device rep”) the surgeon relies on when they go into surgery.
Our new study in PLOS One explores the relationships between surgeons and device reps and how these relationships impact patient care. The authors did in-depth interviews with 14 orthopedic and ENT surgeons, three former and current medical device reps, and a former medical assistant to an orthopedic practice. This is an enthographic study - one that documents the beliefs and practices within a culture (in this case the occupational cultures of surgeons and device reps) from the perspective of people within that culture.
We found that medical device representatives not only sell surgeons the tools they use in the operating room; they have also become integral members of the OR team, standing by to assist in the use of their company’s products, if needed, during joint replacements and other surgical procedures. The device reps provide information regarding the newest products and presumed improvements in implantable devices, as well as the availability of relevant training sessions offered by their companies. Surgeons often develop close working relationships with specific device reps and rely on their expertise to enhance efficiency in the OR and, should an unexpected problem arise, to aid in trouble-shooting. It is the device reps’ job to cultivate these relationships, the avowed objective of which is optimal patient care. But is patient care helped or harmed by the promotion of the newest, relatively untested devices by unregulated surgical assistants who receive commission on every device sold? There are also issues of informed consent, as many patients don’t know that a salesperson in scrubs will attend their surgery.
Our study reveals ethical dilemmas and financial considerations in the recommendation of specific products; challenges the adequacy of continuing surgical education; calls for earlier device safety and efficacy data gathering and dissemination; and suggests that neutral entities may be able to provide the services currently provided by industry representatives. Several hospitals, including Loma Linda (Calif.) University Medical Center, have trained hospital personnel to replace sales reps as surgeon assistants – and have cut the price of implants in half.
Our study is available at: http://dx.plos.org/10.1371/journal.pone.0158510.
Blood Money: Pharma targets people with hemophilia
Physicians have been targeted by drug companies with gifts, meals, and money for decades, but the use of the same tactics on patients is virtually unknown. PharmedOut’s investigation of Direct-to-consumer Marketing to People with Hemophilia is the first to document pharmaceutical companies’ use of gifts, jobs, copays and other financial incentives to be published in a medical journal. Andrew Pollack first broke the story in the New York Times in January.
A years worth of factor (which people with hemophilia need to help their blood clot properly) can range from $60,000 to $300,000. Because hemophilia is a genetic, lifelong disease, gaining the loyalty of a single hemophilia patient can mean millions of dollars worth of business.
At a young age, people with hemophilia attend camps where camp counselors are drug reps. As they get older, patients are given college scholarships, internships, and jobs. Companies offer to help patients fill out insurance papers and cover the co-pay for their factor.
Patient organizations, including the National Hemophilia Foundation, receive a lot of funding from Pharma. Our paper questions whether industry funding creates industry mouthpieces of advocacy organizations and buys silence on questions about what the best therapies and regimens are.
We hope this article raises awareness that Pharma's attention follows marketshare, and that whoever controls market share, whether that is prescribers, patients, or payers, will receive the most attention from pharma. There are now ongoing efforts to limit – and disclose – physician interactions with pharmaceutical companies. What limitations and disclosures need to be put in place for patients – and patient advocacy organizations?
Stuffed animals and a beach ball for specialty pharmacies that supply factor.
Frisbee, coffee mug, lanyard, and coloring book for Novo Nordisk's 'changing possibilities in hemophilia' campaign.
Pharma Backed Co-Pay Charities
Consumers are protected from the actual cost of drugs. Most Americans have insurance with tiered coverage for prescription drugs; generic drugs may have little to no co-pay, branded drugs have a higher copay, and unnecessarily expensive drugs have the highest copay. This is how payers attempt to incentivize rational use of prescription drugs. Pharmaceutical companies calculated that consumers don’t care how much drugs cost, they only care how much they pay, so they launched programs covering drug copays. It took more thought to get around Medicare, which considers direct gifts to its beneficiaries illegal kickbacks.
Enter the copay charities, also known as patient-assistance charitable organizations. A great Bloomberg Businessweek expose by Ben Elgin and Robert Langreth exposed Patient Services Inc (PSI), the Patient Assistance Network Foundation (PAN), the Caring Voice Coalition, Good Days from CDF and other copay charities, which receive almost all their funds from pharmaceutical companies. The seven largest copay charities received over a billion dollars in pharma contributions in 2014. A good investment. As a PSI newsletter stated, “We provide a way for pharmaceutical companies to turn their ‘free product’ programs into revenue by finding long-term reimbursement solutions”. The “charities” provide public relations cover to pharmaceutical companies – how magnanimous for them to help patients – but in fact they allow companies to skirt the law. By paying copays, pharma enables patients to start and stay on expensive drugs. Copay “charities” favor donor’s drugs, thus bilking Medicare into footing the bill for outrageously priced drugs.
These skeevy relationships are starting to draw attention. Gilead Sciences Inc, Biogen Inc, Jazz Pharmaceuticals PLC, and Valeant Pharmaceuticals have all received subpoenas related to copay “charities”.
Pharmaceutical companies are allowed to give away drugs for free. If they really cared about saving patients money, that’s what they would do.
Pharma Should Invest in Take-Back Programs
By Nicole Dubowitz
This month, pressure has ramped up on pharmaceutical companies to fund drug take-back programs, regionally or nationally, that will ensure safe drug disposal and keep unused products out of their homes or waterways.
Unused prescription medication, especially pain medication, is often kept in the house "just in case." In a 2015 survey of young adults, a third said it would be easy for them to find opioids, most frequently from a parent's or friend's medicine cabinet. And flushing drugs down the toilet can land them in municipal water supplies; a 2008 Associated Press investigation found the drinking water of at least 46 million people to be contaminated with antibiotics, hormones, seizure medications, blood pressure medications, and antidepressants.
Currently, drug take-back programs are voluntary and managed by local governments. You may have heard about "drug take-back days" or events near you (National Drug Take-Back Day was April 30) hosted by law enforcement officials to ensure your drugs get disposed of according to DEA guidelines. But with varying levels of funding or organization, availability of programs vary widely state-to-state or county-to-county.
Due in part to panic over the opioid epidemic, interest has peaked in getting pharmaceutical companies in on the programs. Seven counties in California and one in Washington state have adopted laws requiring industry buy-in, and laws have been proposed in New York State and additional Washington, Illinois, and California counties. In March, Massachusetts Governor Charlie Baker (R) signed a landmark opioid bill that required take-back program funding from drug companies.
Rep. Louise Slaughter (D-NY) is thinking bigger by introducing a bill that would require pharmaceutical companies to contribute financially to programs nationwide, probably according to their market share. Her call is echoed by 22 socially responsible investment funds recently imploring large drug makers to provide a national program. Their joint letter states "Most U.S. communities lack free, convenient, ongoing collection programs that could help alleviate these problems. [...] We believe that companies that put medications on the market and profit from them should be primarily responsible for take-back.”
How could drug companies be opposed, given their supposed eagerness to curb the opioid epidemic? As summarized in Fortune, they like voluntary campaigns on drug disposal, but say it is "unfair" for legislation to "shift the cost burden of a traditionally local government function to out-of-state and even international drug manufacturers." Big Pharma even challenged Alameda County's ordinance on these grounds in California, but the Supreme Court declined to hear the case. So, the circuit court's opinion held that these laws "don’t unfairly discriminate against companies or burden interstate commerce."
It is not proven that drug disposal programs are important in mitigating opioid overuse; there are many other issues with the industry and prescribers to address. However, the debate has raised the important point that Pharma should be held responsible for the effects of their products, once the drugs are no longer needed.
ProPublica Proves Why Lunch, and Other Gifts, Matter
By Nicole Dubowitz
For years, ProPublica has provided a public service by culling data into meaningful tools for healthcare consumers. Dollars for Docs is an easy-to-use database that allows you to find out how much money the pharmaceutical and device industries spent on, or gave to, your physician last year, and the Surgeon Scorecard assesses surgeons based on death and complication rates they have experienced for eight elective, common surgical procedures.
ProPublica has also been a standard-bearer in using this data to investigate important and fascinating stories. In March, they used 2014 physician payment records from pharmaceutical and medical device companies and matched them with Medicare prescription data for doctors.
The result is an eye-opening finding about how industry payments affect prescribing for Medicare beneficiaries and, quite possibly, other patients: "Doctors who got money from drug and device makers—even just a meal—prescribed a higher percentage of brand-name drugs overall than doctors who didn’t ... Indeed, doctors who received industry payments were two to three times as likely to prescribe brand-name drugs at exceptionally high rates as others in their specialty."
This comes as no surprise to PharmedOut, since our mission is to raise awareness about how industry marketing, particularly that which targets physicians, influences their prescribing decisions. And, how even gifts as small as lunch can make physicians feel subconsciously beholden to industry. It's a psychological phenomenon that we've written about and presented on, but that there has been relatively little research in this area.
That is what makes ProPublica's study so monumental to this cause. Even though it is common knowledge in the medical community that generic medications work just as well as their brand-name counterparts, and save patients and other healthcare payers money, industry payments have effectively given physicians temporary amnesia on this front.
As ProPublica notes, their analysis does not go so far as to point to the influence of one company or category of drugs. What it does show is that the systemic use of industry payments is having its desired effect: to boost branded drug prescriptions among targeted physicians.
Harvard Medical School professor and advocate Aaron Kesselheim is quoted as saying, "it again confirms the prevailing wisdom … that there is a relationship between payments and brand-name prescribing. This feeds into the ongoing conversation about the propriety of these sorts of relationships. Hopefully we're getting past the point where people will say, 'Oh, there's no evidence that these relationships change physicians' prescribing practices.'"
Yes, we hope so, too. Thank you ProPublica!
Problems with Clinical Trials
By Nicole Dubowitz
We rely on clinical trials of drugs to be held to the highest scientific standards. FDA uses trial results to approve treatments for their safety and efficacy, and doctors trust peer-reviewed journals to share accurate information about new treatments.
But in February, and in many months before that, we have repeatedly heard about trials that aren't up to par, whether in their design or reporting of results.
Here are three top ways clinical trials can be manipulated:
1. Industry influences study reports. This was a primary concern raised in Dr. Robert Califf's nomination for FDA commissioner. His research institute at Duke University took ample pharmaceutical industry funding, and during confirmation hearings, he was questioned about industry's role in studies.
Califf explained that while drug companies consult in study designs, academic researchers have the "final say." That may be, but the link between industry funding and more favorable results has been proven repeatedly.
2. Not reporting at all. Since the U.S. does not require the registration or reporting of all clinical trials, researchers often is not published. Last month, it became apparent that this is systemic at academic institutions: One-third of clinical trials conducted at 51 top U.S. universities and academic hospitals were never published in a peer-reviewed journal or government registry, according to a new BMJ study. Two-thirds of all the trials were not published within two years.
As one of the study authors wrote in NPR, "Not reporting results violates the basic principle of the scientific method. It hurts patients, society and science. It also dishonors the people who gave their consent and bore the risk of participating in the studies. Who would agree to be in a study with the knowledge that the results wouldn't be shared?"
All clinical trial results should be reported.
3. Outcome switching. Before starting a clinical trial, researchers are supposed to pre-specify which outcomes they are studying. Doing this makes it easier to see whether outcomes have been switched. Researchers shouldn't pick and choose which outcomes to reveal.
Journals are supposed to check for outcome switching, but too often, they do not, and cherry-picked outcomes get published, presenting false impressions of drugs. As the COMPare project reports, a recent PLOS One review of 137 randomized controlled trials found that 18% had some form of discrepancy relating to the primary outcome, 15% changed the definition of the primary outcome, and 64% of the trials had discrepancies between pre-specified and reported outcomes for non-primary endpoints.
The FDA, academic institutions, and medical journals must commit to raising expectations for clinical trials. If they don't, who will?
Pharma's Role in the Opioid Crisis
By Nicole Dubowitz
As we know from the headlines, opioid addiction and its devastating effects have been building for the past couple of years. State by state, local governments and law enforcement have worked to address the drug's prevalence in their communities, and last December the Centers for Disease Control and Prevention (CDC) announced that opioid overdose deaths hit a record high in 2014.
But doctors could have seen this coming since the 1990s. They were targeted with an onslaught of advertisements, events, and free CME opportunities in the last decade that encouraged more generous painkiller prescribing. They were pressured by patient groups that lobbied heavily for more access to treatment.
Each mechanism shared a common denominator: They were sponsored by pharmaceutical companies, who were most interested in making a profit off of painkiller sales.
The liberal prescription of opioids is a major contributor to the annual opioid overdose death toll — which now exceeds car crash fatalities. And drug companies cannot just pin it on heroin — as U.S. News reported, "People are 40 times more likely to be addicted to heroin if they are addicted to prescription painkillers. Abuse of prescription painkillers is incredibly common — one in 20 Americans age 12 and older reported using painkillers for non-medical reasons in the past year." Prescription drug abuse is still more common than heroin abuse, killing more people than heroin and cocaine combined. Also, the skyrocketing heroin addiction rate is fueled by addicts who switch from prescription opioids to heroin, which is cheaper and more readily available.
Now, Pharma pretends to be part of solution, as they publish new guidelines for physicians and tout their research on abuse-resistant formulations of drugs they are overpromoting. But if the astroturf patient advocacy groups and new child-size dosages are any indicator, Pharma’s eyes are still firmly fixed on the bottom line.
Unethical Trials on Unethically Long Shifts
By Nicole Dubowitz
In 2009, the Institute of Medicine (IOM) recommended that medical residents work no longer than 16 hours at a time without sleep. They cited studies that show "the detrimental effects of fatigue on human performance," especially a concern when relatively inexperienced doctors are making life-or-death decisions about patients.
Some critiqued IOM's report, saying that residents needed more training and that shorter shifts would lead to worse care coordination for patients. One study at the Johns Hopkins University Hospital found that shortened shifts did not increase residents' sleep but did decrease "educational opportunities", and that residents handed off patients up to three times more often. Researchers argued that handing off patients to the next team is a "known risk factor" for medical errors.
In an effort to find out whether more sleep for residents really leads to better outcomes, two randomized studies are currently comparing IOM's recommendations versus 30-hour shifts at teaching hospitals. However, the institutional review boards that approved the studies concluded that these studies presented only "minimal risk" to doctors and patients, and waived the requirement to obtain informed consent for all subjects. Therefore, patients and doctors did not need to be notified that they were enrolled in a study or have a reasonable chance to opt out.
These studies, and the notion of going back to 30-hour hospital shifts, are unconscionable. Even if patient outcomes are not markedly improved by shorter resident shifts, doctors should know better than anyone that sleep is a physiological need that cannot ethically be deprived.
Working for that many hours presents more than a "minimal risk" to doctors and patients. As Public Citizen said in a statement, "Substantial evidence shows that sleep deprivation due to excessively long work shifts increases the risk of motor vehicle accidents, needle-stick injuries and exposure to blood-borne pathogens and depression in medical residents." One resident at a hospital taking part in the studies likened working 30 hours straight to "essentially working while intoxicated."
A doctor's impaired judgment obviously puts patients at risk in a way they are also uncomfortable with. A national study found that out of 1,200 respondents, only one percent approved of shifts longer than 24 hours. Eighty percent said that they would want to be told if their resident physician had been awake longer than that, and another 80 percent said they would ask for another doctor. The patients in these two studies do not have that luxury.
The American Medical Student Association and Public Citizen wrote to The Department of Health and Human Services and the Accreditation Council for Graduate Medical Education to call for the end of the studies. See their letters and more information about the studies and participating institutions here.
Doctors Speak Out on DTC Advertising
By Nicole Dubowitz
In November, physicians at a meeting of the American Medical Association (AMA) voted in support of a ban of direct-to-consumer (DTC) drug advertising. AMA Board Chair-elect Patrice A. Harris said the vote "reflects concerns among physicians about the negative impact of commercially-driven promotions, and the role that marketing costs play in fueling escalating drug prices ... direct-to-consumer advertising also inflates demand for new and more expensive drugs, even when these drugs may not be appropriate."
DTC drug advertising is only allowed in two countries: New Zealand, since 1981, and the United States, since 1997. Although some print ads appeared in U.S. publications before then, FDA's new guidelines in 1997 effectively allowed for broadcasted pharmaceutical ads by implementing an “adequate provision” standard for risk information.
According to market research firm Kantar Media, television ads make up the majority of drug advertising ($2.8 billion out of $4.5 billion spent in 2014). Expenditures had dipped since 2006's peak of $5.4 billion, but 2014 represents the highest spend since that year.
It is essential to note that while the AMA is taking issue with DTC advertising, targeting the public through television, radio, and mainstream publications, Pharma spends much more on marketing to physicians — $24 billion in 2012. This has been primarily done through detailing (drug rep visits and promotions), free samples to physicians, and educational and promotional meetings. A relatively smaller fraction of $90 million was spent on print ads in medical journals.
Still, DTC advertising reaches a vast population and leads to major ROI. Online advertising has been most lucrative, with data showing a 5:1 ROI in past years. And the average American television viewer is said to watch up to nine drug ads a day, totaling 16 hours per year. A 2015 survey by Treato, a pharma analytics firm, found that 21% of respondents said they talk to a doctor about a drug or treatment after watching a TV ad, and an additional 5.8% suggest the treatment to someone else.
What is the likely outcome from the AMA vote? Thus far, pharmaceutical companies have successfully deflected calls for restrictions on marketing by citing their right to free commercial speech. One of the arguments made by DTC advertising proponents is that the ads promote provider-patient dialogue and strengthen their relationship. But ads are often inaccurate and may encourage overprescribing.
A DTC advertising ban would require Congressional action. AMA certainly may have the clout needed to make a difference as the #2 lobbyist to Congress this year.
To avoid the Constitutionality argument of a full-out ban, more regulation may be a logical intermediate step. Rep. Jarrold Nadler (D-NY) introduced the Say No To Drug Ads Act, most recently in 2013, which would have amended the IRS Code to prevent drug companies from claiming tax deductions for the cost of DTC ads. Perhaps with the momentum of the AMA announcement and hopefully, their support, Rep. Nadler or another member of Congress will reintroduce this common-sense piece of legislation.
By Nicole Dubowitz
After completing four rigorous years of medical schools, and up to six more in residency, doctors in 46 states are required to obtain continuing medical education (CME) credits every year in order to keep up with the medical times and retain their licenses to practice. After all, why wouldn't we want our physicians to continue learning about the latest updates in medicine?
Like communism, what sounds good in theory does not always work in practice. CME has unfortunately been an example of that. The issue received increased attention this past month thanks to John Fauber's coverage in the Milwaukee Journal-Sentinel and their four-part series "Risk/Reward", on various ways in which how the pharmaceutical industry funds CME in order to promote new or upcoming drugs to doctors.
We have talked about bias in CME before; in fact, it is one of the first issues PharmedOut addressed when we formed in 2006. Around that time, Congress started investigating pharmaceutical companies for using CME for marketing purposes. In response, many companies turned away from CME, spending 32% less on the courses between 2007 and 2010.
But, as Fauber shows, "that funding is again on the rise." Pharma spending on courses today is back to pre-investigation levels and is an almost $3 billion industry. However, due to heightened scrutiny and stricter rules regarding relationships with Pharma, much of the money that used to go to CME offices in academic medical centers and hospitals is now going to medical education companies that technically host the CME courses.
As part of the Physicians Payment Sunshine Act provision of the Affordable Care Act, the Obama administration has sought to require payment disclosure when these third party medical education companies are involved. CMS's Open Payments currently requires disclosure of indirect payments to physicians through third parties starting in 2017 (unless the 21st Century Cures Act passes, which contains a CME exemption along with many other anti-public health provisions).
PharmedOut supports this disclosure and calls for an end to pharma-funded CME courses. Until then, perhaps every pharma-funded CME invitation, course, and certificate should be prominently labeled "Pharma University".
Making an Example of Martin Shkreli
By Nicole Dubowitz
In late September, it was reported that the price of a 62-year old little-known drug, Daraprim (pyrimethamine), rose overnight from $18 to $750 a pill. About 100 pills are needed to treat toxoplasmosis, a disease caused by a parasite that lives inside a third of humans but can cause life-threatening infestations in people with AIDS, cancer, or other conditions that compromise the immune system. The eye-popping price increase followed Daraprim's acquisition in August by Turing Pharmaceuticals, a small drug company founded and led by 32-year old Martin Shkreli, a former hedge fund manager. Shkreli handled the newfound press attention less than gracefully, and quickly became the face of cold-hearted greed in the pharmaceutical industry.
Since then, pundits have disparaged the ability to do what Shkreli did, presidential candidates have vowed to restrict price gouging, and Democrats in the House Committee on Oversight and Government Reform requested a hearing with Shkreli. We're fine with making an example of the young CEO, as long as we remember that Turing is one of dozens of drug companies — large and small — doing exactly the same thing.
The antibiotic tetracycline (around since 1948) and the antidepressant clomipramine (used since the 1960s) went up in price 2,200% and 3,600% respectively over the last few years. Another infamous case is of colchicine, a drug derived from the autumn crocus, a plant used in ancient Greece and ever since to treat gout. Available as a generic drug since the 1800s, exclusive rights for colchicine were sold to a drug company in 2009. The company promptly raised the price from about 10 cents to six dollars per pill.
According to the National Prescription Coverage Coalition, so far in 2015, the average wholesale price of almost 50 drugs more than tripled since last year. An AARP study found that prices of brand-name drugs are rising more from year to year — from 5.7% in 2006 to 12.9% in 2013.
The reasons, or lack thereof, for price increases of Daraprim and other drugs are the same, and they go back to the lack of regulation of drug prices in the United States. As Marcia Angell explained in the Washington Post, companies raise prices simply because they can.
Drug companies cite many reasons for the increases. A popular one, deployed by Shkreli, is that higher prices cover the cost of innovation, or research and development. In fact, drug companies spend at least three times as much on marketing as they do on research. Angell also pointed out that many drug discoveries come out of university labs with public funding from NIH, with little real innovation coming from drug companies.
Amid all the outrage, Shkreli announced that Turing would lower Daraprim's price. The new price has not been set, but it will probably still be closer to $75,000 for a course of treatment than the original $1,800 price tag before Turing bought the drug.
The pharmaceutical lobby is still incredibly powerful, so we are not optimistic about a policy change. But if the Daraprim incident raises Americans' understanding about the Wild West of prescription drug pricing, that is a major step.
Opioids for Kids
By Nicole Dubowitz
On August 13th, the FDA approved the use of OxyContin (oxycodone), an opioid painkiller, for kids between 11 and 16 years old who have severe pain. Until now, generic painkiller oxycodone has been used in this age group on an off-label basis, mainly for long-term illnesses such as cancer or back injuries.
The approval, however, was for extended-release OxyContin, which is still on patent; the company will ask for a six-month patent extension based on the pediatric approval, enhancing the profits for a company that has marketed OxyContin unethically. Senator Joe Manchin (D-W. Va), slammed the decision in a letter to the FDA. The FDA claims that the guidance available in a label will help physicians. "What you really have to understand is these kids are already on opioids,” agency spokesman Eric Pahon said. "Since the drug was being used to treat children, we wanted prescribers to have the information they needed to ensure safety and efficacy. That was the underlying reason for this approval."
FDA and other proponents call it a step in the right direction that will lead to more responsible and educated prescribing of a strong and potentially dangerous medication.
But we think the decision overlooks the problem of opioid addiction plaguing communities across the country; one the Centers for Disease Control calls an "epidemic." Half of drug overdose deaths (the leading cause of injury death in the United States) were related to prescription drugs; almost three-quarters of prescription drug-related deaths involved opioids. Overdose deaths surpass deaths from traffic accidents, guns, and falling.
In light of this FDA decision, some have said young adults are less prone to opioid addiction and abuse. In fact, adolescents may be more likely to become addicted than adults. Surveys continually show that young people underestimate the power of prescription painkillers, and believe they are safer or less addictive than heroin. And, 70% of people who have misused prescription painkillers, and over half of teens, obtained the drug from someone else to whom they were prescribed.
Expanding access to OxyContin increases the opportunity for addiction and abuse among children, both those who were prescribed the drug and those who got the drug from someone else. If the goal is to curb the opioid epidemic, FDA's decision is a step backward, not forward.
Let's Keep Transparency in CME
By Nicole Dubowitz
On July 10th, the 21st Century Cures Act passed the House of Representatives. It now moves on to the Senate, and we hope it will die there. We've expressed concerns about the law, and what it would do to lower FDA standards for drug and device approvals, but there's more. Section 3041 of 21st Century Cures would eliminate the Affordable Care Act's Physician Payments Sunshine Act reporting requirements in CME. Therefore, the Pharma-sponsored "educational" conferences for providers would not have to report gifts and payments made to participating physicians.
One of PharmedOut's founding principles back in 2006 was to root out Pharma influence from CME activities. Unfortunately, financial relationships between CME and Pharma are still incredibly strong. According to the Accrediting Council for Continuing Medical Education (ACCME), commercial support for CME rose from $659.9 million in 2013 to $675.9 million in 2014. Advertising in CME has also risen over $100 million in nine years.
Pharma praises this 21st Century Cures provision, calling the reporting requirement a deterrent to physicians participating in CME. If there was nothing wrong with Pharma-sponsored CME, why would physicians be deterred?
Experts have already confirmed that transparency for physicians' financial relationships with Pharma is a good thing. In a 2009 Senate hearing on this topic, Dr. James Scully of the American Psychiatric Association testified that "patients should know about their physicians' potential conflicts of interest where they truly exist. Only then can they have confidence in decisions made about their medical care." Dr. Fugh-Berman submitted testimony emphasizing that drugmakers sponsor CME for a reason: it is shown to increase product sales.
As a side note, hotel and restaurant workers who serve the physicians wined and dined by Pharma during CME events are voicing their disapproval of industry sponsorship. This month, it was reported that the UNITE HERE hotel workers union is petitioning against these events because they believe industry influence affects their high drug costs.
We agree with UNITE HERE and many others that Pharma should be kept out of CME, period. But reporting requirements in CME were an important step that we must not walk back.
If you don't want the Senate to vote in favor of a bill that may not only harm patient safety through lax regulation, but also reinstate a cloudy, secretive policy surrounding physician relationships with Pharma, please contact your Senators' offices to voice your opinion today.
More on the Flibanserin Fight
By Nicole Dubowitz
Even the Score continues to purvey wrong information on its website, claiming that 43% of women suffer from sexual dysfunction — not true — and that there are 26 drugs for male sexual dysfunction and zero for women. This statement was vigorously denied by the FDA at the June 4th FDA Advisory Committee meeting that considered flibanserin. In fact, there are three drugs approved for painful sex for women and eight drugs (in only two drug categories) approved for difficulty achieving and maintaining an erection in men. There are zero FDA-approved drugs for either men or women for sexual arousal, sexual desire, or orgasmic disorders.
The FDA Advisory Committee recommends to the FDA whether or not a drug should be approved. None of the FDA Advisory Committee voted for outright approval of flibanserin, but 18 members voted for approval with a risk evaluation and mitigation strategy; six members voted against approval. The FDA will formally decide on the approval of flibanserin by August 18th. The Committee’s reluctance to vote for approval with labeled risks only shows their discomfort with the adverse effects of this drug, which include sudden unconsciousness, dangerously low blood pressure, and sedation in normal use that is equivalent to four drinks. The drug interacts dangerously with alcohol, and adverse effects are more common when used with the birth control pill. A bad deal compared to psychosexual therapy, which works without side effects.
We question the very existence of HSDD, as there is no scientifically established norm for sexual activity, feelings, or desire. Decreased interest in sex may be temporary and can be affected by life stresses, relationship problems, illness, medication, fatigue, or boredom. In fact, medication — especially antidepressants — probably accounts for many case of low libido that are not explained by other factors.
Psychiatry Under The Influence
By Nicole Dubowitz
Pharmaceutical company influence strongly pervades the field of psychiatry, from drug rep visits in both medical schools and private practices, to the television ads broadcast to consumers, to where it all starts with the Diagnostic Statistical Manual (DSM).
The DSM, a glossary for all psychiatric conditions, medicalizes the human experience today more than ever. For example, grief lasting a month after a loved one dies, once considered normal, is now grounds for an antidepressant prescription. What changed?
Though we eagerly await all of the presentations at PharmedOut's upcoming conference, Lisa Cosgrove PhD's talk on "Psychiatry Under The Influence", also the title of her new book, is especially bound to resonate with people from all fields. Dr. Cosgrove, a professor at the University of Massachusetts and fellow at Harvard University's Edmond J. Safra Center for Ethics, will discuss the most recent, controversial edition of the DSM and the integrity of its diagnostic boundaries. Does a "pill for every ill" really help people, or is it causing a health and financial burden? Dr. Cosgrove will examine this question and more in the state of psychiatry.
Burning Questions to Be Answered at PharmedOut Conference
By Nicole Dubowitz
Does anyone escape a diagnosis? What factors underlie the opioid addiction epidemic? Does the FDA adequately protect the public? Is there corruption in how drugs are tested? Could overtreating elders lead to iatrogenic morbidity and mortality? What are the public health consequences of high-priced drugs? How is testosterone marketed for men in the same way menopausal hormone therapy was marketed to women? How does overpromotion and overuse of anticoagulants, antipsychotics, fluoroquinolone antibiotics, and hypoglycemic drugs affect public health? Come discuss these and other topics at a wonderful interdisciplinary conference that attracts scholars from many fields. Twelve CME credits are offered.
21st Century Pandering
By Nicole Dubowitz
In March, the Senate Health, Education, Labor and Pensions Committee held several hearings to discuss many of the themes presented in the House of Representative's "21st Century Cures" draft legislation. The Senate is considering its own version of the bill, which is described as Congress's opportunity to, "for the first time ever ... take a comprehensive look at what steps we can take to accelerate the pace of cures in America." Why? Because although FDA approved 51 new drugs in 2014 (nearly a 20-year high), and the agency's average approval rate is faster than all other advanced nations, some lament federal agencies like the FDA as barriers to "innovation."
As Senator Elizabeth Warren noted at one of these hearings, "we could abolish the FDA tomorrow and we'd see tons of new products on the market," but the goal is not just more products, but safe and effective ones. While the Pharmaceutical Research and Manufacturers of America (PhRMA) is a big fan (and participant) in the 21st Century Cures efforts, we have concerns.
Here are areas of the draft bill that, if it becomes law, could pose harm to patients:
Pharmaceutical companies would be allowed to promote off-label (non-FDA-approved) uses of drugs to physicians and other prescribers (such promotion has been illegal, and efforts are already underway to reverse that).
For drugs found to be “promising” in early studies, the law would encourage the FDA to grant approval based on very preliminary evidence, no longer requiring evidence from any controlled clinical trials until years after the drug is on the market.
FDA staff would be required to receive training every year on ensuring that safety and efficacy studies would be less burdensome to pharmaceutical companies.
Several changes to market exclusivity limits would allow companies to charge higher prices for longer periods of time, with no competition. "Specialty drugs," those that meet a complicated or rare medical need, would get 15 years of market exclusivity instead of their current 12. Two additional years of exclusivity would be granted to existing drugs if "improvements" are made, which may have nothing to do with the drug's beneficial effects. And finally, to incentivize antibiotic development, companies introducing new antibiotics will be able to transfer a year's worth of exclusivity to "one or more drugs."
The bill also seeks to create a "fast lane" for certain medical devices and drugs. However, we see the lane as already too fast for the 95% of moderate- and high-risk medical devices that were not required to be tested in humans, and the drugs found to be dangerous after they're on the market.
Government's role ought to be protecting public health before industry profits. FDA Commissioner Margaret Hamburg said, shortly before resigning at the end of March, that seemingly burdensome regulations were put in place for a reason — often, after medical disasters that resulted in injuries and death. Those lessons should not be forgotten as this legislation is discussed.
The Real Risks of Rx Drugs
By Nicole Dubowitz
Maybe we just have conference fever (is there a drug for that?), but we can't resist telling you about our fifth annual conference, "The Real Risks of Rx Drugs". After taking last year off to work on projects past and new (like this newsletter), on June 11-12 we will again bring together health care providers, policymakers, advocates, media, students and others to discuss some of the most important issues facing our health care system.
The 2015 conference will shed light on the dark side of prescription medications, such as opioid overuse, high costs that drive up spending and bankrupt people, pharmaceutical marketing to medical students and residents, research misconduct, and much more. We will welcome the accomplished speakers listed above, and a full agenda will be announced soon. Carolyn Clancy MD, former director of the Agency for Healthcare Quality and Research and current Interim Under Secretary for Health for the Department of Veterans Affairs, will be our keynote speaker.
The first PharmedOut conference was at Georgetown University in 2010 and honed in specifically on the pharmaceutical industry's role in continuing medical education (CME). It was such a success that we held three more June conferences here on campus. Dozens of speakers have addressed the gamut of issues pertaining to marketing pharmaceutical drugs and medical devices, and we consistently receive rave reviews about the expert talks, compelling discussions, and unparalleled networking opportunities. Our interdisciplinary conferences aren’t just for doctors: this may be the only CME event attended by policymakers, lawyers, sociologists, nurses, government employees, industry, consumer advocates and students of such diverse disciplines. More information about past conferences, including how to order DVD footage, can be found on our website.
Demanding Results of Clinical Trials
By Nicole Dubowitz
Imagine you have enrolled in a clinical trial. You made the difficult decision to take an untested drug or remain untreated with a placebo, and dutifully performed your regimen every day. Maybe you got better, or maybe you experienced adverse effects and were left in worse shape than when you started. At the very least, you would expect that your experience would ultimately contribute important information to the medical community and other patients.
But as we know, clinical trial data are often never shared. Around half of clinical trial results are kept hidden, and trials that had negative results are twice as likely to go unreported. Many don't get officially registered in the first place, making them that much easier to sweep under the rug. It might be good business for industry to pretend that their unflattering data doesn't exist, but it's not good ethics. In the words of one trial participant regarding Ben Goldacre's AllTrials campaign, "I believe it is immoral to recruit patients to clinical trials and then not report or share the results. We participate in order to increase knowledge and to help others. We do not expect the knowledge to be kept secret or the help for others to be denied.”
This month, the Institute of Medicine (IOM) released a report calling on trial sponsors to share details of their data. As Katie Thomas for The New York Times reported, IOM recommends that trial data be published within 30 days of the product’s approval or 18 months of the study's completion — even if the company decides to drop the product. IOM President Victor Dzau stated, "The rapidly changing landscape of clinical trials and the movement toward greater transparency create a need to establish professional standards and set expectations of how to share clinical trial data ... We need to develop a culture that supports data sharing, and we need to provide incentives and develop trust."
Professional standards and expectations for researchers must include the release of clinical trial data. The IOM emphasizes the role of funders, journals, the IRB, and universities in accomplishing this. One huge funder, Johnson & Johnson, has set the precedent by agreeing to share detailed results from their medical device and diagnostic test trials, "making it the first large device manufacturer to systematically make such data public," Thomas also reported. In addition, requiring trial sponsors to register with ClinicalTrials.gov would keep trials from disappearing into oblivion.
That is not too much to ask when trial participants are risking their lives, regulators are entrusted with protecting the public health, and the rest of us are waiting for evidence. If you agree, you can sign AllTrials's petition and donate to their campaign here.
The Rising Costs of Prescription Drugs
By Nicole Dubowitz
Drug pricing has been a recent subject of debate, regarding both brand-name and generic treatments. In previous months, we addressed the enormously high prices of branded cancer drugs like Zaltrap and hepatitis C drug Sovaldi — examples of "corporate chutzpah" that contribute to the high costs of health care.
Rising prices of generics are concerning for the same reason, and are startling patients who were used to their affordable drugs. The Generic Pharmaceutical Industry Association estimates that generic drugs saved the American health system nearly $1.5 trillion dollars from 2004–2013, but that may change; while in 2010, consumers and insurers paid an average of $13.14 per prescription for the most popular generics, they paid $62.10 in 2014 — a 373 percent increase.
Some experts attribute the rising costs to factors like raw material shortages, medical advancements, and consolidation in the industry. We also point to the rigged competitive market for generic drugs.
When a company's drug patent expires (typically about 10 years after being marketed), generic drugmakers have the opportunity to sell generic versions. But, the company that originated the drug may also produce a generic version to compete with other generics and its own brand-name drug.
The FDA has granted that company's generic version the title of "authorized generic." This label may make the drug appear superior to other generics, especially to patients hesitant to take a generic drug. Lower profits for generic drugmakers might discourage them from continuing to produce the drug. For example, the heart drug digoxin used to be offered by eight generic drugmakers, but after its "authorized generic" was released in January 2014, only three manufacturers remain, and the price has gone up 637 percent.
For now, the Senate has convened panels to investigate price increases for prescription drugs, and we implore regulators to monitor the impact of branded drugs, generic drugs, and "authorized generics" on costs in our public and private health care systems.
There's a (Pharma) App For That
By Nicole Dubowitz
Data mining makes it possible not only to suggest new friends on your social media account and follow you around online shopping, but also to promote prescription drugs through doctor-only platforms. Big Pharma's modus operandi has long been drug rep visits, article reprints, and peer pressure, but more and more, manpower and paper are being exchanged for digitally automated marketing strategies.
Certainly, drug companies still rely on face time with drug reps to promote their products. But according to several news stories this year, digital marketing efforts are increasing. The November Vox article that quoted Dr. Fugh-Berman focused on three of Pharma's digital platforms: Electronic health records (which are replacing hospital paper records); physician social media sites (the Facebook or LinkedIn equivalents for health care providers); and phone apps (which provide on-the-go information about drugs and ailments).
These are ideal places for Pharma to advertise, and they're upping the ante on audience engagement. For example, hard-copy reprints of journal articles favoring a company's drug used to be Pharma's second-highest marketing expenditure. Last year, Medical Marketing & Media reported that reprints — even electronic versions — are out of favor: "They have to find a way to make the content more engaging and interactive than a PDF," said Nicole Woodland-De Van, SVP of buying services and deliverables at Compas. According to Christopher Manz MD in The New England Journal of Medicine, physician social media site Sermo created games like "an 'Alzheimer's Challenge' that allowed physicians to read through clinical trial data (in a format similar to print journal advertisements) for a brand-name medication and answer questions about its indications to earn points redeemable for cash."
Electronic health records (EHRs) and phone apps also make data collection far easier for drug companies. "For decades, companies have been able to tell which drugs I prescribe but with EHRs they can tell when and why I prescribe," said Manz. And as Dr. Fugh-Berman told Vox, searches from Epocrates and other apps are also collected by Pharma for targeted marketing purposes.
Regulations have yet to catch up with pharmaceutical digital marketing practices, and it may be difficult to achieve. Consumers are so accustomed to custom-picked ads every time we use the Internet that it has become a normal, expected part of a streamlined online experience. PharmedOut has focused on exposing subtle marketing messages that evade regulations on drug rep visits and advertising. It doesn't get much more subtle than "targeted banner advertisements, e-coupons, or even curated drop-down menus" on digital tools for physicians.
Standards For FDA Drug Approval
By Nicole Dubowitz
In late October, John Fauber and Elbert Chu wrote an important article on how the FDA approves cancer drugs. Basically, a drug may be approved if a clinical trial shows success with surrogate markers (i.e. tumor shrinkage) even if clinical endpoints (i.e. surviving cancer, or a better quality of life) show no benefit.
In the 1990s, pharmaceutical companies pushed the federal government to get drugs approved more quickly. Silvana Martino MD, who is director of the Angeles Clinic and Research Institute and has served on FDA cancer drug advisory committees, is quoted in the article: "If you are a drug company, what is your goal? It is to provide sufficient data to get your drug approved. You will aim for whatever that least amount is. I think the bar is too low." She speaks to the pressure put on FDA to "make potentially beneficial therapies available as soon as reasonably possible," even if shortcuts are taken. "You don't have deep, solid studies that prove a point," she said. Fauber and Chu found that only three of 26 cancer drugs approved based on surrogate markers between 2004 and 2011 increase survival, and the benefits of successful drugs were modest.
60 Minutes also touched on this topic with their October 5th segment, "The Cost of Cancer Drugs", which focused on the $11,000/month price tag of Zaltrap (ziv-aflibercept), a colon cancer drug approved in 2012. Leonard Saltz MD at Memorial Sloan Kettering Cancer Center wanted to know if Zaltrap was really better than other treatments, and compared its clinical trial results to those of $5,000/month cancer drug Avastin (bevacizumab). Both drugs extended median survival by 42 days.
FDA requires all cancer drugs to yield better results than placebos and indicate progress on surrogate markers. But is that enough? Surely expensive cancer drugs should have to save more lives than placebos to be approved. We think these examples stress the need for comparative effectiveness research (CER), pitting drugs against each other and not just placebos to find the best treatment.
The Institute of Medicine, the Dartmouth Institute for Health Policy and Clinical Practice, The Agency for Healthcare Research and Quality, and the New England Comparative Effectiveness Public Advisory Council are working to make CER a greater part of our health care system. For now, barriers still exist, as Pharma is the biggest lobbyist in the country. Also, because of the Prescription Fee User Drug Act (PDUFA), FDA relies on industry for drug approval application fees.
Oncologists at Memorial Sloan Kettering rejected Zaltrap due to its unconscionable price, and its manufacturer quickly issued a discount. Perhaps this kind of physician activism, directed at industry and the FDA, could raise approval standards and make healthcare costs worthwhile.
"Where's The Female Viagra?"
By Nicole Dubowitz
PharmedOut distributed flyers countering misleading information at a September 16th Senate briefing on Female Sexual Dysfunction (FSD). The Senate briefing was called "Where's the female Viagra?" and was arranged as part of "Even The Score", an aggressive PR campaign created by Sprout Pharmaceuticals and renowned PR firm Edelman. Sprout owns flibanserin, a drug meant to treat Hypoactive Sexual Desire Disorder (a subset of FSD), but has been rejected twice by the FDA for failing to show adequate efficacy and safety. Hypoactive Sexual Desire Disorder no longer exists as a diagnosis; the newest wording is Female Sexual Interest/Arousal Disorder.
Sprout has raised $15 million to try to get the FDA to approve the drug in 2015. The “Even The Score” campaign accuses the FDA of sexism, claiming that there are 26 drugs to treat male sexual dysfunction, but none for its female counterpart. Our flyer clears up that rumor and skewers other myths created to pressure the FDA.
Most of the panel of six women who spoke at the Senate briefing were paid by Sprout, as we found out when we asked at the end of the panel. It was a good opportunity for PharmedOut to pass out our flyers with our own message: “Don’t Need Drugs to Score”.
Is Sprout behind the FDA's decision to prioritize FSD for patient-focused drug development this year? On October 27th and 28th, the FDA will host a public meeting and scientific workshop on the subject. PharmedOut will attend these meetings; we ask others to do the same so that we can counter Sprout’s efforts and make our voices heard.
When Pharma Meets Medical Journals
By Nicole Dubowitz
Pharmaceutical companies still advertise heavily in medical journals, but as data on returns increasingly become available, some companies are demanding "anything and everything about [journals'] business models: circulation, audiences, you name it", according to a Medical Marketing & Media article.
This is the latest development in the complicated pharma-medical journal relationship. A recent study found that the volume of ads varies widely among journals, but print media often relies on advertising revenue. Many medical journals only accept ads for medical devices and medications, and some doggedly pursue advertisers. For example, the New England Journal of Medicine offers "several effective marketing vehicles to promote products on a global scale" and "conducts independent market research to track physicians' reading and prescribing habits and makes this information available to advertisers free of charge."
Back in 2006, PharmedOut recommended that journals forgo pharmaceutical advertising in an article called "Pharmaceutical advertising in medical journals; should current practices change?" In the meantime, several studies suggest that pharmaceutical advertising may affect journal content, and pharmaceutical companies purchase reprints of articles that support marketing goals.
The Medical Marketing & Media article also includes information on medical journal ad spending on specific drugs and drug classes for the past five years. Invokana (canaglifozin), Janssen's diabetes drug, leads the list for 2014 ad spending at $11.29 million, followed by Takeda's antidepressant Brintellix (vortioxetine, at $6.7 million) and Forest's antidepressant Fetzima (levomilnacipram, at $4.6 million).
Here is a table of the drugs that topped the list for journal ad spending in the first half of 2014:
Sunshine Still Misses CME
By Nicole Dubowitz
One story in July's News Round-Up barely made waves in the media, but it made PharmedOut do a double-take. The announcement was that continued medical education (CME) would no longer be exempt from the Affordable Care Act's "Physician Payments Sunshine" provision requiring drug companies to disclose any payments to physicians.
This is an important issue for PharmedOut since one of our primary goals is to rid CME of drug industry influence. Physicians are required to obtain CME credits each year to renew their medical licenses, but CME options are frequently funded by pharmaceutical companies looking to promote a treatment or "disease awareness." At first, this news seemed to imply that drug companies would have to disclose payments made to physician speakers or authors involved in CME. That would allow conscientious physicians to avoid, or at least be aware of, CME activities with drug company influence.