The Research Pathway

Bench to bedside – the long road to finding a new treatment

The phrase ‘bench to bedside’ – the process of scientific discovery to launching a new intervention for patients – might sound like a relatively direct route, albeit with various steps along the way. Yet getting from that very first stage to actually delivering to patients is a long and exhaustive route, with numerous twists, turns and uncertainties at every corner. Getting a new treatment on to the market takes years of hard work and testing – not to mention significant costs. The bench to bedside journey can be long and frustrating for both scientists and those eagerly awaiting the prospect of a new therapy.

Bench to bedside sums up translational research, defined by the US National Institutes of Health (NIH) as ‘the process of applying ideas, insights, and discoveries generated through basic scientific inquiry to the treatment or prevention of human disease.’ Thus, translational research encapsulates the earliest stage of new scientific knowledge and discovery through to research, testing and delivery of new approaches for prevention, diagnosis and treatment of disease. Research is put into practice, ensuring that new treatments reach the appropriate populations and are correctly implemented.

The ultimate objective is to improve health, wellbeing and prognosis.

Scientists are constantly conducting new research and making new discoveries, exploring different ways for therapies to reach the human body and improved ways to make a difference. Yet of all the research taking place, only a small fraction will actually see the light of the day. The majority of endeavours will fall by the wayside at some point during the extensive research and rigorous testing process.

As the process is typically painfully slow, often taking up to a decade or longer, it can mean some patients may be past the point of benefitting before a promising new intervention becomes available. The myriad of procedures along the way can all present their own challenges.

Where does it all begin?

The journey begins in a research laboratory, involving exploratory work and preclinical trials. While basic science refers to gaining greater scientific knowledge, applied research is putting that knowledge to the test in an attempt to get a better intervention.

Researchers are looking at disease processes and potential new targets for treatments. For example, this could be a gene or protein instrumental to the disease that a new treatment could work by blocking; then the researchers would set about finding a compound that acts on this target. Not so long ago researchers were limited to studying the biology of around 500 target proteins or genes. But, with major scientific advances – including knowledge of the sequence of the human genome – so many more biological targets can now be studied.

A huge amount of scientific research goes on behind the scenes in laboratories worldwide, much of trial and error. If researchers believe they have identified as potential new target for a particular disease, they will then seek chemical compounds to modify the target, if, for example, they are looking to develop a new drug treatment. It is only when, after a great deal of work, scientists make a ‘breakthrough’ that further investigations begin.

Sometimes, these ‘Eureka moments’ can even occur by accident. During the 1980s, for example, researchers found that the drug they were using to treat angina was ineffective – but they did find that it served another purpose. Eventually, more than 10 years later, this drug, sildenafil, went on to treat erectile dysfunction and become better known by its brand name Viagra.

Applying for funding

Long before any trials can begin, a significant amount of research and data collating has taken place in an attempt to prepare a case and apply for funding to continue.

It can even be several decades before an original discovery finally gathers pace. Julie Daniels, professor of regenerative medicine and cellular therapy, and founder of director of the cells for sight tissue stem cell therapy research unit at Moorfields Eye Hospital, is certainly familiar with this. She and her fellow researchers work on the cornea (the front of the eye), using stem cells and tissue equivalent to create tissues for transplantation in patients.

She says: “The first research in this area goes back to the 1970s, where scientists were culturing skin cells to transfer on to burns. It was 1997 before there was published research showing that growing cells and transplanting them into patients could be useful for cornea. It was subsequently decided that we could grow these stem cells here, at Moorfields Eye Hospital.

“We had a patient population who didn’t have any other therapy so we set up a specific laboratory – a clean room – to enable us to grow these cells for patients. After trial and error, we found the best way to grow the cells. This was actually using collagen based tissue equivalent, rather than amniotic membrane as we had originally done. We then managed to get enough funding to develop a tissue for reliably growing stem cells, which we could then take to patients.”

Now, the team has carried out safety studies and worked tirelessly to develop their application for the next round of funding, which will enable a first clinical trial to get underway.

“It takes months to write a clinical trial application for funding. There are multiple parties involved – scientists, your clinical trials unit, your clinicians, statisticians and potentially a company as well. We need to ensure that our application is as good as it can possibly be,” says Professor Daniels.

“After submission of the outline application we’ll find out if we are invited to submit a full application – so we might not even get that far! That process will take about a year in itself. Then, following a full application, there will be further whittling down – this involves interviews and a real ‘grilling’. It is critical to have enough good science and data to back up any idea, but you’ve also got to prove why you are the right team in the right place to do it.”

If successful, it could easily be another five to 10 years from this point. With drug discovery the whole process can take approximately 15 years, but as regenerative medicine is a new field and it is generally slower, taking 15 to 20 years from initial research.

“We have seen a lot of hype about stem cells in the press, but we are now starting to see trials come to fruition and treatments getting approved, which is really amazing,” says Professor Daniels.

Gathering the right evidence

Gathering relevant statistics and facts is clearly at the heart of good clinical evidence, but there are significant variations in how evidence is gathered – all of which will have an impact on its credibility.

Firstly, a thorough understanding of existing knowledge must be demonstrated. Says Richard Wormald, consultant ophthalmologist, Moorfields Eye Hospital: “There is a lot of duplicated research out there so you have to show that you have thoroughly researched existing literature and are not attempting to answer something already addressed.”

Patient involvement is key, as researchers must be able to show that they have listened to patients and considered their genuine needs and expectations as far as the NIHR [National Institute for Health Research] is concerned. As Dr Wormald explains: “No matter how good your science or research, if you have not involved patients, then you will not get funding. Your research must be a priority for people with the condition. Over the last few years, patient involvement has become increasingly important.”

What are the outcomes for patients? This information needs to be very clear from the outset. How will the proposed treatment affect quality of life? What are the health economic measures and what is the real difference for patients? Says Dr Wormald: “You have to show that your proposed intervention is a priority for people with the condition. This must be in addition to all other areas relevant to patients’ concerns, such as social science and clinical psychology.”

Trial phases

With funding in place and following an already long research trail involving preclinical studies, researchers can begin a formal test involving people – a Phase I trial, the first phase of a full clinical trial. Clinical trials evaluate the effectiveness and safety of a new treatment or procedure for prevention, diagnosis and treatment of any given disease or condition. Designing, setting up detailed protocol and recruiting patients for a trial can be a lengthy process, taking at least several months.

Clinical trials are the gold standard for evaluating medical interventions. They are a key part of the research pathway and the means to not only gaining a license for use but also for helping to guide healthcare professionals with treatment decisions.

A Phase I trial usually involves a small group of patients and primarily looks at safety, any side effects and therapeutic value. Safety needs to be very carefully investigated before proceeding further.

“In a phase I trial you are giving a treatment for the first time to a select group of patients to see if it is safe, given in the right concentration and the right frequency,” explains Frank Larkin, consultant ophthalmic surgeon, Moorfields Eye Hospital.

All being well, the treatment can move forward to a phase 2 trial, which will involve a larger number of patients. This study takes a closer look at how the body responds to the treatment and aims to establish the optimal dose. It examines how the treatment affects, for instance, a particular eye condition.

The phase 2 study could assess variations in one new treatment (different doses, for example). It may compare the new treatment with existing, often standard, treatment. Sometimes patients may be randomised in these trials, meaning that there are at least two different groups, with patients randomly placed in these groups. People having the standard treatment are called the control group (a rondomised controlled trial).

In other trials, the control group may be taking a ‘placebo’ – or dummy treatment (also sometimes referred to as a ‘sham treatment’). This treatment is designed to have no medical effect, but is used to compare patients’ responses with the actual treatment on trial.

These types of trials – more typically used for testing drugs or vaccines – are usually ‘double blinded’, whereby neither patient nor researcher knows who is receiving the actual treatment and who is receiving the dummy. This is to ensure the results are as objective and accurate as possible, without any bias.

Furthermore, despite the fact that placebo treatment is a non-active substance, it can sometimes nevertheless have a powerful effect as patients believe they are taking a specific treatment for their condition. This is known as the ‘placebo effect’ – when patients experience an improvement in symptoms or have certain side effects even though they are only taking a dummy treatment.

By a phase 3 trial, investigators are finally reaching the last few miles in the journey – but there is still significant work ahead. A phase 3 study is usually significantly larger, often involving hundreds and potentially thousands of patients (these numbers also depend on the numbers of people with certain conditions, as in some cases it may not be possible to include such large numbers). These trials compare new treatments with existing treatments or no treatments, confirm effective optimal doses, identify any contraindications (reasons why the treatment should not be given to certain patients as it could cause harm) and side effects.

Larger trials often involve more than one site, known as ‘multi centre trials’. This means that a number of research centres each conduct a trial at the same time, involving the same intervention. Sometimes this helps to recruit more patients, particularly for more rare conditions when eligible patients are spread throughout the country (or countries if it is an international study). It can also be considered an advantage to gather data from a more diverse group of clinics and patients populations, thus more closely reflecting actual use once the intervention becomes available.

Gaining approval

Despite the phase protocol, getting through clinical trials is far from straightforward. Furthermore, a large number of investigational medical products are withdrawn from development somewhere along the way, as there are safety problems or the product simply does not work as well as hoped.

“It can take a very long time to get from early phase I to phase III. It can easily take a decade – or longer,” says Dr Larkin. “Recruiting large numbers of patients can take a long time, particularly in rare diseases.”

Following phase 3, approval may be sought from the regulatory bodies. In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA), sponsored by the Department of Health and Social Care, is responsible for ensuring that medicines and medical devices meet adequate standards of safety, quality and efficacy.

The MHRA reviewers carefully consider the intervention and scrutinise all available data, weighing up the pros and cons, as well as risks versus benefits. They meticulously review safety and effectiveness and ensure that the clinical trials have met the stringent standards expected. If it is considered that there is an urgent need for a particular treatment – perhaps due to an existing shortage – the approval process can sometimes be ‘fast tracked’ so that the treatment can reach patients more quickly.

Occasionally phase IV studies are undertaken and these further examine a treatment in a ‘real life’ setting – thus given to patients after approval has been granted. (They are also known as post-marketing surveillance trials.) These trials enable a greater understanding of any given treatment as they involve larger numbers of patients and subgroups of patients.

Participating in a clinical trial

Taking part in trials gives people with particular medical conditions the opportunity to be at the forefront of pioneering medical research. Participants may be among the first to test a potentially promising new intervention, which, if proven effective, could be a major step forward in treatment and/or prevention.

To participate in any given trial, patients need to meet specific criteria for that particular trial – ‘eligibility criteria’. So, for example, a trial may require patients with a disease affecting a very specific area of the eye, or the trial may call for patients with a family history of a genetic change. Age, other medical conditions and any previous treatment may also be part of the eligibility criteria.

Researchers recruiting patients for a new trial are always on the lookout for people wanting to participate. Explains Dr Larkin: “ We have dedicated staff – research coordinators – attending our clinics who identify patients suitable for trials and provide patients with relevant information.

“Nevertheless, it is a good idea for patients to take the initiative. When attending a clinic, patients can, and sometimes do, ask if there are any trials involving their eye disease. It is always worth quizzing doctors and nurses about different trials.

“People can also find out about trials through patient groups, which have networks and regular meetings. Patient groups often know which trials are happening around the country.”

Once patients have been recruited into a trial, they are introduced to the study’s research team. The trial’s principal investigator leads the research, while the clinic coordinator is in charge of arranging clinic visits and explaining the processes. The treatment plan is known as the study protocol – this outlines the trial’s objectives and ensures that all patients are treated safely and in a standard way.

Risks are also clearly explained to patients before they commit to participating in any trial. Some treatment trials have more risks than others, but the nature of these, as well as any potential side effects, are openly outlined and people considering taking part in a trial should feel very clear about all aspects of that trial.

Regulations stipulate that anyone participating in a trial must do so of their own free will and patients should never feel obliged. People also have the right to withdraw from a trial at any time (but similarly investigators may withdraw participants if they do not follow the protocol or if there are any medical concerns). Formal consent must be obtained from all participants before beginning the trial.

For information on clinical trials and research studies carried out at Moorfields Eye Hospital patients can contact res-admin@moorfields.nhs.uk.

Publishing data

When trials are completed and all data collated, the results must be published in an ‘open access’ journal, which can be easily accessed by anyone. As more evidence is gathered regarding any particular treatment, this must also be published and made available.

“A single trial is rarely enough to show that something actually works,” explains Dr Wormald. “The more evidence that you have, the more certain you can be that there is a consistent effect. This is because different studies may give different results, even when you are conducting the same tests. Repeatable and consistent findings from several studies increases the strength of the evidence.”

The MHRA and the USA’s Food and Drug Administration (FDA) – both of which must approve safety and efficacy of new treatments – require a minimum of two studies for any new intervention.

“Systematic reviews of properly conducted trials collated in a meta analysis are considered the highest level of evidence. These need to be rigorously conducted and according to strict protocol,” says Dr Wormald. “Data from systematic reviews are used for clinical guidelines such as those produced by the National Institute for Health and Care Excellence (NICE) when deciding which drugs and treatments should be available on the NHS.”

However, it’s not only quantitative data that is considered relevant: qualitative research is also recogised as important. Qualitative measures address the broader questions, identifying what really matters to patients and assessing levels of improvement. Just as this is important to report when applying for funding, it must be proven when taking any new treatment forward.

It is only when a new intervention begins to truly benefit patients that the long and extensive journey has finally been completed and the significant costs involved can start to be recouped. After many years in the making, the product now has the potential to change – or in some cases even save – patients’ lives.

Moorfields CRF: specialist built centre for new clinical research

The National Institute for Health Research (NIHR) Moorfields Clinical Research Facility (CRF) is dedicated to testing new treatments in a specially designed unit with dedicated researchers. Here, patients participate in exciting research programmes in a safe and relaxed but pioneering environment.

Much of the equipment within the CRF is distinctive and cutting-edge. “Some of the equipment is the only example of its kind in the country, Europe or even the world,” says Frank Larkin, consultant ophthalmic surgeon at Moorfields Eye Hospital.

“One such piece of equipment is our AOSLO – adaptive optics scanning laser opthalmoscope. This gives us pictures of the retina – we take photos through the patient’s pupils and can see individual cells in the retina while the patient is wide awake. We can use this before and after a treatment to see the effect on cells of the living retina. Other equipment and devices are more widely available worldwide – but we have exceptionally expert staff members managing them.”

“Fundamentally, the equipment is aimed at getting more detailed information on a particular eye disease. We spend a great deal of time examining the eye in ways we are not resourced to do in routine care. So for example, a patient with glaucoma might typically have one or two tests in an outpatient clinic, but in the CRF that patient might have six or seven tests.”

Research undertaken at the CRF includes basic science, translational, applied and clinical research. Patients may be involved in research from laboratory work through to phase I, II, III and IV clinical trials.

Patient experience

Nearly all patients treated at the CRF are trialing new treatments, are or involved in trials comparing new treatments with older treatments.

The idea of the CRF is to create a smaller and much more focused environment, which has advantages for both patients and researchers. For patients, visiting the CRF is generally a calmer and quieter experience than attending regular outpatient clinics.

Says Dr Larkin: “There are far fewer patients at the CRF so they are not usually kept waiting. We aim to offer patients a ‘business lounge’ experience, whereby staff members are ready to welcome them.

“Patients are helping us by taking part in key research projects, so in addition to ensuring they are treated safely and expertly, we aim to make patients feel valued. Some patients might be at our centre for a few hours a day to allow all the examinations necessary for early phase trials.

By Nicola O'Connell