How To Overcome The 3 Major Challenges In Conducting Rare Disease Clinical Trials
By Sharon H. Hrynkow, Ph.D., chief scientific officer, Cyclo Therapeutics
Designing and conducting clinical trials to develop treatments for rare diseases often requires drug developers to plan for and address many challenges that are often not associated with or are less severe in larger trials for more common diseases and conditions. If they are not adequately understood and addressed, these challenges can result in trial delays or even discontinuations. Trials that do reach the finish line may have an increased risk of rejection by regulatory agencies because they do not provide the levels of robust data necessary to adequately demonstrate that a drug is safe and effective. Niemann-Pick disease type C (NPC) is just one example of a rare disease where there have been several setbacks in clinical research in recent years.
While each failure in clinical research is devastating news for patients and families, it can often be possible for drug developers to review prior trials to identify more effective protocols and strategies to drive future research. In preparation for our upcoming Phase 3 trial evaluating a potential therapy for the treatment of NPC, our team at Cyclo Therapeutics was able to build on our experience in clinical research by reviewing many other drug development programs. These insights have helped us identify the most common challenges in clinical research in this disease state and the strongest opportunities to overcome them. The following is a summary of the three major challenges we identified and how we worked to address them.
1. Defining The Primary Outcome Measures
In designing any clinical trial, one of the first considerations is identification of the primary patient benefit and efficacy measures (i.e., endpoints) that can be used to define a positive outcome associated with administration of an investigational therapy. It is generally easier to identify and define primary endpoints for clinicals trials in diseases that affect larger patient populations such as cancer or diabetes, because in many cases the most effective endpoints have been established in prior research. But for many rare diseases there is limited or no prior clinical research, requiring drug developers to identify appropriate endpoints, an often-complex task, and then confirm with regulators that these endpoints have the potential to provide the insights necessary to confirm efficacy and safety.
In some cases, regulators will allow use of “surrogate markers” to measure therapeutic effect. For example, if a disease state is associated with high levels of cholesterol, reduction in cholesterol levels might be acceptable as a surrogate marker. In cases where no surrogate markers are available or acceptable to regulators, clinical outcome measures must be used. To identify outcomes measures, the trial protocol must position investigators to rate changes in disease progression and symptom severity based on an accepted set of parameters. In NPC, as in other lysosomal storage diseases (LSDs) and other rare diseases in general, there is often no confirmed or widely accepted outcome measure. In many cases, stakeholders including regulators, academics, clinicians, and patients have different opinions about the best ways to assess efficacy.
The effort to identify an appropriate outcome measure must often involve close collaboration with regulators and other stakeholders. Before initiating the pivotal Phase 3 TransportNPC trial, Cyclo had several discussions with regulators from the FDA and European Medicines Agency (EMA) to determine the best primary outcome measure for NPC – a disease that is still highly under-researched. Based on many productive discussions, the trial will use a uniquely designed four-domain NPC Severity Score as its primary outcome measure in U.S. trial sites and a five-domain NPC Severity Score in trial sites in Europe. The statistical analysis plan for the entire group of participants is structured to account for the variability in outcome measures and deliver an accurate measure of drug efficacy. This is the first instance in NPC where a single global trial will be conducted with parameters approved in multiple national jurisdictions to support potential approval of an investigational drug based on a shared data set.
2. Addressing Patient Avoidance Of Being In The Placebo Group
Placebo-controlled trials have long been the gold standard in clinical research, providing important insights about the impact of a drug on patients. In the TransportNPC trial, two-thirds of patients will be randomly assigned to the study drug and one-third will be assigned to the placebo. Use of a placebo control can help eliminate the risk of bias or influence in interpreting patient response to treatment and help to confirm that efficacy and safety results are directly related to treatment. In rare diseases, the use of placebo can be a major concern for patients and their families. In many cases, patients do not want to participate in research if they think they might be treated with a placebo – potentially putting their health at risk. Despite the benefits of using placebo controls, many patients may decline to participate, making recruitment an even more difficult and time-intensive process.
One option for addressing concerns associated with placebo-controlled trials in rare diseases is to include a “rescue function,” a process where patients who show signs of disease progression during a trial within a certain period of time can be moved into an “open-label” study where all patients are treated with study drug. In the TransportNPC trial, any patient who shows a decline in their health based on specific criteria agreed to with regulators at 48 weeks or thereafter can be moved into the open-label portion of the study. Using a rescue function process can help drug developers in rare diseases continue to use a placebo arm while addressing concerns among patients and families about the potential health risks associated with placebo-controlled trials.
3. Deciding On The Trial Duration
In many rare diseases, heterogeneity in disease progression can have a direct impact on considerations in clinical trial design and interpretation of study results. While the goal of any clinical trial is to be able to evaluate a drug’s safety and efficacy, differences in rates of disease progression can make it difficult to determine how much time must pass before trial investigators can accurately assess treatment effectiveness. It may be necessary to extend trial timelines to have an accurate assessment of efficacy. Extending trial timelines, however, can increase the burden on patients, caregivers, and investigators and potentially affect recruitment and compliance.
The TransportNPC trial is designed as a 96-week study, which is twice as long as the longest previous NPC trial to date. When discussing the trial design and duration with regulatory agencies, it was determined that a two-year study period would be appropriate to evaluate our drug’s therapeutic effect in NPC patients.
In an effort to ameliorate concerns about the duration of the study, the TransportNPC trial includes a plan to conduct a critical evaluation of the data after 48 weeks. This strategy is based on results seen in our previous Phase 2 trial that showed encouraging signals of efficacy after this amount of time. (This is another example showing how prior research can inform and improve trial protocols moving forward.) If efficacy is adequately demonstrated following an evaluation after 48-weeks, there may be opportunity for Cyclo to stop the trial and file for market authorization at that time. If it is determined that additional data are required, the trial will continue through the full 96 weeks.
Using New Insight To Shape Future Clinical Research
There are nearly 7,000 rare diseases,1 many with limited or no treatments. Many patients and families are eagerly waiting for researchers to initiate clinical trials for promising therapies in the hopes that a treatment may soon be approved and widely available. Despite the challenges associated with clinical trials in rare diseases, there are many examples of innovation and opportunities for drug developers to think strategically and creatively about how to address them in efforts to advance promising therapies as quickly as possible. Drug developers should also take steps to make sure that patients feel safe and that a trial is designed to deliver results as quickly and effectively as possible while achieving the goal of delivering an approved therapy. Reviewing best practices and even clinical trial setbacks can help developers better anticipate the concerns of patients and potential trial risks and develop effective plans to circumvent them. It is also essential for drug developers to engage with and collaborate closely with stakeholders, including regulators, clinicians, patients, and families, to incorporate their considerations and perspectives into trial design.
References:
About The Author:
Sharon H. Hrynkow, Ph.D., is the chief scientific officer and senior vice president of medical affairs at Cyclo Therapeutics. Prior to joining Cyclo Therapeutics, Hrynkow served in a range of leadership roles in global health at the National Institutes of Health (NIH), including as deputy director and acting director of the Fogarty International Center, associate director of the National Institute on Environmental Health Sciences, and senior advisor to the NIH deputy director. A developmental neuroscientist by training, Hrynkow has received several awards, including the U.S. President’s Merit Award for Senior Executives and the Order of Merit from the King of Norway, and as an elected Fellow of the American Association for the Advancement of Science and as an elected member of the Council on Foreign Relations. She served for one year as a presidential appointee on the President’s Council of Advisors on Science and Technology.