FDA Panel Discusses Role of Patients in Clinical Trials for Rare Diseases


Members from the FDA came together to participate in an informative session and discuss the traditional pathway and future outlook of clinical trials in rare diseases.

Clinical trials are pivotal for any disease, as the US Food and Drug Administration (FDA) bases their decision to approve new treatments on the data made available by these trials. With only 5% of the approximate 7,000 rare diseases having approved treatments available, the structure and timeline of clinical trials is of the upmost importance in the rare disease community.

Since this is such an important topic, members from the FDA came together to participate in an informative session at this year’s National Organization of Rare Diseases’ Rare Diseases & Orphan Products Breakthrough Summit (NORD Summit 2018) to discuss the traditional pathway and future outlook of clinical trials in rare diseases.

The panel was comprised of the following FDA members: CAPT Nicole Wolanski, PharmD, acting deputy director of the Office of Orphan Products Development; Dragos Roman, MD, associate director of the Division Gastroenterology and Inborn Errors Products (DGIEP); Tejashri Purohit-Sheth, MD, director of the Division of Clinical Evaluation and Pharmacology/Toxicology; and Ellis Unger, MD, director of the Office of Drug Evaluation-I, Office of New Drugs, Center for Drug Evaluation and Research.

Dr. Roman led the panel by addressing the key criteria considered in clinical trials for rare diseases, which include the “totality of evidence” and “flexibility.” He explained that the totality of evidence depends on perception—to a degree—since different biomarkers and endpoints can have different meanings depending on the disease being studied.

Reviewers on clinical trials go into a lot of detail when trying to understand the significance of the data, he added. If they don’t understand the “totality of evidence,” they won’t able to put that data together and make real conclusions. Regulations very clearly indicate that substantial evidence, or data, is needed for a treatment.

“If you cannot connect the dots, you have a problem,” he stressed.

Flexibility, in combination with the totality of data, help create an informative program, he reiterated. As long as the dots connect, flexibility can be good.

Captain Wolanski supported Dr. Dragos’s points on flexibility in that it is a key criterion to consider in orphan drug requests. There are 2 questions she stressed were imperative to ask when it comes to an orphan drug application: (1) Will the drug work in the disease? And (2) Is the disease rare?

Clinical data has the strongest support for drug effectiveness, she said, adding that animal data in an appropriate animal model can also be accepted if the pathophysiology is relevant to the specific drug and disease in question.

Oftentimes, rare diseases have to race against a fast clock since they can be fast-progressing and irreversible in nature. As such, the panelists discussed the importance of weighing the risks versus the benefits for each situation. Dr. Unger pointed out that if the risks of a treatment outweigh those of the disease, that can be a deterrent for the treatment.

Dr. Purohit-Sheth added that sufficient and substantial evidence of safety and effectiveness always have to be considered with a treatment; considering the pathophysiology is also important. Data regarding a disease’s natural history is also critical as it can provide further insight.

Dr. Unger added that "because many rare diseases are slowly progressive, the usual end points—how patients feel, function, or survive, are not practicable. For situations where diseases take many years to progress, it can be useful to use a surrogate endpoint as the basis of accelerated approval. We don't have the luxury of time to wait, possibly many years, to assess the effectiveness of a drug for a rare, progressive disease”

An accelerated approval does not guarantee an automatic, long-term approval, the panel pointed out. After an accelerated approval is granted, it is incumbent on the company to then develop the clinical benefit long-term. In other words, the company has to prove to the FDA they were correct in saying this treatment is effective.

“The surrogate endpoint, for the purpose of an accelerated approval, is an endpoint that is reasonably likely to predict the clinical benefit of a treatment,” said Dr. Unger.

When a study fails to show an improvement in symptoms, that is not the time for a surrogate endpoint to come in and “rescue” the drug in development, he explained.

Dr. Purohit-Sheth added that if an endpoint that is readily measurable for survival can be assessed in a reasonable timeframe, it is better to measure that endpoint than go with a surrogate endpoint. A more traditional pathway can be better in some cases.

In light of all the important factors to consider and address in clinical trials, the panel agreed that patient input is also another significant contribution in the structure of clinical trials.

Investigators need to rely heavily on patients in order to understand just how a disease impacts them, especially in the realm of rare diseases where information is sometimes limited. Dr. Unger mentioned how patient feedback helped inform the decision to add the 6-minute walk test into clinical trials that were evaluating therapies for pulmonary hypertension, as it proved to be an important factor to consider.

With the promise of gene therapies on the horizon, knowing what clinical data is needed and what endpoints need to be considered depends largely on patient input as patients can help accurately decide what is clinically meaningful, Dr. Purohit-Sheth concluded.

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