When Sarepta Therapeutics’ Duchene muscular dystrophy (DMD) drug, Exondys 51, got the green light from the US FDA last September, it became most controversial drug approvals of 2016. FDA Commissioner at the time, Robert Califf, decided to go against the recommendation of an FDA panel of advisors, who voted against recommending the drug, 7-3. This panel claimed that there was little evidence of efficacy from the clinical trial, given that the study was limited to just 12 boys.

To understand why Califf approved the drug, despite the advice given by the advisory panel, it is important to consider the challenges that rare disease companies, like Sarepta Therapeutics, face when trying to get their drugs approved for market use.

One of the biggest challenges for companies is designing an effective clinical trial, given that there is very little known about most rare diseases. Having a detailed understanding of the natural history of a disease is important for trial sponsors, as it helps a company identify key milestones in disease progression. This will allow a company to determine the appropriate study length, develop appropriate inclusion/exclusion criteria, and define suitable clinical trial endpoints.

However, rare diseases are usually poorly understood, which means that patients are often misdiagnosed or diagnosed too late for meaningful data to be collected on the progression of their disease. As such, rare disease companies often have a limited knowledge base to pull from, meaning they must spend a lot more time and effort thinking about an appropriate trial design and must be a lot more flexible than those companies developing drugs for more common conditions.

Once a company has a suitable trial design, the next challenge is finding enough patients to actually enroll into the trial. This is especially difficult for rare disease companies given that each rare disease affects fewer than 200,000 people in the US, and 1 in 2000 people in Europe. Such small patient populations make it difficult to find trial participants, especially when you consider that patients will most likely be dispersed sporadically all over the world.

A sponsor will, therefore, have far fewer patients to study, and will have to spend a lot more time and money capturing meaningful data from these patients, than would a company developing a drug for a more common condition. This is not feasible for many companies, as rare disease manufacturers are not expected to make huge revenues once their drugs come to market, as their consumer base is so small. Because of this, the classic clinical trial design is too costly and time-consuming for them to follow.

To add to this, once patients are identified and enrolled in a clinical trial, rare disease companies also face the ethical issue of using placebo or control drugs. The use of controls strengthen trial design by addressing any concerns surrounding clinical variability. As such, placebo-controlled trials are considered the gold standard when it comes to collecting meaningful clinical data.

However, because rare disease patients usually have no valid treatment options available to them outside of a clinical trial, and have potentially shortened lifespans, it is considered grossly unjust to give some patients in the trial a new drug that could help save their lives and give others a placebo product. Rare disease companies, therefore, must be sensitive to the needs and expectations of desperate patients and, as a result, often find that they cannot justify conducting placebo-controlled clinical trials.

Given the issues discussed above, it is easy to see why the FDA might warrant flexibility when it comes to approving drugs, like Exondys 51, which are intended to treat rare diseases. And, although there were many critics of Califf’s decision at the time, the US now has a new president with new goals for speeding up drug approvals, so rare disease patients across America will likely be waiting to see if such flexibility will soon become the new norm.