FDA Issues Drug Development Guidance for Duchene Muscular Dystrophy

A year after a consortium of stakeholders issued a proposed wish-list of approaches to the development of drugs for Duchenne Muscular Dystrophy, the FDA issued draft guidance giving drugmakers more leeway in how those drugs are created.

In a unique approach, the FDA has formalized what patient advocates have been seeking for years, allowing drugmakers to create clinical trials that allow a higher tolerance for risk, depending on the age of the patient and the severity of the patient’s situation.

The guidance cites lack of treatments and says that clinical trials will be allowed to proceed if the risks are not “unreasonable” in the context of the DMD phenotype.

It is unique in that it builds on draft guidance drawn up by a consortium of DMD stakeholders and published by the FDA for comment in June 2014. The consortium called on the agency to consider a higher tolerance for risk in developing treatments for the disease.

To minimize risks and adverse events, trials should be conducted under the oversight of a safety assessment committee with access to real-time unblinded safety data. The FDA will weigh the life-threatening nature of DMD when determining the minimum number and duration of patient exposures.

The FDA devotes a great deal of attention to discussing clinical endpoints. Trials should include as many biomarkers as feasible to establish clinically meaningful endpoints. In some situations, the FDA may consider accelerated approval based on intermediate clinical endpoints if the endpoints appear to reasonably predict the drug’s effect, the guidance says.

The FDA and drugmakers have struggled over what are suitable endpoints for measuring efficacy of DMD drugs. In November, the FDA delayed Sarepta Therapeutics’ NDA submission for eteplirsen, asking for additional data, after a study of a similar drug by GlaxoSmithKline and Prosensa Therapeutics failed.

The guidance recommends using performance-based outcomes — such as time to climb stairs or perform a task — to show clinical effectiveness. The agency will also consider patient-reported outcomes, particularly those associated with the quality of the patient’s life.

The agency strongly recommends randomized placebo-controlled trials. Studies using external controls may be adequate, but to be persuasive sponsors should present detailed evidence that the study design and conduct adequately controlled for bias.

For drugs whose safety and efficacy is tied to a specific patient’s genetic mutation, sponsors should develop a companion diagnostic, the FDA says. However, given the life-threatening nature of the disease and the lack of alternative treatments, the agency could approve a drug without a CDx if the benefits clearly outweigh the risks.
Comments on the draft guidance are due Aug. 9. Read it at www.fdanews.com/06-15-dystrophyguidance.pdf. — John Bechtel