FDA Releases Highly Anticipated Guidance on Duchenne Muscular Dystrophy

Regulatory NewsRegulatory News | 09 June 2015 |  By 

A new draft guidance document released today by the US Food and Drug Administration (FDA) aims to clarify the development process for new drugs intended to treat Duchenne Muscular Dystrophy (DMD), a progressive, fatal disease for which there is currently no cure.


DMD is a rare disease almost exclusively affecting young men. Due to a genetic defect, the body does not produce dystrophin, which ensures the proper function of muscle tissue. Over time, this results in a progressive weakening of the body's muscles resulting in eventual paralysis and death.

For years, DMD patient advocates have been strenuously lobbying FDA for greater guidance and access to experimental drugs. One of the principal challenges of drug development is determining which clinical outcomes are meaningful for patients and which are unlikely to benefit them. Another challenge: determining the adequate trial size and design (e.g. placebo-controlled).

For drug companies, choosing the incorrect endpoint or trial design can result in tens—even hundreds—of millions of dollars in wasted development dollars, as FDA will typically send a Complete Response Letter (CRL) to a company requesting additional trials of other, more suitable endpoints.

Suitable endpoints have been a point of contention between FDA and companies developing DMD treatments. In one notable example, FDA asked Sarepta Therapeutics, developer of the DMD drug eteplirsen, for additional data to support the company's proposed New Drug Application (NDA) for the drug. The number of patients enrolled in the study was too small, FDA said, and additional data was needed from natural history studies.

The Push for Guidance

As a result of perceived challenges in the DMD drug development space, in December 2013 a consortium of DMD stakeholders began work on the development of a proposed draft guidance document meant to establish recommendations for the development of new drugs to treat DMD and other related muscular dystrophies.

The guidance is unique among FDA guidance documents in that it was first developed not by FDA, but rather by what FDA characterized as "a consortium of stakeholders including patients, parents and caregivers, clinicians, scientific experts and industry representatives."

For more information, please read Regulatory Focus' article on the development and submission of the proposed DMD guidance here.

While the group had the blessing of FDA to generate the guidance, it was ultimately the DMD stakeholders who authored the first draft of the guidance. That guidance was submitted to FDA on 25 June 2014.

FDA Guidance

FDA has now given its blessing to a draft version of the DMD guidance, releasing it for public review and comment on 9 June 2014.

The guidance, Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment, outlines the considerations companies should take into account when designing a clinical trial.

One notable admission made by FDA in its guidance is that DMD patients are, in general, "willing to accept greater risks and greater uncertainty about risks." However, FDA said companies will need to have a nuanced understanding of these risk tolerances when undertaking clinical development.

"It is important that drug developers understand from affected individuals how treatment goals and risk tolerance are related to specific patient circumstances, such as age, disease stage, and phenotype, among others," FDA wrote. "For example, tolerance for risk may differ between patients with the more severe dystrophinopathy phenotypes and those with less severe phenotypes."

Children may also be more risk-averse than adults, FDA noted. Even so, "Within the bounds of these ethical considerations, even if risk of serious or irreversible harm is possible, drug development studies may be allowed to proceed under FDA’s regulatory framework if the risks are not 'unreasonable' in the context of the seriousness of the disease phenotype," FDA said.

The guidance also delves into the design of clinical trials, including the patients needed, the safety concerns to be accounted for and desirable endpoints.

FDA said it "strongly recommends" a randomized placebo-controlled trial be the basis of any DMD drug trial. In some cases, "trials using external controls, such as historically controlled trials, may be considered adequate and well-controlled." However, such trials are only suitable when a company is using well-established, objective endpoints "less susceptible to bias."

Indeed, controlling for or eliminating bias seems to be one of FDA's most pressing concerns for the proper design of DMD trials.

Efficacy Endpoints

Perhaps the most important part of FDA's DMD guidance is its extensive section on recommended efficacy endpoints.

In it, the agency recommends a wide range of potential endpoints, and expresses a willingness to consider others as well.

"Sponsors are encouraged to propose, and, if necessary, develop, endpoints that can be used to validly and reliably assess patients with a wide spectrum of symptoms and disease stages," FDA wrote. "FDA should be engaged by a sponsor early during the selection and/or development of efficacy endpoints. Assessment of multiple efficacy endpoints should be included when feasible, to characterize the breadth of effects on dystrophin-related pathologies, including skeletal, respiratory, and cardiac muscle function, even if the study primary endpoint is only one of these measures."

The endpoints chosen for use in the study will determine the number of patients that need to be enrolled, FDA noted.

In addition, the guidance explains that performance-based outcomes may act as a meaningful way to demonstrate clinical efficacy. Measurement of a patient's ability to perform a task, the time required to perform a task, objective measurement of an ability or developmental milestones are all mentioned in FDA's guidance as being potentially useful. For example, a trial might measure the time it takes a patient to climb four stairs or walk 10 meters. Other accepted measurements include the six-minute walk test, which measures the strength and endurance of a patient.

FDA said it will also accept respiratory and cardiac endpoints, such as progression to mechanically assisted ventilation or evidence of effectiveness in chronic heart failure.

In addition, companies may also consider patient-reported outcomes (PROs), especially those determined to be meaningful to daily life as a DMD patient.

The guidance also notes that accelerated approval based on surrogate endpoints or biomarkers may be appropriate "in some situations."


Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment


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