FDA has embraced many of the recommendations put forward in a community group’s proposed guidance for development of drugs to treat Duchenne muscular dystrophy, including use of biomarkers for accelerated approval and consideration of patient willingness to accept greater risks.

FDA released its 13-page draft guidance, "Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment," on June 9. In an accompanying statement, the agency said that for the first time, its development of a guidance was preceded by the submission of a proposed draft guidance independently prepared by an advocacy group, Parent Project Muscular Dystrophy.

That 71-page proposal, submitted in June 2014, advised sponsors to consider the preferences of patients and family members in making benefit-risk assessments. The group also included detailed proposals for clinical trial design, outcome measures, and the use of biomarkers ([A#00140707011]).

Pat Furlong, president of Parent Project Muscular Dystrophy, said the release of the draft FDA guidance marks “a historic day for our community.”

“While the level of specificity may differ between the two versions, it appears that the themes and intent are consistent,” Furlong said. “We understood at the inception of this process that the work products of FDA and PPMD would be complementary and not identical. We learned from FDA that the community’s proposed draft guidance will stand on its own as a companion to FDA’s guidance.”

Flexibility On Placebo-Controlled Trials

Furlong noted that FDA had advised the group to expect certain differences, such as with regard to clinical trial design. PPMD’s document noted that there is widespread support in the DMD community to move away from placebo-controls. It suggested that other trial designs might be warranted, such as age-matched and stage-matched natural history controls.

FDA’s draft guidance states that “randomized placebo-controlled trials are strongly recommended, and generally are the most efficient way to demonstrate efficacy for drugs for dystrophinopathies.” However, in some circumstances “trials using external controls, such as historically controlled trials, may be considered adequate and well-controlled, and may provide or contribute to evidence of efficacy to support approval.”

The agency adds that historically controlled trials lack important design features that reduce bias, such as randomization and masking of treatment assignment and “generally are persuasive only when drug effects are large on objective endpoints that are less susceptible to bias.”

FDA Open To New Outcome Measures

PPMD’s document also said that the current focus on the six-minute walk test as the primary endpoint had limited participation in clinical trials. It advised sponsors to use a single primary endpoint in trial designs, such as a clinical outcome or a pharmacodynamic biomarker, along with appropriate secondary endpoints. It also suggested consideration of novel trial designs, including delayed placebo or rapid roll over trials.

FDA’s draft guidance says that in determining drug efficacy, there is no defined set of required or recommended clinical outcome measures for studies in dystrophinopathies. The agency says it will consider proposals for the use of new outcome measures that are capable of measuring clinically meaningful effects in patients. FDA encourages sponsors to propose and, if necessary, develop endpoints to assess patients with a wide spectrum of symptoms and disease stages and when feasible assess multiple efficacy endpoints.

The draft guidance notes that the six-minute walk test, or shorter versions such as the two-minute walk test, can measure both strength and endurance and can be appropriate for patients as young as five years old. It says that a challenge of using the test in older patients is the floor effect of losing ambulation.

“The aggregated data analysis of change in 6MWT is strongly influenced by the inclusion or exclusion of patients who lose ambulation during the trial, which leads to zero values,” the guidance states.

The guidance says efficacy can also be demonstrated by an effect on respiratory and/or cardiac endpoints. And it says patient-reported outcomes can be useful to assess the clinical meaningfulness of an objective finding of relatively small magnitude and to contribute to assessments of benefit and risk.

The agency advises that chronically administered drugs should be shown to be effective for at least three months. And that efficacy studies of 18 to 24 months duration may substantially increase statistical power.

Right Biomarker Could Support Accelerated Approval

The draft guidance also notes that biomarkers that “reliably reflect the health and amount of skeletal muscle at a biochemical, cellular, or tissue level may be useful across the drug development process,” including in some instances as surrogate endpoints to support accelerated approval, “if supported by sufficient scientific evidence and acceptable analytical methods.”

“Even if it cannot be concluded that a given biomarker can serve as a surrogate endpoint, positive findings based on a biomarker may help support the mechanism of action of a drug, help to identify the appropriate patient population to study or treat, or support the validity of findings on other endpoints,” the draft states. It adds that it is important to include as many biomarkers as feasible to help establish their correlation with clinical endpoints.

The potential for a biomarker to predict clinical benefit in dystrophinopathies is inseparable from such factors as the magnitude of change of the biomarker and tissue in which it is measured, FDA states. And the draft guidance notes that the meaning of a change in a biomarker might depend on the age or disease stage of a patent or other patient factors.

FDA encourages sponsors to consider the use of other biomarkers, such as those measured with magnetic resonance imaging or magnetic resonance spectroscopy.

The draft guidance also notes that in some situations, accelerated approval can be based on an intermediate clinical endpoint, such as myometry and certain respiratory measures.

At a March FDA-NIH workshop on methodologies to detect and quantify the dystrophin protein, scientists and other stakeholders urged FDA not to push too hard to find ideal biomarkers in disease areas with great need ([A#00150330002]).

DMD is a muscle-wasting disease that affects young boys and gradually diminishes their ability to walk. It is caused by mutations in the dystrophin gene that prevents the expression of functional dystrophin, a structural component in muscle tissue. It occurs in approximately 1 in 3,500 to 6,000 males.

Companies have had trouble using biomarkers in development of drug candidates. Two years ago, FDA rejected Sarepta Therapeutics Inc.’s use of dystrophin as a biomarker to support accelerated approval of its DMD treatment eteplirsen ([A#14131112004]).

The company continued development and announced last month that it was initiating a rolling NDA submission with the final component of the NDA to be submitted by mid-year.

In April, BioMarin Pharmaceutical Inc. completed a rolling NDA submission for its DMD drug drisapersen. Both eteplirsen and drisapersen are intended to treat a subset of the population with a mutation on exon 51, about 13% of the total DMD population. BioMarin acquired the candidate with its acquisition of Prosensa Holding BV in November.

PTC Therapeutics Inc. is also developing a DMD drug candidate, ataluren, and expects to have results of a Phase III study in the fourth quarter of 2015.

Less Safety Data But From Broad Range Of Patients

With regard to drug safety, the draft guidance says applications must be supported by an adequate number and duration of patient exposures to characterize drug risks. “Drugs shown to provide an important benefit may need less safety data to provide adequate assurance that risks are commensurate with benefits.”

But the guidance adds that as much safety data as possible should be collected from patients across the spectrum of disease stages and severities, including, whenever possible, from patients who may not have been included in efficacy studies but in whom it could be possible to conclude that the drug might be effective.

FDA also acknowledges that those affected by life-threatening and severely debilitating illnesses with unmet medical need are generally willing to accept greater risks and greater uncertainty about risks.

“Nonetheless, 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,” the draft guidance states.

Duchenne Muscular Dystrophy: FDA Supports Broader Outcome Measures, Biomarkers

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