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Posted: May 16, 2013
Rare Disease Group Pushes Endpoint Discussion In FDASIA Guide
Without key changes to FDA's consideration of surrogate and intermediate endpoints, drugs in the pipeline to treat muscular dystrophy will not make it to approval, a rare disease group said in pushing suggestions for FDA Safety and Innovation Act-mandated guidance on accelerated approval. An industry consultant also urged the agency to seize on flexibility provided in the law to incorporate new clinical endpoints into and apply more flexibility to the review of a variety of therapeutic areas.
Parent Project Muscular Dystrophy issued a white paper in late April outlining recommendations on how FDA could improve its review of drugs for serious and life-threatening diseases that currently lack treatments. The group, which advocates for Duchenne muscular dystrophy patients, said FDA granted orphan drug designations to 26 compounds being investigated to treat the disease, but none would be approved by FDA unless the agency makes significant changes to its regulatory review process.
FDA should address how it plans to incorporate patient perspectives into its benefit-risk assessments and clarify how the agency will address the use of surrogate and intermediate endpoints in an FDASIA-mandated accelerated approval guidance FDA is required to issue in July, PPMD says in the document.
"What we really wanted to do was get out ahead of that guidance," said PPMD President and CEO Pat Furlong. "We've spent some time with the FDA to educate them. Families have felt that FDA wasn't very flexible but we've learned from [FDA] that they are very interested in learning about what families are willing to risk." There is also a broader effort by the rare disease community to influence the highly anticipated agency document.
The primary endpoint used for most clinical trials for Duchenne is a six-minute walk test. FDA refused a new drug application for Duchenne in 2011 because it did not have data significant to that endpoint but retrospective analysis showed that the product did improve function, PPMD said. The group also said there is a lack of validated endpoints for patients who cannot complete the walk test and that FDA should generally provide guidance on the use of surrogate and intermediate endpoints in the accelerated approval process.
"In particular, the FDA should outline the level of acceptable evidence for accelerated approval of a new drug using a novel endpoint, which presents a critically important potential pathway for providing commercial access to new therapies for Duchenne," the document says.
Further, PPMD said "opaque evaluation metrics" and the industry perception that FDA is reluctant to approve products based on surrogate endpoints has discouraged investment in treatments for neurological disorders. When the agency issues guidance on accelerated approval, it should provide clearer requirements on the use of surrogate and intermediate endpoints used to approve drugs for serious or life-threatening diseases, the group said.
A provision on accelerated approval in the statute says that based on advances with biomarkers, trial enrichment techniques, and novel clinical trial designs like adaptive clinical trials, FDA should more broadly implement expedited review of drugs for unmet medical needs and serious or life-threatening diseases. PPMD also recommends FDA expand the use of accelerated approval to treatments for rare diseases and pilot the use of adaptive approval for disorders with unmet medical need.
An industry consultant said she also sees the FDASIA provision as an opportunity for the agency to expand accelerated approvals beyond oncology and HIV drugs and include other therapeutic areas like rare diseases.
"If you look specifically and very carefully at the language that's in the statute, in many ways it's different from what's in regulations," Virginia Beakes-Read, executive director of global regulatory affairs at Eisai, Inc., said at a recent food and drug law event.
She said the current statute provides FDA with more flexibility to use the program in a variety of areas and incorporate new endpoints. Beakes-Read added that she would also like to see the agency discuss how it plans to incorporate new clinical endpoints into reviews and what it believes those new endpoints should look like.
PPMD said FDA should also establish other mechanisms to incorporate the patient perspective into its review process, pointing out that although the agency has initiated patient-focused drug development meetings, the five-year timeframe for the meetings is too long for patient groups that have been waiting years for FDA to take such actions.
FDA announced earlier this month that it had selected the first 16 of 20 disease areas it will focus on during patient-focused drug development meetings mandated by FDASIA. The first two-day meeting on chronic fatigue syndrome took place April 25. FDA's process for selecting the 20 disease areas became a contentious issue last year as groups representing diseases not included on the agency's preliminary list advocated for the agency to cluster diseases with similar symptoms so that more could be included in the meetings.
The agency grouped some disease areas but also encouraged groups whose disease areas were not included to pursue other opportunities to meet with the agency (see FDA Week, April 12).
Muscular dystrophy was not included on the list although several muscular dystrophy treatment advocacy groups did organize a meeting with the agency in February. PPMD Vice President of Research Sharon Hesterlee said even if the disease had been on the list, it would consider the five-year time frame for FDA to incorporate patient perspectives into the benefit-risk framework to be too long.
"I think we felt like the timeframe, even if we were included on that list, that it was a very slow timeframe," she said.
Furlong added that PPMD's goal with the white paper is to encourage the agency to apply flexibility to its review of rare disease treatments and show that there is an urgent need to make those treatments available to patients.