Rare Diseases: Growing Understanding Will Unlock Accelerated Approval, FDA Says

US FDA officials believe sponsors may be able to help eventually make abbreviated approval pathways more accessible for rare disease drugs, but cautioned that preparations should begin now.

Billy Dunn, director of the Division of Neurology Products in FDA's Office of New Drugs, which handles many rare disease treatment applications, offered a hopeful prediction for the advancement of science in rare diseases, saying an explosion of knowledge about natural history and disease biology is coming that should make it easier for sponsors to use pathways like accelerated approval.

"The knowledge has to accelerate … which will then allow us to invoke mechanisms like accelerated approval," Dunn said Oct. 17 during the National Organization for Rare Disorders' Rare Diseases and Orphan Products Breakthrough Summit. "What we need to do is get the knowledge to allow us to have confidence in that."

Sponsors, as well as patient advocates, often question FDA's flexibility when it comes to allowing orphan drugs to use accelerated approval. Agency officials have argued for years that they are flexible with the evidence required for approval of orphan drugs. (Also see "Orphan Products Mostly Approved With Regulatory Flexibility, NORD "Catalog" Finds" - Pink Sheet, 17 Oct, 2011.)

Dunn said there needs to be a fundamental understanding of the disease to find and use surrogate endpoints that can support accelerated approval.

Finding Better Surrogates

Dunn said often sponsors will tell FDA "we've identified a nail and I want to hit it with a hammer." He said that strategy may work, but added that in his review division it often occurs when little is known about the effect on the disease.

"Generally our understanding of our diseases doesn't allow us to know whether or not that's good," he said.

Robert Temple, Center for Drug Evaluation and Research deputy director for clinical science, also said that surrogate endpoints are difficult to find and accept in areas where the agency does not understand what is causing the disease.

Rare disease groups have pushed for increased access to accelerated approval for rare diseases. But FDA said it would not give an all-encompassing guideline on what qualifies as a surrogate endpoint. (Also see "Biomarkers In Orphan Studies Still Need Past Experience, FDA Says" - Pink Sheet, 27 May, 2013.)

The lack of fundamental understanding of many rare diseases is part of the reason why FDA has encouraged advocates and other stakeholders to conduct or fund natural history studies. They can be used as a control in studies when new treatments are ready for testing or inform new endpoints. (Also see "Rare Diseases Need Ongoing Natural History Studies To Speed Trials, FDA Says" - Pink Sheet, 14 Nov, 2011.)

FDA recently announced grants for several natural history studies for rare diseases. (Also see "FDA Orphan Disease Clinical Trial Grants Aim To Reduce Financial Risk" - Scrip, 6 Oct, 2017.)

Be Ready For Disease Knowledge Opportunity, FDA Says

Dunn also said that as disease understanding improves, sponsors, patient advocates and FDA must be ready with novel trial designs and other approaches to take advantage.

"As this knowledge accumulates, we have to be ready and actually eager to embrace the opportunity that fundamental understanding will bring to us an ability to diagnose disease, actual disease, at a truly pre-symptomatic state," he said.

Dunn also said that it can lead to other advantages in drug development, like the creation and use of patient-reported outcomes.

"As that knowledge explodes, particularly the scientific knowledge informing us about the fundamental pathophysiological underpinnings of these diseases, ways that we can target them, the behavior of patients with those conditions so that we can design outcome measures and studies that target appropriate phases of the diseases and assess things of great relevance to patients in a most efficient way possible with designs that enhance that efficiency, that's what it's all about," he said.

Among the most contentious elements of FDA's controversial accelerated approval of Sarepta Therapeutics Inc.'s Exondys 51 (eteplirsen) in Duchenne muscular dystrophy was the question about the product's efficacy compared to the natural history of DMD. FDA officials argued that it appeared patients on the drug still were following the natural course of the disease. (Also see "Duchenne Muscular Dystrophy: Second Product Isn't The Charm" - Pink Sheet, 15 Jan, 2016.)

More Knowledge, Alternative Trial Designs

Clinical trial designs also can be enhanced by increased disease knowledge, but Dunn and others at FDA said there still is virtue in randomized, placebo-controlled trials in the rare disease space.

Patients again complained during the conference that in many rare diseases large placebo control trials are not desirable or possible, while Temple said understanding the natural history and mechanism can allow the trials can be small because the drug can have a dramatic effect.

FDA has said often the fastest route to approval is a placebo-controlled trial, because it can show efficacy quickly. And in those cases trials can be designed to move the placebo group to study drug, if appropriate. (Also see "Moscicki's Move From FDA To PhRMA About 'Best' Use Of Leadership Skills" - Pink Sheet, 18 Oct, 2017.)