Anavex Life Sciences Corp (AVXL)

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Breakthrough-Therapy Designation — An FDA Perspective
TO THE EDITOR:
Recent medical advances, such as targeted therapies for specific tumor genomic defects, checkpoint inhibitors for cancers, and direct-acting antiviral agents for hepatitis C, have led to increasing numbers of potentially important candidate drugs for patients with serious or life-threatening diseases. These advances challenge the Food and Drug Administration (FDA) to prioritize and focus resources on the most promising products in the pipeline that target diseases for which no satisfactory treatment options exist. Fast-track and breakthrough-therapy designations1,2 are intended to do just that. The added focus, along with greater interactions with FDA staff, may help accelerate development but does not alter the standard for approval — the requirement to provide substantial evidence of effectiveness.

The FDA shows flexibility (described in a statute and regulations3) in the design of programs for drugs targeting a serious or life-threatening disease, especially for rare diseases or uncommon cancers, since it may not be feasible or ethical to conduct a randomized trial. This flexibility relates to the diseases being targeted and not the priority designation. Single-group trials with historical controls can provide substantial evidence of effectiveness — for example, in late-stage cancer in which metastases regress with treatment or in a progressive neurodegenerative disease that stabilizes with treatment. The FDA’s toolbox also includes accelerated approval, which can bring drugs to patients with a serious or life-threatening disease who have limited options on the basis of an intermediate clinical end point or a surrogate that is considered “reasonably likely” to predict benefit. After such an accelerated approval, clinical benefit must be confirmed.

To gain designation as a breakthrough therapy, the candidate drug must show potential for benefit above that of available therapies. Such therapies have usually been approved by the FDA but can be an unapproved use of a drug or surgical intervention, provided there is compelling evidence of safety and effectiveness, including extensive evidence in published literature.1 The FDA excludes from available therapies any drug that is approved through the accelerated-approval process until confirmatory evidence regarding a clinical end point is obtained, a policy decision that errs on the side of facilitating the development of additional options until definitive evidence of clinical benefit is shown.

Not all drugs with the breakthrough-therapy designation ultimately deliver on their promise. The standard criteria include preliminary clinical data showing substantial improvement over existing therapies with respect to a relevant end point, rather than the “substantial evidence” needed for approval. One can argue that if the preliminary evidence for all drugs with the breakthrough-therapy designation were to be confirmed in later-stage trials, the bar for the designation was set too high.

Rapid medical advances have led to a steady increase in the number of applications for investigational new drugs. The FDA needs the tools to identify and accelerate the approval of drugs that can substantially improve the lives of patients with serious or life-threatening diseases who have inadequate options. Fast-track and breakthrough-therapy designations have done just that — while not without challenges, certainly without compromising the thoroughness of our review or the standards of evidence to support approval.

Jacqueline Corrigan-Curay, J.D., M.D.
Amy E. McKee, M.D.
Peter Stein, M.D.
Food and Drug Administration, Silver Spring, MD
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http://www.nejm.org/doi/full/10.1056/NEJMc1801222