New FDA Breakthrough Drug Category – Implications for Patients

To the Editor:

Darrow et al. (March 27 issue)1 present an incomplete and misleading review of the Food and Drug Administration (FDA) programs that are available to expedite drug development, review, and approval. As the authors note, drug regulation involves balancing the potential benefits of access to a therapy against the potential risks associated with the drugs and the prognoses of patients with the diseases that the therapies are intended to treat, on the basis of evidence of safety and effectiveness. Any evaluation of drug regulation should present a complete picture of the available evidence regarding the effect of reforms, including their impact on facilitating the generation and effective use of evidence.

The FDA has four distinct mechanisms to speed the development and availability of drugs for treating serious or life-threatening conditions: priority review, accelerated approval, fast-track review, and most recently, breakthrough therapy.2 Although these approaches all aim to advance the availability of safe and effective products, they use different selection criteria and target different parts of the drug-development process.

Darrow et al. claim that the FDA applies expedited-approval programs too liberally, noting that 56% of drugs approved in 2012 used expedited-approval pathways. However, the authors offer no analysis of these drugs and do not acknowledge that almost half the new drugs that were approved in 2012 were for orphan diseases or cancers, many of which had no effective treatment option.

Most drugs that have received accelerated approval have completed rigorous postmarketing studies, been converted to full approval, and often become standard of care. Furthermore, the FDA has taken notable steps, including its Sentinel Initiative, to enhance the availability of postmarketing safety evidence that is very difficult to obtain in the premarket setting.3

Nothing in law or FDA guidance indicates that the breakthrough-therapy designation lowers the standards for approval, nor do the authors provide evidence to support this claim. The breakthrough-therapy designation was created to facilitate a collaborative “all hands on deck” approach between the FDA and the drug sponsor on the basis of preliminary clinical evidence of substantial improvement over existing therapies for a serious or life-threatening disease.4 This approach does not confer a less rigorous path to approval. The majority of the drugs receiving the designation are still undergoing clinical trials, and only four have received FDA approval. All four are clear advances in the treatment of life-threatening diseases that previously lacked effective therapies. FDA programs have evolved over recent years to support the development and review of products that have had a lasting effect on disease treatment in the United States, positively affecting thousands of lives.

Mark McClellan, M.D., Ph.D.
Brookings Institution, Washington, DC

Ellen Sigal, Ph.D.
Friends of Cancer Research, Washington, DC