November 14, 2013


Rachel E. Sherman, M.D., M.P.H., Jun Li, J.D., Ph.D., Stephanie Shapley, M.B.A., Melissa Robb, R.N., and Janet Woodcock, M.D.

N Engl J Med 2013; 369:1877-1880 November 14, 2013 DOI: 10.1056/NEJMp1311439

Many people with serious or life-threatening illnesses for which there are no satisfactory treatments are understandably eager to gain access to new therapies and are willing to trade off greater certainty about a drug's performance for speed of access. Because the typical clinical drug-development program takes about 7 years, during which a substantial body of safety and efficacy data is generated, the Food and Drug Administration (FDA) has long-standing expedited pathways available for drugs being studied for such illnesses. However, many patients and their advocates continue to believe that clinical development is sometimes prolonged beyond what is necessary. During the congressional considerations leading up to passage of the FDA Safety and Innovation Act of 2012 (FDASIA), a variety of provisions related to this theme were put on the table. When the bill was enacted, two modifications of the Federal Food, Drug, and Cosmetic Act addressed the issue of drug development for serious illnesses: a new “breakthrough therapy” designation for investigational drugs and expansion of the statute regarding accelerated approval. The breakthrough-therapy designation has since been introduced into the FDA portfolio of expedited programs for serious conditions.

The genesis of the new designation can be traced to several emerging trends in drug discovery and development. Most notable is the rise of molecularly targeted therapies, often paired with companion diagnostics, for treatment of cancer, genetic diseases, and increasingly, other serious illnesses. These therapies are directed at subgroups of patients (within the larger population with a given disease) who are predicted to benefit from them. Some of these targeted therapies achieve a much larger treatment effect than currently available therapies — effects that are obvious even in the initial trials in humans. When a large effect in a serious disease is observed early in drug development, it seems excessive to conduct a prolonged clinical development program that encompasses traditional trial phases; approaches to expediting drug development in this circumstance, however, have not been well defined. Responding to this problem, the advocacy organization Friends of Cancer Research and the Brookings Institution sponsored workshops on possible development pathways for such drugs. After extensive discussion in the drug-development community, the concept was embodied in law.

Section 902 of the FDASIA articulates two general criteria according to which the FDA may designate an investigational drug as a breakthrough therapy. First, this designation can be applied only within the context of a “serious or life-threatening disease or condition.” Second, it must be predicated on “preliminary clinical evidence indicat[ing] that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints.” The FDA has interpreted the second criterion to mean that data from studies in animals or conducted in vitro showing that a drug has promise are not sufficient to justify this designation; data from clinical trials in humans are needed.

Once a drug is designated as a breakthrough therapy, the FDA commits to working particularly closely with the drug sponsor to devise the most efficient pathway for generating additional evidence needed about safety and efficacy. The amount of additional data needed will vary, depending on the disease, the magnitude and robustness of the initial data, and the availability of alternative therapies. The statute also calls for reducing exposure of patients to a potentially less-effective active control drug (i.e., when clinical equipoise is not present). Although this ethical principle is applicable to all development programs, it is especially pertinent to drug development under the breakthrough-therapy program in cases in which impressive early clinical data are available. In such cases, the immediate needs of patients must be balanced on an ongoing basis against the need to generate reliable data to inform therapy. In addition, rapid clinical development for breakthrough-therapy drugs will put more pressure on other components of drug development, such as drug manufacturing: development of a final formulation and scale-up of processes will have to occur more rapidly than they traditionally do. It is possible that manufacturing will become the rate-limiting step in some breakthrough-therapy drug-development programs.

It is not expected that all products designated as breakthrough therapies will in fact turn out to have the potential suggested by the early clinical data. Subsequent trials may reveal a smaller treatment effect, or unacceptable adverse effects may occur. It is also important to recognize that a breakthrough-therapy designation is not a drug approval. Like all drugs in development, drugs designated as breakthrough therapies will be reviewed by the FDA to determine whether they are safe and effective for the intended use before they can be approved for marketing. This review will be expedited for drugs designated as breakthrough therapies, if the clinical findings warrant doing so. Since enactment of the FDASIA about 1 year ago, more than 80 requests for a breakthrough-therapy designation have been submitted to the FDA, and 26 have been granted. The designations that have been publicly announced by drug sponsors, along with the conditions being studied, are listed in Table 1


TABLE 1 Drugs with Breakthrough-Therapy Designations Announced as of September 30, 2013.

How does the breakthrough-therapy designation differ from other FDA programs that expedite drug development? Fast track, which was implemented under the FDA Modernization Act of 1997, is for drugs that are intended to treat a serious condition and for which nonclinical or clinical data demonstrate the potential to address an unmet medical need. This tool allows applicants opportunities for frequent interactions with the FDA review team and permits the applicant to submit portions of an application to the FDA for review before submitting the complete application. Priority-review status is given when a new drug application is filed for a drug that, if approved, would provide a significant improvement in safety or effectiveness for a serious condition. Priority review shortens the target period for FDA review by 4 months. Accelerated approval allows for approval of drugs, again in the context of serious illness, that demonstrate an effect on a surrogate end point or intermediate clinical end point that is reasonably likely to predict clinical benefit and that also provide a meaningful advantage over available therapies. The FDASIA included language that provided flexibility in application of the accelerated-approval pathway and clarified the use of an intermediate clinical end point as a basis for accelerated approval. In Table 2, we compare the qualifying criteria and features of each of the four expedited programs.


TABLE 2 Comparison of the FDA's Various Expedited Programs for Serious Conditions.

The FDA has recently released draft guidance on expedited programs for drugs for serious conditions, including the breakthrough-therapy designation.1 The draft guidance outlines the qualifying criteria and the process for requesting a breakthrough-therapy designation for investigational drugs, and it describes features of the program that are intended to streamline drug development for highly promising agents.

The breakthrough-therapy designation program is of great interest to patients and patient advocates. Because designations are given to drugs in development, it will be some time before the program's effect on access to important therapies can be assessed. This program may represent the initiation of a new paradigm for investigational drugs undergoing development in a setting of extensive mechanistic understanding of disease pathogenesis. As the pace of scientific discovery continues to increase, drug-development pathways will need to evolve in parallel.



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