New FDA breakthrough-drug category--implications for patients.

U.S. pharmaceutical regulations are based on the principle that patients should not be exposed to new prescription drugs until their efficacy and safety have been shown. Since 1962, the Food and Drug Administration (FDA) and Congress have balanced the efficient review of investiga­ tional drugs with the need to withhold judgment until sufficient evidence is available to clarify the benefit–risk relationship. Misjudging these competing interests in either direction causes important problems. On the one hand, the evi­ dentiary hurdles of the FDA are often criticized by pharmaceutical companies and patient advo­ cacy groups for slowing access to promising therapies. On the other hand, truncated premar­ ket review can lead to the approval of drugs that are ineffective, unsafe, or both. These dangers were once again made clear in October 2013 when approval was briefly sus­ pended for ponatinib, a medication to treat leu­ kemia that had been approved just the year be­ fore on an accelerated basis. Emerging data showed that 24% of the patients who had been followed for a median of 1.3 years and 48% of those who had been followed for a median of 2.7 years had serious thromboembolic events, including myocardial infarction and stroke.1 The drug was allowed back on the market in December 2013 with more limited indications and a restricted distribution system. The latest development in the FDA approach to ensuring the safety and effectiveness of mar­ keted prescription drugs occurred in July 2012, when Congress created a new category of “break­ through therapy” in the FDA Safety and Inno­ vation Act (FDASIA). A breakthrough therapy was defined as a new product to treat a serious disease for which preliminary clinical evidence suggested substantial superiority over existing options on one or more clinically significant end points.2 Lawmakers intended the designation to speed to market a limited number of prod­ ucts that showed “exceptional results for pa­ tients.”3 Lauded by policymakers,4 consumer advocates,5,6 and the FDA itself,7 the break­ through­drug pathway has been embraced by industry8 and has produced early results far ex­ ceeding predictions. From October 2012 through September 2013, the FDA received 92 applica­ tions for the breakthrough­therapy designation, of which 27 were approved and 41 denied (24 applications were still pending).9 Although some of these agents may end up being truly transfor­ mative for patient care, the breakthrough­therapy designation also raises the possibility of a surge in new drugs that have been approved on the basis of limited clinical data. There is ongoing controversy over the FDA standards for the approval of investigational drugs. In this article, we briefly summarize pri­ or government efforts to expedite the availabil­ ity of new therapeutics, and we discuss the clin­ ical, ethical, and regulatory implications of the breakthrough­therapy designation.