key: cord-0889088-mtxog2z9 authors: Van Norman, Gail A. title: Update to Drugs, Devices, and the FDA: How Recent Legislative Changes Have Impacted Approval of New Therapies date: 2020-08-24 journal: JACC Basic Transl Sci DOI: 10.1016/j.jacbts.2020.06.010 sha: 7539d2b1af63dfa3570db6726f397ee18e3dd84d doc_id: 889088 cord_uid: mtxog2z9 Two major legislative actions since 2015, the 21st Century Cures Act of 2016 and the U.S. Food and Drug Administration (FDA) Reauthorization Act of 2017, contain significant provisions that potentially streamline drug development times, and by extension, may reduce costs. Evidence suggests, however, that development times have already been significantly affected by previous legislation and FDA programs, through accelerated approval pathways and adoption of more flexible definitions of clinical evidence of efficacy. The COVID-19 pandemic is pushing researchers and commercial entities to further test the limits of drug and vaccine development times and approvals, at an as yet unknown level of risk to patients. COVID-19 drug and vaccine trials are even now making use of accelerated drug approval programs, blended trials, and adaptive trial design to accelerate approval of therapeutics in the pandemic. Before progressing from either Phase I or II, the investigator must pause and provide information on the safety of the new drug, any new information discovered in each of those phases, and any changes in manufacturing or drug preparation. If there is no objection from the FDA at each of these stages, the drug can proceed to the next clinical phase. Upon completion of successful Phase III studies, a process that takes around 8 to 10 years for most common drugs, the investigator or sponsor pays an application fee and files a New Drug Application (NDA) that includes extensive information on the drug, the results of all phases of testing, manufacturing and facilities, quality control, labeling, and risk evaluation and mitigation. For an NDA, the FDA requires "substantial evidence" of a drug's safety and efficacy, a requirement that until recently was interpreted to mean at least 2 adequate and wellcontrolled Phase III trials with convincing demonstration of efficacy (4) . The FDA has 60 days to file the application, unless it raises questions, and after the filing, it must review the application within 180 days. Two other pathways for approval exist to be used only under very extraordinary circumstances. In some situations, such as a nuclear accident or terrorism attack involving a biological or radiation weapon, DABs can be approved and deployed in the absence of human trials altogether-primarily because to carry out human trials that, required, for example, exposure to lethal doses of radiation, would be unethical (7) . Additionally, in the face of an officially declared public health emergency, the FDA can provide Emergency Use Authorizations (EUAs) (8) that permit public release of the DAB after Phase II efficacy has been shown. Phase III human clinical studies are deferred, and once the emergency has abated, confirmatory studies must be carried out after market approval (they are then usually termed Phase 4 studies). This latter "pathway" is of particular interest in the COVID-19 pandemic. Table 1 (9-11). Driven largely by budget limitations that prevented the FDA from employing sufficient personnel to provide timely processing of NDAs, FDA review times ran around 33 months in 1987 (12). In the face of a growing AIDS crisis, the pharmaceutical industry offered funding to the FDA in the form of "user fees" in press concern that there has been a weakening of the Regenerative medicine advanced therapy (cell therapy therapeutic tissue engineering product, human cell and tissue product, or any combination product using these) used to treat, modify, reverse, or cure a serious or life-threatening condition, and preliminary clinical evidence indicates that it has the potential to address an unmet medical need *The FDA defines a serious condition as one that will have an impact on day-to-day survival, functioning or the likelihood that if left untreated a condition will progress from a less serious one to a serious one. DAB ¼ Drugs and Biologics; FDASIA ¼ U.S. Food and Drug Administration Safety Innovations Act; other abbreviations as in Table 1 . These changes decreased development times significantly (4.8 vs. 8 years) (19) . Yamashita et al. (24) found that for anticancer therapies, pursuit of any of the expedited programs was associated with reduced review times (Table 3) , by a range of 2.0 to 3.4 years. This finding is similar to a previous study by Hwang et al. (32) . Most DAB approvals that they examined in the AA program (88%) used a noncomparative study design (24) . As more and more diseases are genetically subclassified, more drugs qualify for AA tracts. Almost two-thirds of all INDs (64%) now qualify for such programs (14) . The RMAT drug classification went live in March of 2017 and is too new to determine whether it has been associated with reduced development timelines (33) . IS PATIENT SAFETY BEING COMPROMISED? Accelerated drug approval pathways shave time off of the approval process and may theoretically reduce DAB Average times in years from Investigational New Drug application to U.S. Food and Drug Administration (FDA) drug approval for anticancer drugs and biologicals achieving accelerated track designation at the FDA from 2012 to 2017 compared with overall anticancer drug approval times for the same period (median of 8.3 ys, n ¼ 115 drugs), and separated by categorization as a drug for "minor" versus "major" cancer. (24) . *Regenerative Medicine Advanced Therapy designation was created too recently to comment on review times. which announced on June 10th, 2020, that it would begin a Phase I/II study (42) . Oxford University has also indicated that trials of their vaccine will proceed along a process blending Phases I and II, and will certainly be applying for EUAs if efficacy is shown (43) . With reportedly around 100 companies and academic institutions competing to develop a COVID-19 vaccine (44), it is a virtual given that they will all try to make full use of the innovative trial designs and accelerated programs combined with early EUAs to race for approval. FDA's Origins and Functions: Part III. Drugs and Foods Under the 1938 Act and Its Amendments Drugs, devices and the FDA: part 1. An overview of approval processes for drugs How FDA Approves Drugs and Regulates Their Safety and Effectiveness Single patient investigational new drug, and the "right to try Food and Drug Administration Food and Drug Administration Food and Drug Administration. 21st Century Cures Act Public Law 115-52. 115th Congress. 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Trump Administration Announces Framework and Leadership for 'Operation Warp Speed /An-Overview-of-Bayesian-Adaptive-Clinical-Trial-Design announces-acceleration-of-its-covid-19-vaccine-candidate-phase-1-2a-clinical-trial-tobegin-in-second-half-of-july The Oxford Vaccine Group Vaccine to Begin Phase II/III Human Trials Trump Seeks Push to Speed Vaccine Despite Safety Concerns. The New York Times