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Speed, Safety, and Industry Funding — from PDUFA I to PDUFA VI

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Speed, Safety, and Industry Funding — from PDUFA I to PDUFA VI The new england journal of medicine Health Law, Ethics, and Human Rights Mary Beth Hamel, M.D., M.P.H., Editor Speed, Safety, and Industry Funding — From PDUFA I to PDUFA VI Jonathan J. Darrow, S.J.D., J.D., M.B.A., Jerry Avorn, M.D., and Aaron S. Kesselheim, M.D., J.D., M.P.H. In August, President Donald Trump signed into of user-fee legislation on FDA operations and the law the sixth version of key legislation for the legislative process. Food and Drug Administration (FDA), known as the Prescription Drug User Fee Act (PDUFA VI). Expanding Fees and FDA The legislation continues a policy that authorizes Commitments, Shrinking the agency to collect user fees from pharmaceuti- Review Times cal companies, providing funds that the FDA uses to hire additional staff to review new drug prod- Starting in 1962, the FDA required that manu- ucts and thereby reduce approval times. PDUFA VI facturers conduct clinical trials to demonstrate is part of the FDA Reauthorization Act of 2017 the efficacy and safety of an investigational drug (FDARA),1 which also renewed similar user-fee before its approval6,7 — a major new require- programs for medical devices, generic drugs, and ment created in the wake of the thalidomide biosimilars. disaster. As Congress increased the oversight User fees emerged after the growing AIDS crisis responsibilities of the FDA without commensu- of the 1980s and early 1990s, when concern rate increases in funding,8,9 the average time it mounted that regulatory delays — caused in large took the FDA to review a new drug application part by inadequate public funding that did not swelled from 14 months in 1963 to more than allow the FDA to hire sufficient personnel — were 35 months by 1979.10,11 Complaints from the phar- slowing the approval of promising new treatments. maceutical industry and patient-advocacy groups In the face of this persistent financial shortfall, led to the first enactment of PDUFA in 1992 to the pharmaceutical industry stepped forward to help the FDA address this problem. offer funding in the form of “user fees,” in ex- PDUFA I authorized the collection of three change for FDA commitments to accelerate drug types of fees. A fee of $100,000 was to be collected review. From the beginning, some policymakers with most new drug applications. To ensure fund- and patient advocates argued that although user ing stability notwithstanding fluctuations in the fees could help the FDA carry out some of its number of applications, annual establishment fees statutory functions, the funding could create an ($60,000) and product fees ($6,000) were to be uncomfortable dependence of the FDA on the paid for each manufacturing facility and manu- industry it regulates.2-5 factured drug, respectively.5 Fee amounts increased As the FDA prepares to implement FDARA, annually over a period of 5 years according to a we trace the evolution of the key provisions of the statutory schedule, with additional upward ad- law — which affect the funding of the FDA and justment for inflation. Smaller companies paid the timeliness and safety of the products it ap- 50% of the application fee, and the FDA could proves — from its inception in 1992 to the pres- waive or reduce fees if necessary to protect pub- ent, including a review of the major user-fee provi- lic health. sions of the new law. We then consider the effect In return for paying user fees, the pharma- 2278 n engl j med 377;23 nejm.org December 7, 2017 The New England Journal of Medicine Downloaded from nejm.org at BWH on December 11, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved. Health Law, Ethics, and Human Rights ceutical industry received several explicit assur- structure to ensure timely meetings between ances. To prevent the fees from being diverted to the FDA and sponsors throughout product de- other regulatory purposes, PDUFA required that velopment.17 they be used only for expediting the review of The initial PDUFA regulations permitted sal- human drug applications. The most important ary support only for FDA staff involved in the drug- assurances, however, were performance goals approval process, but not for the much smaller set forth in “commitment letters” that required FDA program that evaluated drug safety after the FDA to review standard applications within marketing. That changed with PDUFA III, which 12 months and priority applications — for drugs in 2002 allowed user fees to be applied to drug- determined by the FDA to treat serious or life- safety studies as well: $71 million in PDUFA funds threatening conditions that offer improvements over a period of 5 years could be applied to re- in safety or effectiveness — within 6 months.12 search on postapproval adverse effects.18 It also In 1992, then–FDA Commissioner David Kess- required the FDA to consult with stakeholder ler estimated that the user fees would allow the groups, particularly the pharmaceutical industry, agency to hire 620 new employees to help achieve before the next reauthorization. these goals.13 Fees had to be paid equally for stan- In 2004, the nonsteroidal antiinflammatory dard and priority applications whether or not an drug rofecoxib (Vioxx) was abruptly removed from application was approved, though approximately the market after 5 years of use by tens of millions 77% of applications were approved during the of Americans when it was found to substantially 1990s, a figure that has since risen to approxi- increase the risk of cardiovascular events,19,20 a mately 86%.14 Staff increases and the proportion risk later determined to also be present for other of applications reviewed by the deadlines were to cyclooxygenase-2 selective drugs, although to a be phased in over a period of 5 years, with the lesser extent.21 Public outcry and Congressional aim of hiring all planned staff and reviewing at hearings focused attention on the fact that the least 90% of newly submitted applications on FDA did not have in place a systematic, proactive schedule by the expiration of PDUFA. system for adverse-event surveillance once a drug The legislation was written to expire auto- was on the market, even though the increasing matically in 1997. Kessler explained that this digitization of health care records and modern 5-year sunset provision would provide the op- pharmacoepidemiologic approaches made this portunity “to see whether we at the Agency are quite practical.22 Congress used PDUFA IV (part meeting our performance goals and to allow the of the 2007 FDA Amendments Act) as a vehicle public, the industry . and Congress to decide to expand funding for such postmarketing sur- whether the program should be continued.”13 veillance, authorizing additional fee revenues of Industry also supported a sunset provision, ex- $225 million over a period of 5 years to support plaining that if performance goals were not met, the drug-safety activities of the FDA.23,24 it would recommend that the legislation be A major innovation of PDUFA V (part of the abolished.8 By the end of PDUFA I in 1997, the 2012 FDA Safety and Innovation Act) was to re- FDA reported meeting its goal of reviewing duce the number of FDA review cycles. By 2011, 90% of applications submitted in the previous approximately 70% of approved drugs were ap- fiscal year within either 6 or 12 months after proved after the first review cycle. From the be- submission.15 ginning of PDUFA, the FDA has had 60 days after Judging PDUFA a success,16 Congress reau- an application is received to assess whether it is thorized user fees in 1997, 2002, 2007, and 2012 complete enough for substantive review, at which (PDUFA II to V). PDUFA II phased in a reduction time the application is considered to be filed.25 in review times for standard applications from Under PDUFA V, the 6-month and 10-month re- 12 months to 10 months. It also moved beyond view periods for new drugs were changed so that speeding the FDA review period and authorized this 60-day period no longer counted toward the the use of user fees to help shorten the time PDUFA deadlines, providing the agency with ad- spent on clinical trials, which averaged approxi- ditional time to complete the first cycle of review.26 mately 7 years.17 PDUFA II also created a formal The goal of reducing multicycle reviews was n engl j med 377;23 nejm.org December 7, 2017 2279 The New England Journal of Medicine Downloaded from nejm.org at BWH on December 11, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved. The new england journal of medicine 25 20 15 Standard applications 10 5 Average Review Time (mo) Priority applications 0 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 Figure 1. FDA Review Times for Priority and Standard New Drug Applications and Biologics License Applications. Data are from the Food and Drug Administration (FDA).39 Shown is the average review time by the FDA Center for Drug Evaluation and Research. The peak in 2002 for priority applications coincided with an increase in approvals after the first review cycle to 47%, from 15% the previous year.40,41 achieved; within 3 years, the FDA reported that After the success of PDUFA, Congress enact- 95% of approved applications were being ap- ed the Medical Device User Fee and Moderniza- proved after the first review cycle. Despite the tion Act (MDUFA) in 200230 and the Generic Drug growing emphasis on the need for postapproval User Fee Act (GDUFA) and the Biosimilar User safety studies, PDUFA V deleted the provision Fee Act (BsUFA) in 2012.27 These acts, modeled on allocating $225 million to drug-safety activities.27 PDUFA, required industry to pay user fees to help To address industry concerns that the agency speed application reviews, but included some needed to be more transparent about its expecta- modifications.
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