Drug Information Journal - March 2009 - (Page 201) DRUG DEVELOPMENT 201 Factors Associated With Multiple FDA Review Cycles and Approval Phase Times We examined the regulatory review histories of 298 approved new drugs and biologics with new drug applications (NDAs) or new biologic license applications (BLAs) submitted to the US Food and Drug Administration (FDA) during fiscal years 1996–2006 for factors that were associated with multiple review cycles and with longer or shorter total approval phase times (sum of FDA action and sponsor response times) for a given number of review cycles. Using logistic regression models, we found that the likelihood of multiple cycle review varied by therapeutic class, product type (odds ratio = 3.1 for BLAs), fast track status (odds ratio = 0.3), limited sponsor regulatory experience (odds ratio = 2.1 for first US approval), and more recent submissions (odds ratio = 1.7 for fiscal year 2000–2003 submissions compared to fiscal year 1996–1999 submissions). We also applied least squares multivariate regression analysis to explain the variation in total approval phase times with a number of drug, sponsor, and regulatory characteristics. After controlling for the number of review cycles and other factors, we found longer average approval phase times for more recent submissions (56% longer for priority rated compounds with multiple cycle reviews and submissions during a later period, P < .0001), compounds approved in CDER versus CBER (1 longer for single-cycle NDAs versus 8% single-cycle CBER approvals, P = .0372; 35% longer for single-cycle BLAs approved by CDER versus single-cycle CBER approvals, P = .0264; and 44% longer for multiple-cycle BLAs approved by CDER versus multiple-cycle CBER approvals, P = .0209), compounds with December submissions (1 longer for compounds 8% with multiple cycle reviews, P = .0069), and compounds with advisory committee meetings (13% longer for compounds with a single review cycle, P = .0344). We found shorter average approval phase times for compounds with a fast track designation (21% shorter for compounds with multiple cycle reviews, P = .0825) and accelerated approval status (24% lower for compounds with a single review cycle, P = .0010). Statistical models such as those presented here can help improve the precision with which drug developers and regulators predict approval times and assess the effectiveness of regulatory programs designed to speed the drug approval process. Joseph A. DiMasi, PhD Tufts Center for the Study of Drug Development, Tufts University, Boston Laura Faden, MPH Tufts Center for the Study of Drug Development, Tufts University, Boston Key Words Approval times; Food and Drug Administration; Review cycles; Sponsor response times Correspondence Address Joseph A. DiMasi, PhD, Tufts Center for the Study of Drug Development, Tufts University, 75 Kneeland Street, Suite 1100, Boston, MA 02111 (email: joseph.dimasi@tufts.edu). The time to approve new drugs once a marketing application has been submitted to regulatory authorities has long been a topic of concern and analysis (1–1 Lengthy approval times 1). mean patients get access to useful therapies later than otherwise and new drug development is more expensive (higher time costs) than it could be (12). For example, DiMasi found that, other things being equal, a one-year reduction in regulatory approval phase time reduces development times cost by 10% (13), while the Congressional Budget Office found that, on a present discounted value basis, a one-year reduction in the approval phase is more valuable to a firm than a one-year patent extension (14). Numerous studies have demonstrated that the length of the regulatory approval process in the United States became significantly shorter on average following passage of the Prescription Drug Use Fee Act of 1992 (PDUFA) and its reauthorization three times since (PDUFA I in 1997, PDUFA II in 2002, and PDUFA III in 2007) (3,5,9,10). PDUFA was enacted with FDA review performance goals that were phased in during PDUFA I and made slightly more restrictive in PDUFA II. For new molecular entities (NMEs) and their biologic equivalents, the FDA committed to taking an action on 90% of applications for marketing approval within 6 months for compounds that received a priority therapeutic significance review rating from the FDA and 10 months for compounds with standard therapeutic significance ratings (12 months under PDUFA I). Submitted for Publication: October 2, 2008 Accepted for Publication: January 2, 2009 Drug Information Journal, Vol. 43, pp. 201–225, 2009 • 0092-8615/2009 Printed in the USA. All rights reserved. Copyright © 2009 Drug Information Association, Inc.
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