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Previous Volume 359:95-98 July 3, 2008 Number 1 Next

PDF PDA Full Text Supplementary Material Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear Related Article by Carpenter, D. PubMed Citation

To the Editor: Carpenter et al. (March 27 issue)¹ report that new molecular entities (NMEs) approved in the 2 months before the first review deadlines established under the Prescription Drug User Fee Act (PDUFA) showed a higher rate of postmarketing safety problems — as measured by safety-based withdrawals, new black-box warnings, or dosage-form discontinuations — than drugs approved at any other time. They suggest that pressure to respond within the allotted time leads to poorer decision making. We consider the questions they raise to be important and have tried to replicate their analysis of safety-based withdrawals and new black-box warnings. In trying to replicate their analysis, using their definitions but with data from the Food and Drug Administration (FDA), we obtained different counts of drugs approved just before deadline as compared with those approved at other times for reviews classified as priority versus standard, for rates of drug withdrawal, and for black-box warnings. These differences may substantially affect the results of an analysis such as theirs.

PDUFA review deadlines are different for priority drugs (drugs that represent substantial improvements over marketed products) and standard drugs. On the basis of charts provided in their article, it appears that the authors classified 101 approvals as priority and 212 as standard during the PDUFA period they included in the analysis. FDA data show 132 priority approvals and 182 standard approvals. Figures 1B, 1C, and 1E of their article also suggest that 25 standard NMEs were approved before month 10, whereas FDA data show only 4 such approvals. A list of the drugs and deadline classifications used in their analysis would help pinpoint discrepancies between their data and ours. We are providing the FDA data² to help identify those differences.

In trying to replicate their analysis of safety-related events for drugs approved just before deadline versus all other drugs approved using FDA data, we found major differences in rates of safety withdrawals and black-box warnings. The authors reported that of 11 safety-based withdrawals for drugs approved during the PDUFA period, 7 were approved just before deadline; according to FDA data, only 5 of 11 drugs meet the authors' definition of just-before-deadline approvals. Carpenter et al.'s analysis cites 14 black-box warnings; the FDA's database of postmarketing black-box warnings lists 29 NMEs with warnings added after approval.

The analysis using FDA data is summarized in Table 1. The FDA data show a somewhat greater rate of withdrawals and new black-box warnings in the just-before-deadline approvals than in approvals for all other drugs, but the difference is small, is not statistically significant, and could easily represent a chance finding. The black-box warnings are most common among priority drugs approved during the first cycle, including drugs for human immunodeficiency virus infection, AIDS, and other life-threatening conditions, for which greater safety risks may be accepted and for which approvals may be based on more limited data.

View this table: [in this window] [in a new window]   Table 1. Approved New Molecular Entities (NMEs) for Which Applications Were Received between January 1, 1993, and December 31, 2004.

 

Clark Nardinelli, Ph.D.
Michael Lanthier, B.A.
Robert Temple, M.D.
Food and Drug Administration
Silver Spring, MD 20993

References

1. Carpenter D, Zucker EJ, Avorn J. Drug-review deadlines and safety problems. N Engl J Med 2008;358:1354-1361. [Free Full Text]
2. Food and Drug Administration. FDA data on PDUFA drug approvals, safety withdrawals and new boxed warnings. (Accessed June 13, 2008, at http://www.fda.gov/oc/pdufa/FDADrugAppSafetyData_files/NMESafetySumm.html.)

View this table: [in this window] [in a new window]   Table 1. Reanalysis of Data.

 
The differences between the number classified by us and that classified by Nardinelli et al. as being approved just before deadlines do not reflect errors in our data set but were the result of our intentional rounding of numbers such that drugs approved within 2 weeks of the deadline's expiration were classified as having been approved just before deadline. When we reanalyzed our data without rounding, the results were similar (Table 1, second section). Of note, the information posted by Nardinelli et al. is a new data set never before published. It differs significantly from data posted elsewhere on the FDA Web site, from data that the agency has published, and from other published medical literature.¹

There is a large difference in the number of black-box warnings in our data set and that in the set from Nardinelli et al., but most of this difference stems from the different time frames used in the two analyses. We included black-box warnings issued through July 2005; 17 of the 29 drugs with black-box warnings (58%) included by Nardinelli et al. were added between 2005 and 2007. In addition to the differences resulting from the different time windows, we believe that both our analysis and that by Nardinelli et al. omitted postmarketing black-box warnings, and we have corrected our data set to account for this (see the Supplementary Appendix). When we reanalyzed our corrected data set, with the addition of data through December 2007, we found more modest but still significant associations between just-before-deadline approvals and safety problems (odds ratios, 2.1 to 3.6) (Table 1, third section).

The difference in the results of our analyses of data through December 2007 and the analyses of Nardinelli et al. can be accounted for by their omission of two ofloxacin antibiotics from the safety-based withdrawal count and by their omission of five drugs (adefovir, emtricitabine, entecavir, tenofovir, and tipranavir) from the new black-box warning count. In these cases, drugs with a black-box warning at the time of approval were subsequently relabeled and important safety information and new content were added to the warning.²

Daniel Carpenter, Ph.D.
Harvard University
Cambridge, MA 02138
dcarpenter{at}gov.harvard.edu

References

1. Difference between Carpenter/Zucker/Avorn data and Nardinelli et al data, and re-analysis of data adjusting for these difference, and robustness and sensitivity checks on analyses. Investigations details. May 2008 (memorandum). (Accessed June 13, 2008, at http://people.hmdc.harvard.edu/~dcarpent/fdaproject/nejmresponse20080517.pdf.)
2. Section 8. Coding of black-box warnings. (Accessed June 13, 2008, at http://people.hmdc.harvard.edu/~dcarpent/fdaproject/nejmresponse20080517.pdf.)

PDF PDA Full Text Supplementary Material Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear Related Article by Carpenter, D. PubMed Citation