Article type
Year
Abstract
Introduction:
Objectives: As part of the New Drug Application (NDA) approval process, the United States (US) Food and Drug Administration (PDA) generates a review of each NDA. The use of data from these unpublished FDA Reviews in meta-analysis is controversial. In a meta-analysis to assess the risk of dyspepsia from nonsteroidal antiinflammatory drugs (NSAIDs), we compared PDA Reviews and published reports on the quantity and quality of available data and the pooled relative risk for dyspepsia
Methods: RCT's of NSAIDs were identified by an unrestricted search of MEDLINE, EMBASE, HEALTSTAR and BIOSIS from 1966-1997. Titles, abstracts and/or reports were reviewed to identify studies that included a placebo group, studied adults, used oral NSAIDs for more than 4 days, and reported dyspepsia by subject. All PDA NDA Reviews were obtained for the 5 NSAIDs with the largest US market share: diclofenac, etodolac, ibuprofen, nabumetone, and naproxen. NDAs were hand-searched to identify unpublished studies with inclusion criteria identical to those used for published reports. Data extraction was performed in duplicate with consensus resolution of discrepancies. All studies were assessed for the quality of reporting using the scale developed by Jadad. Summary measures of risk difference were calculated with a random effects model; meta-regression was used to assess the effect of study covariates.
Results: 4849 published titles were identified, from which 1768 articles were selected, 96% of which were retrieved and reviewed, yielding 37 published studies. 27 NDA Reviews contained 141 studies, of which 11 met inclusion criteria. PDA reviews and published reports were of equivalent sample size (mean N = 261 v 216, p=0.7). 89% of published reports and 82% of PDA studies had Jadad scores of 3 or more (p=0.53), although the mean Jadad score for PDA reports was lower than the mean for published reports (2.8 vs. 3.5; p=0.03). The pooled relative risk for dyspepsia was 1.5 for published reports, and significantly different than 1 (95% CI 1.2,1.8), while using PDA reviews this value was 1.1, which was not significantly different than 1 (95% CI 0.7,1.6). In a meta-regression adjusting for study covariates, the adjusted measures of treatment effect were essentially unchanged.
Discussion: PDA Reviews contain a substantial amount of unpublished data regarding NSAID-related dyspepsia that is of comparable quality to published data. The conclusion reached by the PDA Review data is that use of NSAIDs is not associated with dyspepsia, while that reached by published data is that use of NSAIDs is associated with dyspepsia.
Objectives: As part of the New Drug Application (NDA) approval process, the United States (US) Food and Drug Administration (PDA) generates a review of each NDA. The use of data from these unpublished FDA Reviews in meta-analysis is controversial. In a meta-analysis to assess the risk of dyspepsia from nonsteroidal antiinflammatory drugs (NSAIDs), we compared PDA Reviews and published reports on the quantity and quality of available data and the pooled relative risk for dyspepsia
Methods: RCT's of NSAIDs were identified by an unrestricted search of MEDLINE, EMBASE, HEALTSTAR and BIOSIS from 1966-1997. Titles, abstracts and/or reports were reviewed to identify studies that included a placebo group, studied adults, used oral NSAIDs for more than 4 days, and reported dyspepsia by subject. All PDA NDA Reviews were obtained for the 5 NSAIDs with the largest US market share: diclofenac, etodolac, ibuprofen, nabumetone, and naproxen. NDAs were hand-searched to identify unpublished studies with inclusion criteria identical to those used for published reports. Data extraction was performed in duplicate with consensus resolution of discrepancies. All studies were assessed for the quality of reporting using the scale developed by Jadad. Summary measures of risk difference were calculated with a random effects model; meta-regression was used to assess the effect of study covariates.
Results: 4849 published titles were identified, from which 1768 articles were selected, 96% of which were retrieved and reviewed, yielding 37 published studies. 27 NDA Reviews contained 141 studies, of which 11 met inclusion criteria. PDA reviews and published reports were of equivalent sample size (mean N = 261 v 216, p=0.7). 89% of published reports and 82% of PDA studies had Jadad scores of 3 or more (p=0.53), although the mean Jadad score for PDA reports was lower than the mean for published reports (2.8 vs. 3.5; p=0.03). The pooled relative risk for dyspepsia was 1.5 for published reports, and significantly different than 1 (95% CI 1.2,1.8), while using PDA reviews this value was 1.1, which was not significantly different than 1 (95% CI 0.7,1.6). In a meta-regression adjusting for study covariates, the adjusted measures of treatment effect were essentially unchanged.
Discussion: PDA Reviews contain a substantial amount of unpublished data regarding NSAID-related dyspepsia that is of comparable quality to published data. The conclusion reached by the PDA Review data is that use of NSAIDs is not associated with dyspepsia, while that reached by published data is that use of NSAIDs is associated with dyspepsia.