Post-approval safety issues with innovative drugs: a European cohort study.
BACKGROUND
At time of approval, knowledge of the full benefit risk of any drug is limited, in particular with regards to safety. Post-approval surveillance of potential drug safety concerns is recognized as an important task of regulatory agencies. For innovative, often first-in-class drugs, safety knowledge at time of approval is often even less extensive and these may require tighter scrutiny post approval.


OBJECTIVE
We evaluated whether more post-approval serious safety issues were identified for drugs with a higher level of innovation.


METHODS
A cohort study was performed that included all new active substances approved under the European Centralized Procedure and for which serious safety issues were identified post-approval from 1 January 1999 to 1 January 2012. Serious safety issues were defined as issues requiring a Direct Healthcare Professional Communication to alert individual healthcare professionals of a new serious safety issue, or a safety-related drug withdrawal. Data were retrieved from publicly available websites of the Dutch Medicines Evaluation Board and the European Medicines Agency. The level of innovation was scored using a validated algorithm, grading drugs as important (A), moderate (B) or modest (C) innovations or as pharmacological or technological (pharm/tech) innovations. The data were analyzed using appropriate descriptive statistics and Kaplan-Meier analysis, with a Mantel-Cox log-rank test, and Cox-regression models correcting for follow-up duration, to identify a possible trend in serious safety issues with an increasing level of innovation.


RESULTS
In Europe, 279 new drugs were approved between 1999 and 2011. Fifty-nine (21 %) were graded as important, 63 (23 %) moderate, or 34 (12 %) modest innovations and 123 (44 %) as non-innovative (pharm/tech), while 15 (25 %), 13 (21 %), 8 (24 %) and 17 (14 %) had post-approval safety issues, respectively (p = 0.06, linear-by-linear test). Five drugs were withdrawn from the market. The Kaplan-Meier-derived probability for having a first serious safety issue was statistically significant, log-rank (Mantel-Cox) p = 0.036. In the final adjusted Cox proportional hazard model there was no statistically significant difference in occurrence of a first serious safety issue for important, moderate and modest innovations versus non-innovative drugs; hazard ratios 1.76 (95 % CI 0.82-3.77), 1.61 (95 % CI 0.76-3.41)], and 1.25 (95 % CI 0.51-3.06), respectively.


CONCLUSIONS
A higher level of innovation was not clearly related to an increased risk of serious safety issues identified after approval.
Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, FB20, P.O. Box 196, 9700 AD, Groningen, The Netherlands, p.g.m.mol@umcg.nl.
Peter G M
PG
Mol
Arna H
AH
Arnardottir
Domenico
D
Motola
Patrick J
PJ
Vrijlandt
Ruben G
RG
Duijnhoven
Flora M
FM
Haaijer-Ruskamp
Pieter A
PA
de Graeff
Petra
P
Denig
Sabine M J M
SM
Straus
D000465:Algorithms; D015331:Cohort Studies; D003257:Consumer Product Safety / Q000592:standards*; D017277:Drug Approval; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000209:etiology; D005060:Europe; D006801:Humans; D011358:Product Surveillance, Postmarketing / Q000592:standards / Q000706:statistics & numerical data; D016016:Proportional Hazards Models; D056737:Safety-Based Drug Withdrawals / Q000706:statistics & numerical data