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...

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Published in:Drug safety 2013-11, Vol.36 (11), p.1105-1115
Main Authors: Mol, Peter G. M., Arnardottir, Arna H., Motola, Domenico, Vrijlandt, Patrick J., Duijnhoven, Ruben G., Haaijer-Ruskamp, Flora M., de Graeff, Pieter A., Denig, Petra, Straus, Sabine M. J. M.
Format: Article
Language:English
Subjects:
Algorithms
Ambulatory care
Biological and medical sciences
Classification
Clinical trial. Drug monitoring
Communications
Disease
Drug Safety and Pharmacovigilance
General pharmacology
Innovations
Medical sciences
Medicine
Medicine & Public Health
Original Research Article
Pharmaceutical industry
Pharmacology. Drug treatments
Pharmacology/Toxicology
Studies
Substance abuse treatment
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Summary: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. Conclusion A higher level of inno
ISSN:0114-5916
1179-1942
DOI:10.1007/s40264-013-0094-y