Safety Surveillance During Drug Development: Comparative Evaluation of Existing Regulations.

Drug safety monitoring is essential for developing efficient and safe treatments. It starts with preclinical toxicology studies and continues with the observation and analysis of potentially harmful effects in humans throughout the whole drug life cycle. Safety surveillance during the clinical phase is of paramount importance for protecting the health of clinical trial (CT) participants at a period when relatively little is known about the drug safety profile, and for reassuring that detected risks are minimized when the product obtains marketing approval. This review aimed to investigate current safety surveillance methods during drug development worldwide, in order to identify potential gaps and opportunities for amelioration. To this end, international guidelines, standards, and local legislations about CTs were reviewed and compared. Our review revealed common strategies, mainly in alignment with international guidelines, especially concerning the systematic collection, assessment, and expedition of adverse events by investigators and sponsors and the preparation of periodic aggregate safety reports by sponsors, as a means to inform health authorities (HAs) about the evolving benefit-risk balance of the investigational product. Inconsistencies in safety surveillance mainly concerned local expedited reporting requirements. Significant gaps were identified in the methodologies for aggregate analyses and the responsibilities of HAs. Addressing the regulatory discrepancies and harmonizing the safety surveillance processes at a global level would increase the usability of safety data accumulated by clinical studies worldwide, thus enabling and hopefully accelerating the development of safe and efficient drug therapies.

Discrepancies Between the Labels of Originator and Generic Pharmaceutical Products: Implications for Patient Safety.

BACKGROUND: All drug marketing authorization holders have the legal obligation to collect data on the use of the products they market and to keep the labels of those products updated. As demonstrated by previous studies, many generic products have labels that are discrepant from the labels of their reference (originator) products. This fact may cause inconsistent messages to be disseminated to healthcare professionals and patients for the same active ingredient. OBJECTIVE: These potential label discrepancies led us to investigate the degree of difference between labels for generic and originator products, the possible consequences of this discrepancy for patients, and its implications for risk minimization. PRODUCTS AND METHODS: Drugs from different Anatomical Therapeutic Chemical classes were randomly selected from the Electronic Medicines Compendium. For each drug, the consistency and discrepancies between the summaries of product characteristics (SmPCs) for originator and generic products were analyzed for each safety-relevant section of the SmPC separately as well as across all of its sections. The percentile distribution of discrepancy classifications was calculated. The same method was applied when determining the potential impact of label discrepencies on patients. RESULTS: Among the 50 drugs selected initially, 31 were eligible for the study and were analyzed further. Of those 31 drugs, 13 (41.9%) presented critical label differences between originator and generic products, 6 (19.4%) showed major label differences, 7 (22.6%) exhibited minor label differences, and 5 (16.1%) showed very minor label differences. Over 60% of the selected drugs (19, 61.3%) presented important (critical, major) label differences between originator and generic products. None of the selected drugs had fully aligned labels of originator and generic products. Label misalignments that could potentially have a fatal or life-threatening impact on the patient were observed for 4 (12.9%) of the selected drugs. Label misalignments that could have a severe patient outcome were noted for 11 (35.5%) of the selected drugs, and label misalignments that could have a medium impact on the patient were seen for 6 (19.35%) of the selected drugs. The label misalignments observed for 10 (32.25%) of the selected drugs would potentially lead to only a minor or no effect on the patient. Almost half (15, 48.4%) of the selected drugs presented label misalignments that could have a critical (fatal, life-threatening, severe) influence on the patient. CONCLUSIONS: In this sample, SmPC alignment between generic and originator medicinal products was found to be inefficient for established drugs, and could lead to the diffusion of discrepant messages to healthcare professionals and patients. In order to address this SmPC alignment problem, health authorities such as the EMA and the FDA must conduct retrospective analyses of all drugs on the market as a first step towards realigning labels. These analyses could be performed during the evaluation of aggregate reports.