Detection of drug safety signals from clinical trials data: Role of SUSARs.

One of the main goals of safety management in clinical trials is to detect suspected unexpected serious adverse reactions (SUSARs). The unexpectedness concerns the nature, frequency or severity of an adverse reaction. Drug safety signals could thus be retrieved, and a study was performed to investigate whether SUSARs allow signal detection in pharmacovigilance. Data from six academic safety units were collected from 2005 to 2016. Characteristics of SUSARs were analysed and signals were identified i) by evaluating the presence of other causes, ii) by assessing the summary of product characteristics (SPC), iii) by searching for specific safety information in Pubmed and health agencies, and iv) by investigating the narrative of each case. Pharmacological plausibility was evaluated by compatible mechanism of reaction and time-to-onset. During the study period, 211 SUSARs were collected. They mostly concerned general disorders (26.1%) and protein kinase inhibitors (24.6%). After eliminating SUSARs with other causes or those considered as expected, 50 SUSARs (23.7%), involving a total of 115 drug-reaction pairs, concerned potential safety signals. Among these pairs, 12 (10.4%) were considered as pharmacologically plausible. This study indicates that one quarter of SUSARs collected in academic clinical trials refers to potential safety signals, especially for oncologic drugs. One tenth of drug-reaction pairs was considered to have a pharmacological plausibility and could merit further evaluation. This is the first study suggesting that SUSARs could be a source of safety signals and that their routine analysis should be complementary to spontaneous reporting.

Serious adverse drug events related to non-investigational drugs in academic clinical trials: another source of safety data for risk assessment?

AIMS: Sponsors of clinical trials have to analyze serious adverse events (SAEs). Both sponsors and investigators determine the relationship between the investigational medicinal product, the investigational device or procedure and SAEs. SAEs related to another cause, such as a non-investigational medicinal product (NIMP), do not have clear pharmacovigilance reporting requirements. The aim of this study was to evaluate the amount and the nature of NIMP-related SAEs recorded by three French academic sponsors and to propose pharmacovigilance requirements for these cases. METHODS: This was a retrospective descriptive study including all cases of NIMP-related SAEs occurring in clinical trials and reported to three academic sponsors between January 2009 and October 2014. RESULTS: Among 5870 cases of SAEs, 300 (5%) were related to a NIMP in 50 clinical trials. Involved NIMPs were mainly antithrombotics, cytostatics and immunosuppressants. Some of these drugs were currently followed by a risk management plan (e.g. rivoxaban). The most frequent NIMP-related SAEs were neurological, gastrointestinal and infectious disorders. Seven NIMP-related SAEs were known as 'rare' or 'very rare' and two were 'unlabelled'. CONCLUSIONS: As far as we know, this is the first study to focus about NIMP-related SAEs occurring in clinical trials. This work highlights the potential high quality source of safety data via NIMP-related SAE collection. Globally, we propose that NIMP-related SAEs occurring in clinical trials should systematically be notified to the pharmacovigilance system of the concerned country. Clearer procedures of interactions between safety units of academic sponsors and pharmacovigilance systems are needed to allow an effective recording of NIMP-related SAEs.

Integrated analysis of randomized controlled trials evaluating bortezomib + lenalidomide + dexamethasone or bortezomib + thalidomide + dexamethasone induction in transplant-eligible newly diagnosed multiple myeloma.

Objective: Providing the most efficacious frontline treatment for newly diagnosed multiple myeloma (NDMM) is critical for patient outcomes. No direct comparisons have been made between bortezomib + lenalidomide + dexamethasone (VRD) and bortezomib + thalidomide + dexamethasone (VTD) induction regimens in transplant-eligible NDMM. Methods: An integrated analysis was performed using patient data from four trials meeting prespecified eligibility criteria: two using VRD (PETHEMA GEM2012 and IFM 2009) and two using VTD (PETHEMA GEM2005 and IFM 2013-04). Results: The primary endpoint was met, with VRD demonstrating a noninferior rate of at least very good partial response (≥ VGPR) after induction vs VTD. GEM comparison demonstrated improvement in the ≥ VGPR rate after induction for VRD vs VTD (66.3% vs 51.2%; P = .00281) that increased after transplant (74.4% vs 53.5%). Undetectable minimal residual disease rates post induction (46.7% vs 34.9%) and post transplant (62.4% vs 47.3%) support the benefit of VRD vs VTD. Treatment-emergent adverse events leading to study and/or treatment discontinuation were less frequent with VRD (3%, GEM2012; 6%, IFM 2009) vs VTD (11%, IFM 2013-04). Conclusion: These results supported the benefit of VRD over VTD for induction in transplant-eligible patients with NDMM. The trials included are registered with ClinicalTrials.gov (NCT01916252, NCT01191060, NCT00461747, and NCT01971658).