When pharmaceutical expertise is challenged in the preparation of investigational medicinal products

Introduction and objective
The proportion of clinical trials requiring preparation of investigational medicinal products (IMP) has significantly increased in recent years. Combined with more stringent protocol requirements, this evolution has reduced the adaptability of clinical trial sites. Recurring disagreements with sponsors are observed during site initiation visits (SIV), often without clear scientific justification, leading to a perception that pharmaceutical expertise is not adequately recognized. This aim of this study was to objectively assess these disagreements and evaluate the associated risks.

Materials and methods
All disagreements occurring during SIVs for clinical trials involving IMP preparation were recorded between November 2022 and December 2024. Data collected included the nature of the disagreement, the pharmaceutical solutions proposed, and the sponsors’ responses. Representative situations were selected to develop scenarios, which were evaluated during dedicated meetings by a national panel of expert pharmacists selected based on comparable practice profiles. Potential risks (organizational, operator-related, and patient-related) were identified and consensually rated using a predefined assessment grid.

Results
Of the 67 SIVs conducted, 35 resulted in at least one disagreement. These involved preparation steps (45%), unsuitable medical devices (15%), or preparation workflows differing from standard commercial practices (15%). Of the 53 total disagreements identified, 29 were considered to have an impact and led to proposals to the sponsor. Seventeen (59%) of these proposals were rejected, with nearly 60% of the rejections occurring without scientific justification, ultimately leading to the suspension of 3 studies. Eighteen scenarios were assessed by 19 expert pharmacists. The risk analysis identified a risk of disruption to the clinical department in 39% of cases and to the pharmacy in 89% of cases (with 44% of risk rated as major to critical). Patient safety risks were identified in 61% of scenarios, with 73% rated as critical and 27% as catastrophic. Finally, 39% of scenarios involved a risk to the pharmacy technician, with 90% rated as critical and 10% as catastrophic.

Discussion and conclusion
This study highlights the high frequency of unresolved conflicts between pharmacists and sponsors during SIVs involving IMP preparation, with the majority of proposed adjustments being rejected. The analysis suggests that these disagreements, beyond organizational constraints, pose significant risks to patients and staff and demonstrate that certain protocol requirements may, paradoxically, compromise the safety and feasibility of IMP preparation. Pharmaceutical expertise is often disregarded in favor of strict adherence to the protocol, preventing any reassessment even when major to critical risks are identified and leaving trial suspension as the only available course of action. Early integration of pharmaceutical expertise is essential to ensure the safety and feasibility of clinical trials.

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