Clinical Trial Safety – The Goldilocks Dilemma – Balancing Effective and Efficient Safety Monitoring
conceivable that the clinical trial subject may not even have received the proper dose of study drug. In this case, attribution of a safety event or of the absence of a safety event would be erroneous. Here, the right thing for effective safety monitoring might be to require serum levels of the compound to be obtained.
Patient-based Risk Factors
Patient-based risk factors are also widely recognised to have an impact on safety monitoring. For instance, both the US Food and Drug Administration (FDA) and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance may mandate a data monitoring committee (aka Data Safety Monitoring Board [DSMB], Independent Data Monitoring Committee [IDMC], Data Safety Monitoring Committee [DSMC]). A trial directed at patients who are considered vulnerable populations (e.g. paediatric or demented) or who have specific physiological or psychological risk factors. Other patient-based factors to include are detailed in Table 2. An example of the impact of patient-based risk factors may be if enrolment is driven by the promise of free medical care. In this instance, subjects may be less likely to report safety events and therefore more intensive, objective monitoring should be built into the protocol. Similarly, if it is adjudged that patients are likely to have concomitant medications, the right thing to do might be to increase clinical monitoring intensity to capture this information.
Operation-based Risk Factors Operation-based risk factors are less commonly considered, but no less important than compound- and patient-based factors. Regulatory guidelines rarely specify required or recommended operational details. There is abundant evidence, however, that due process factors can have a large impact on the overall effectiveness of safety monitoring. Key operational issues that may have an impact on effective safety monitoring are given in Table 3. As an example, false negatives have different implications in a non-inferiority design than they do in a superiority design. Regulators are aware of this. Effective safety monitoring in a non-inferiority trial might therefore require additional resources devoted safety signal detection.
Communication-based Risk Factors
Communication-based risk factors are an often ignored but crucial component of effective safety monitoring in clinical trials. Although related to operational-based risk factors, responsible communication of clinical trial safety is essential. As the trial is ongoing, safety monitoring requires open communication between investigators, sponsors and regulators. In the author’s experience, proactive management of safety communications has been a cornerstone of effective and efficient safety monitoring. Features that may effect safety monitoring are listed in Table 4.
Assessment of communication-based risk factors is important, for example, if there is expected or suspected variability in safety reporting (e.g. pain scales or rate of adverse event reporting). Here effective safety monitoring may require the establishment of an infrastructure that will allow for evaluation and retraining on an iterative, need-based, proactive communication platform.
Additionally, although reporting of serious adverse events is fairly standardised, reporting of suspected, unexpected serious adverse reactions is very complicated, particularly in the EU. Similarly, the
DRUG DEVELOPMENT
Table 4: Communication-based Risk Factors that May Impact on Effective Safety Monitoring
Whether the safety reporting structure is vetted Whether the safety reporting structure can handle realtime data Whether there an interim analysis is planned How the sponsor communicates with investigators If there is a Data Safety Monitoring Board, whether they communicate with investigators
How safety issues are raised within the company Whether there is a plan for realtime retraining of study sites The opinion regulatory agencies have of the sponsor, trial or compound
reporting of safety data is rather complicated and multiple types of listings, charts and tables must be prepared for clinical study reports, integrated safety summaries and marketing authorisation submissions. Although not typically thought of as a ‘risk factor’, failure to accurately adhere to reporting conventions can cause regulatory scepticism and ultimately result in distraction from the actual safety issues.6
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Table 1: Compound- or Intervention-based Risk Factors that May Impact on Effective Safety Monitoring
The known safety signals in humans or animals The potential safety interactions due to in vivo testing Whether the planned intervention is comparable, riskier or safer than standard therapy Whether this is an early or late-phase experience Whether this is a single or combination product The known or suspected drug/food interactions
Whether pre-clinical safety studies (e.g. interaction, toxicology) have been completed
The transport and storage requirements The preparation requirements
Table 2: Patient-based Risk Factors that May Impact on Effective Safety Monitoring
The motivation for patients to enrol in the trial Whether vulnerable populations are likely to enrol in the trial The concomitant diseases study patients are likely to have The concomitant medications/foods study patients are likely to ingest The quality of underlying medical care the subjects are receiving How likely patients are to complete the trial Cultural differences that may influence all of the above
Table 3: Operation-based Risk Factors that May Impact on Effective Safety Monitoring
Whether there is a risk of unblinding by the investigator or study team Whether the study is a superiority or non-inferiority study Possible sources of bias Site technical requirements Site compensation
Site personnel requirements The clinical monitoring plan The data-capture tool used
The turnaround time for completion of adverse events The training regimen
Whether the end-points are hard end-points Geographic, cultural or economic factors that may influence the above
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