Embracing the Risk-Based TMF


The release of the 2017 ICH GCP E6(R2) guidelines marks a paradigm shift in clinical research. Risk is mentioned no fewer than 30 times in the guidance. ICH GCP E6(R2) section 5.1 requires that the sponsor of a trial, “implements and maintains systems for quality assurance and quality and control.” 1 The EMA recognizes, that although these basic systems are generally ‘good enough’ to ensure the quality of a trial, “current practice can… be expensive and there are too many trials in which avoidable quality problems arise.” 2 Their renewed focus on risk is meant to realign current clinical practices with the ultimate goals of clinical research. At the core of this desire to encourage risk-based thinking is the notion of proportionality: ensuring that precious resources are allocated where they can increase the likelihood of positive outcomes in the trial while reducing the negative effects as much as possible.

These advances in decision making and risk management are powered by new electronic systems - allowing instant insight into the innerworkings of a clinical trial. Now, enabled by emerging technology allowing for the creation of an Electronic Trial Master File (eTMF), riskbased quality management systems have the potential to revolutionize the creation and delivery of the most important clinical trial deliverable: the TMF.

Risk-Based Thinking

FDA guidance defines risk as “as the combination of the probability of occurrence of harm and the severity of that harm.”3 A quality system is defined as, “The sum of all aspects of a system that implements quality policy and ensures that quality objectives are met.”3 Combined as one, they are defined as “a systematic process for the assessment, control, communication, and review of risks to the quality of the drug product across the product lifecycle.”3

On their own, these definitions can seem overly-reductive, confusing, and frustrating to apply. Upon the release of the new guidelines many in the industry held or attended ‘R2 impact’ meetings introducing this concept of Risk-Based systems. These meetings often began with a brainstorming session to identify risk, and most often ended with stakeholder pushback, or a lengthy list of complaints.

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