A Pathway to Improved Prospective Observational Post-Authorization Safety Studies


Randomized controlled trials (RCTs) are the gold standard for assessing the efficacy of drugs but not necessarily so for drug safety where inadequate power to detect either multiple or rare adverse events is a major handicap. Furthermore, the conditions under which drugs are approved for market use are often different from the settings in actual use. Indeed, with their control mechanisms, trials are by design largely inadequate for the identification of potential safety signals, especially of the rare type, hence the value of post-marketing surveillance and risk management plan-based activities.

Today, clinical trials constitute only a part of the research that goes into assessing the safety of drugs. Observational studies, where the investigators merely collect data on treatments received by patients and their health status in routine clinical practice are increasing in uptake because they reflect the real-life utility of drugs, despite the absence of random treatment assignment. Although such studies generally provide less compelling evidence than RCTs, they can be far more useful to drug safety assessment activities than generally acknowledged.

An increasing number of post-authorization safety studies (PASS) within the European Medicines Agency’s jurisdiction are of the observational type —considered perhaps as more appropriate vehicles for exploring and documenting how products perform in the real world. A similar trend is emerging in the US following the FDA Amendments Act of 2007; since early 2010, an increasing number of post-approval commitments mandated by the FDA include observational studies. However, despite this pattern, not much is known about ongoing efforts to address many of the recognized inadequacies associated with existing methodologies and practices currently adopted in observational PASS. This current opinion presents an overview of some of the main challenges we face in prospective observational PASS, mainly from practical experience, and proposes certain steps for improvement.

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I am grateful to Professor Gilbert MacKenzie and Dr Maurille Feudjo-Tepie for their encouragement and material support. I am also indebted to the editor and anonymous reviewers for their useful suggestions, which have helped to transform the original draft into a much improved piece of work — one that is humbly dedicated to the memory of my former colleague, Dr George Visick.

No sources of funding were used to assist in the preparation of this current opinion. Dr Kiri was an employee of GlaxoSmithKline Research and Development between November 1999 and April 2007, and Parexel International between May 2007 and June 2011.

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Kiri, V.A. A Pathway to Improved Prospective Observational Post-Authorization Safety Studies. Drug Saf 35, 711–724 (2012). https://doi.org/10.1007/BF03261968

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  • Propensity Score
  • Exposure Misclassification
  • Risk Management Plan
  • Prospective Data Collection
  • Rare Adverse Effect