Head of Research Institute of Pharmacovigilance Sciences, Drug Safety Research Unit Southampton, United Kingdom
Background: Decisions to remove medicines from market are not taken lightly and are often based upon all evidence available to inform a benefit/risk balance. Evidence for benefits and risks of a product can come from a range of sources, such as randomised controlled trials (RCTs), observational research, and spontaneous reporting. Such sources of evidence may be used during regulatory decision making.
Objectives: To assess types of scientific evidence used in decision making for post-marketing product withdrawals for safety reasons between 1999 and 2016 in Europe, and to identify changes in the types of evidence supporting regulatory decision making over time.
Methods: A review of three papers addressing evidence used during products withdrawn due to safety reasons, either by a regulator or a marketing authorisation holder, was conducted. Each study covered a different time period (1999-2001, 2002-2011, and 2012-2016). Results of these studies were synthesised. Products withdrawn in Europe between 1999 and 2016 due to a safety concern were included. Types of evidence used during regulatory decision making were assessed, with frequencies and percentages calculated. Patterns in evidence used over time were evaluated.
Results: In total, 35 products were withdrawn by a regulator in Europe between 1999 and 2016 (N=6 1999-2001 [UK]; N=19 2002-2011 [European Union (EU)]; N=10 2012-2016 [EU]). Overall, 91.4% of withdrawals (n=32) were supported by spontaneous reports and/or published case reports or case series. Of the 35 withdrawals, 60.0% (n=21) were supported by RCTs, 48.6% (n=17) were supported by non-randomised trials, while 40.0% (n=14) were supported by studies of observational designs. Systematic reviews and meta-analyses least frequently contributed to evidence supporting withdrawals (n=11, 31.4%). Over the years, the number of evidence sources cited in regulatory decisions increased. Of note, the percentage of observational studies used to support product withdrawals increased considerably during the study period (supporting 16.7% of 1999-2001 withdrawals; 26.3% of 2002-2011 withdrawals; 80.0% of 2012-2016 withdrawals).
Conclusions: Overall, spontaneous reports and/or published case reports contributed to the most product withdrawal decisions. However, a shift towards more epidemiological research supporting decision making was observed over the study period. Further research is required into the individual studies considered during decision making and whether these are powered for safety .
