Impact of Regulatory Guidances and Drug Regulation on Risk Minimization Interventions in Drug Safety

Abstract

Background: Therapeutic risk management has received growing interest in recent years, particularly since the publication of regulatory guidances in 2005 and 2006, paralleled with a change in drug regulation. The characteristics of risk minimization interventions (RMIs) that have been implemented or approved remain inadequately explored.

Objective: The aim of this study was to review RMIs published in the literature or posted on regulatory agency websites over the past 10 years, and to assess whether publication of regulatory guidances on risk management is associated with changes in the number and types of interventions.

Methods: Sources were searched for RMIs published/posted between 1 January 2000 and 31 December 2009. For the literature search, MEDLINE and EMBASE databases were used using key words related to drug safety (i.e. ‘drug toxicity’) and the individual RMI names. The website review involved searches of major regulatory authority websites such as the European Medicines Agency, US FDA, Health Canada, the UK’s Medicines and Healthcare products Regulatory Agency, Japan’s Pharmaceutical and Medical Devices Agency and Australia’s Therapeutic Goods Administration. The following eligibility criteria were applied for inclusion in the review: published/posted between the years 2000 and 2009, inclusive; involving drug products; use in humans; and involving RMIs, or tools used to increase the reporting of adverse events (AEs). Natural healthcare products, devices, diagnostic chemicals, pregnancy registries without follow-up, medication errors and products not used as therapy for illness were not retained. For each source, the following characteristics were extracted: nature of the intervention, target population, therapeutic area, AE(s) of special interest, country/regulatory agency and year of publication.

Results: A total of 119 unique interventions were identified in the literature (54 published in 2000–4 and 65 published in 2005–9). Interventions included educational material (n = 37; 31%), black-box warnings (n = 22; 19%) and therapeutic drug monitoring (n = 11; 9%). The website review produced a total of 1112 interventions: 326 posted between the years 2000 and 2004, and 786 between the years 2005 and 2009. The main interventions observed were: educational material (n = 956; 86%), black-box warnings (n = 45; 4%) and withdrawals (n = 39; 4%).

Limitations: Additional regulatory resource websites were available in the post-guidances periods that were not available in the earlier years of the pre-guidances periods, and may bias the post-guidances results. Also, not all global regulatory websites were searched. Finally, only English-language websites were searched, limiting the variation of RMIs observed. Classification and categorizing for this particular review may not be consistent with future reviews by other researchers.

Conclusion: The US is the sole region with a substantial increase in published RMIs during the post-guidances period, while the EU, Japan and the US all indicated an increase in the number of interventions on their websites.