https://orcid.org/0000-0002-0014-8625
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ABSTRACT
Background: Prior studies investigated regulatory actions that reflected a negative impact on drug risks. We aimed to evaluate occurrence of regulatory actions that reflected a negative or positive impact on benefits or risks, as well as relations between them.
Research design and methods: We followed EMA-approved innovative drugs from approval (2009–2010) until July 2020 or withdrawal to identify regulatory actions. We assessed these for impact on benefits or risks and relations between actions. Additionally, we scrutinized drug lifecycles for time-variant characteristics that may contribute to specific patterns of regulatory actions.
Results: We identified 14 letters and 361 label updates for 40 drugs. Of the label updates, 85 (24%) reflected a positive impact, mostly concerning indications, and 276 (76%) a negative impact, mostly adverse drug reactions. Many updates (54%) occurred simultaneously with other updates, also if these reflected a different impact. Furthermore, levels of patient exposure, innovativeness, needs for regulatory learning and unexpected risks may contribute to patterns of regulatory actions.
Conclusions: Almost a quarter of regulatory actions reflected a positive impact on benefits and risks. Also, simultaneous learning about benefits and risks suggests an important role for drug development in risk characterization. These findings may impact regulatory analyses and decision-making.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14740338.2021.1952981.
Article highlights
As opposed to previous studies that mainly evaluated post-approval regulatory actions that reflected a negative impact on drug risks, we provide the first comprehensive evaluation of all impactful post-approval regulatory actions that occurred during drug lifecycles, for a sample of 40 innovative drugs and over ten years of follow-up.
We identified five withdrawals for commercial reasons, 14 letters to healthcare professionals and 361 label updates.
While 276 (76%) label updates reflected a negative impact and were mainly risk-related, we also identified 85 (24%) that reflected a positive impact and were mainly benefit-related, for example new or broadened indications, but also included removal of risk-related information.
Of the label updates, 194 (54%) occurred simultaneously with other label updates during 85 regulatory procedures. Of these procedures, 27 highlighted that evidence generated for post-approval drug development such as new indications simultaneously helped to further characterize drug risk profiles.
Specific patterns in post-approval regulatory actions that reflect a positive or negative impact seem to be influenced by levels of patient exposure, innovativeness, needs for regulatory learning and unexpected risks.
These findings may support future comprehensive regulatory analyses, stimulate simultaneous regulatory learning about benefits and risks, and help identify regulatory needs for evidence generation.
Acknowledgments
The authors would like to thank colleagues of the Copenhagen Centre for Regulatory Science at the University of Copenhagen, Denmark for their kind assistance in and contributions to the identification of Dear Healthcare Professional Communications (DHPC).
Declaration of interest
HGM Leufkens reported that he is a member of the Lygature Leadership Team. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
A reviewer on this manuscript has disclosed that they receive personal fees from MNES Inc., outside the submitted work. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Disclaimer
The views expressed in this article are the personal views of the authors and must not be understood or quoted as being made on behalf of the Dutch Medicines Evaluation Board or any of its committees.
Notes
3. See for an overview of national regulatory authorities’ web pages where information on DHPCs is published