Regulatory withdrawal of medicines marketed with uncertain benefits: the bevacizumab case study

Abstract

BackgroundWithdrawal of conditional regulatory approval or subsidization of new medicines when subsequent evidence does not confirm early trial results may not be well understood or accepted by the public. ObjectivesWe present a case study of the US Food and Drug Administration (FDA)’s decision to withdraw the indication of bevacizumab for the treatment of advanced breast cancer and include an analysis of the reactions of stakeholders with a view to identifying opportunities for improving risk management for new medicines with conditional approval or funding.MethodsWe drew on a range of information sources, including FDA documents, medical journals and media reports, to describe the evidentiary basis of the FDA decisions. We analysed the reactions and perspectives of the stakeholders.ResultsIn 2008 bevacizumab was granted conditional approval for treatment of advanced breast cancer by the FDA pending submission of supplementary satisfactory evidence. In 2011 the FDA decision to withdraw the indication was met with a hostile reaction from many clinicians and cancer survivors. There were different interpretations of the therapeutic value of bevacizumab with strong beliefs among cancer survivors that the medicine was effective and potential harm was manageable. High expectations of the public may have been encouraged by overly positive media reports and limited understanding by the public of the complexity of the scientific evaluation of new medicines and of the regulatory processes.ConclusionsImproving understanding and acceptance of approval or coverage schemes conditional to evidence development may require the development of risk management plans by regulatory and funding institutions. They may include a range of strategies such as requirements for formal patient acknowledgment of the conditional availability of the medicine, ‘black-triangle’ equivalent labels that identify full approval is based on pending evidence, and ongoing communication with the media, public and health professionals.

FDA and EMA Approvals of New Breast Cancer Drugs—A Comparative Regulatory Analysis

“…While six of these drugs had already gained non-centralized European approvals in the pre-EMA era, the other six cases reflect a genuinely different approval status between the United States and Europe. Among these, bevacizumab (with market authorization for breast cancer in Europe, but no equivalent approval in the United States) is the most prominent and most recent example [17]. Importantly, we found no further major divergences in regulatory outcomes for breast cancer drugs during the last ten years covered in our analysis (i.e., from 2009 to 2018; the two drugs approved by FDA in 2018, olaparib and talazoparib, both received an EU approval in the first half of 2019.)…”

Advocacy for a New Oncology Research Paradigm: The Model of Bevacizumab in Triple-Negative Breast Cancer in a French Cohort Study

“…This decision was reversed 2 years later as there was no improvement in overall survival (OS) in addition to significant costs. By that time, it was considered that PFS was not an acceptable primary endpoint for approval of first-line therapies in cancer [8-10]. Thereby, bevacizumab has progressively fallen off the radar for the treatment of metastatic breast cancer in most countries, apart from France and Belgium that have maintained its use in first-line treatment of triple-negative breast cancer, by way of derogation [11].…”

Impact of the black triangle label on prescribing of new drugs in the United Kingdom: lessons for the United States at a time of deregulation

“…With such a shift in regulation and increasing reliance on real‐world evidence, it would be increasingly critical for clinicians and the public to recognize which novel drugs were recently approved and had incomplete safety information. Even before the passage of this new legislation, we and others have advocated for the use of labeling schemes similar to the black triangle for newly approved medicines in the US . Such labeling for recently approved drugs in the US might not only raise awareness about the uncertainty of their safety but also promote more judicious prescribing channeled to patients with the greatest need and, thus, the highest benefit‐risk ratio .…”

“…Even before the passage of this new legislation, we and others have advocated for the use of labeling schemes similar to the black triangle for newly approved medicines in the US. 8,23 Such labeling for recently approved drugs in the US might not only raise awareness about the uncertainty of their safety but also promote more judicious prescribing channeled to patients with the greatest need and, thus, the highest benefit-risk ratio. 8 Indeed, the Institute of Medicine recommended the use of a black triangle-like label to promote greater safety of new medications.…”