Introduction Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4β7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory requirement.
Objective The aim of this study was to describe the multiple risk minimisation elements that were incorporated in vedolizumab clinical trials in inflammatory bowel disease patients as part of the risk assessment and minimisation of PML programme for vedolizumab.
Methods A case evaluation algorithm was developed for sequential screening and diagnostic evaluation of subjects who met criteria that indicated a clinical suspicion of PML. An Independent Adjudication Committee provided an independent, unbiased opinion regarding the likelihood of PML.
Results Although no cases were detected, all suspected PML events were thoroughly reviewed and successfully adjudicated, making it unlikely that cases were missed.
Conclusion We suggest that this programme could serve as a model for pragmatic screening for PML during the clinical development of new drugs.
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Joseph R. Berger reports grants and personal fees from Biogen, grants from TEVA, and personal fees from Genentech/Roche, Genzyme, Millennium/Takeda, Novartis, Inhibikase, ExcisionBio, Roche, Amgen, AstraZeneca, Alkermes and Bayer. David B. Clifford is supported by National Institutes of Health (NIH) grants NS077384, AI69495, NR012907, NR014449, NR012657 and UL1 TR000448, and by the Alzheimer Association, and has received research support from Eli Lilly, Roche and Janssen.
Development of the RAMP and the clinical studies in which it was applied were sponsored by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
The online version of this article (https://doi.org/10.1007/s40264-018-0669-8) contains supplementary material, which is available to authorized users.
Parikh, Asit; Stephens, Kristin; Major, Eugene; Fox, Irving; Milch, Catherine; Sankoh, Serap; Lev, Michael H.; Provenzale, James M.; Shick, Jesse; Patti, Mark; McAuliffe, Megan; Berger, Joseph R.; and Clifford, David B., "A Programme for Risk Assessment and Minimisation of Progressive Multifocal Leukoencephalopathy Developed for Vedolizumab Clinical Trials" (2018). Neurology Faculty Publications. 22.