Risk Evaluation and Mitigation Strategies (REMS), Pemoline, and What Is a Signal?

Abstract

, MD, on the subject of pharmacovigilance and postmarketing surveillance. 1-5 In 2007 the Food and Drug Administration (FDA) was authorized to require sponsors to develop a Risk Evaluation and Mitigation Strategy (REMS) whenever there was a suspicion that more information might be needed to ensure the safety of a newly marketed product. 6 A REMS is an anticipatory risk management program intended to pick up unwanted drug effects once more patients are exposed to a drug than occurred during Phase II and III studies. This usually means that problems will be detected that require exposure of more than the typical 3000 to 5000 patients seen in the two pre-NDA (New Drug Application) phases. REMSs may also be important for agents for rare or orphan diseases. Such drugs have usually been marketed after an accelerated approval process, meaning that smaller numbers of patients were exposed before marketing approval. Also, real-world usage may reveal problems from other unstudied situations such as comorbidities or drug interactions. I created the mnemonic MICE to remember the main components of a REMS program. Table I lists the FDA's components in my rearranged order. For clinical safety purposes, the plans for implementation (eg, checking all databases, epidemiologic studies, creation of a registry) and communication (eg, a Dear Clinician letter) should occur early in the process of assuring safe use. The medication guide (an up-to-date version of a patient package insert) should flow from the planning efforts. Table II conveys an example of the types of information needed from patients included in a REMS. What the FDA cannot determine for the sponsor is what and how many unwanted events constitute a strong enough signal to initiate a full-blown REMS. This requires forthright discussions with the FDA, ideally initiated by the sponsor.

What are side effects?

“…Consider the case of pemoline, a stimulant used to treat ADHD that was withdrawn from the US in 2005. After its withdrawal in the US, it was still available in Japan as a narcolepsy treatment (Shrader, 2017). In the US, not only was the use of pemoline withdrawn, but treating narcolepsy would be a side effect, where in Japan it was the intended effect.…”

Drug Safety, Climate Change, Causality, and Predictability

“…Using my six criteria, any of you who read my April 2017 Editor-in-Chief's Note will readily understand why I concluded that the observations linking pemoline and hepatic failure were not conclusive. 6 I feel that causality for that drug-ADR pairing was best classified as somewhere between possible and probable; it surely was not definite. Curiously, in a single-assessor evaluation using the Naranjo items as well as the World Health Organization's (WHO's) criteria to score 913 clinical reports on ADRs from a number of different drugs, causality was most frequently determined to be at the possible level on both scales.…”