Drug safety has emerged as a make-or-break issue for pharma over the past decade. In the wake of media fire storms and congressional investigations into withholding of safety data and deaths and disability linked to the marketing of Wyeth's Fen-phen and Merck's Vioxx, public trust in not only the drug industry but FDA hit bottom—and has remained there. In 2007, Congress took action, instituting a new program at FDA called Risk Evaluation and Mitigation Strategies (REMS) to, as the agency's Web site says, "ensure that the benefit of a drug or biological product outweigh its risks."
The primary objective of the REMS program is to reduce the danger drugs pose to patients by leveraging the existing communication and marketing capabilities of the pharmaceutical industry in one or more of the following ways: providing adequate information to patients, healthcare providers, and others; confirming that stakeholders are fully aware of the drug's risks; improving the appropriateness of drug use ("the right drug to the right patient"); and monitoring and measuring drug-safety outcomes.
Four Levels of Risk
But often FDA has more serious concerns about a product's toxicity. Drugs deemed approvable only if specific risk-mitigation strategies are assured require an ETASU (Elements to Assure Safe Use) and an implementation plan. An ETASU can require the training and certification of the doctor (and sometimes the pharmacist, while drug's distribution sites may be registered; regular audits of both prescribers and distributors can be mandated. At its strictest level, REMS require screening and registry of patients along with regular monitoring of patient records to create an ongoing database to pick up further safety issues. The patient trades confidentiality of his or her record for access to drug, as in the case of Acutane to prevent its use by women who are pregnant.
To determine if a REMS is needed, FDA looks for safety signals in clinical data, with risks to heart or liver health high on its list of concerns. The potential for abuse, as in the case of a controlled substance, is a certain trigger, as is the need to minimize off-label usage. A new compound in a class that already falls into any of these categories is likely to require REMS. To make a final determination on a REMS requirement, the agency will consider, during its drug review process, the amount of information known about the product or drug class in relation to the size of the target population, treatment length, number of reported adverse events, and severity of the indication to be treated. REMS may also be requested of drugs that are already on the market due to reports of adverse events via post-marketing surveillance or due to safety concerns arising from new data from phase 4 studies or literature reviews.