FDA to Require REMS of Opioid-Based Drugs

Citing authority granted to the agency by the FDA Amendments Act of 2007 (FDAAA), FDA sent letters in early February to manufacturers of opioid painkillers, including Ortho McNeil Janssen, Purdue Pharma, Roxanne, King Pharma, Actavis, Xanodyne, Endo, Lavipharm Labs, Mylan Technologies, Teva, Watson, Mallinckrodt (Covidien) Sandoz, KV Pharmaceuticals and Impax Labs. Representatives of those companies were invited to meet with FDA on March 3, and there will be public meetings for comments several months later.

The general goal of a REMS is to provide more extensive protections for patient safety when a drug is marketed. Under FDAAA, FDA can now require a REMS (where before the task of developing safeguards was negotiated between the manufacturer and FDA as part of the drug review process.) A REMS, which is becoming a more common part of drug introductions or reviews, can consist of additional labeling, more extensive medication guides for physicians and patients, or more rigorous safeguards such as developing physician training programs, or developing an IT-driven registry to monitor patient health and outcomes. It is likely that the REMS will ultimately be on the rigorous side, since, as FDA notes, it and industry “have taken a number of steps in the past to prevent abuse,” including labeling and patient communications, but despite these efforts, “the rates of misuse and abuse, and of accidental overdose of opioids, have risen over the past decade.”

Reformulations under consideration
Coincidentally, the week before the announcement, a clinical research organization called LifeTree Clinical Research (Salt Lake City, UT) presented a study at the American Academy of Pain Medicines conference (Honolulu, Jan 27-31). Under a grant from King Pharma, LifeTree has been devising an “abuse quotient” for oxycodone formulations based on a ratio between maximum blood concentration of the drug (Cmax) and the time to maximum concentration (Tmax). The ratio puts a numerical value on euphoria drug abusers experience. By reformulating painkillers to stretch out Tmax (or, conceivably, by lowering Cmax), the level of euphoria might be better controlled without affecting the pain-killing effects of such drugs.

Opioids continue to be problematic for the pharmaceutical supply chain. Besides the eventual REMS requirement, manufacturers, distributors and physicians have the option of filing records electronically via the Controlled Substance Ordering System (CSOS) of the Drug Enforcement Administration. Distributors have had repeated instances of failing to meet DEA recordkeeping requirements. According to a recent equity-research report from JP Morgan Chase, the DEA troubles Cardinal experienced during 2008 cost the company $1 billion in lost revenue. PC

FDA to require REMS of opioid-based drugs

Goal of risk evaluation and mitigation strategy (REMS) will be to reduce abuse and accidental overdosing; researchers devise an ‘abuse quotient’ for such drugs


Citing authority granted to the agency by the FDA Amendments Act of 2007 (FDAAA), FDA sent letters in early February to manufacturers of opioid painkillers, including Ortho McNeil Janssen, Purdue Pharma, Roxanne, King Pharma, Actavis, Xanodyne, Endo, Lavipharm Labs, Mylan Technologies, Teva, Watson, Mallinckrodt (Covidien) Sandoz, KV Pharmaceuticals and Impax Labs. Representatives of those companies are invited to meet with FDA on March 3, and there will be public meetings for comments several months later.

The general goal of a REMS is to provide more extensive protections for patient safety when a drug is marketed. Under FDAAA, FDA can now require a REMS (where before the task of developing safeguards was negotiated between the manufacturer and FDA as part of the drug review process.) A REMS, which is becoming a more common part of drug introductions or reviews, can consist of additional labeling, more extensive medication guides for physicians and patients, or more rigorous safeguards such as developing physician training programs, or registering patients to monitor their health. It is likely that the REMS will ultimately be on the rigorous side, since, as FDA notes, it and industry “have taken a number of steps in the past to prevent abuse,” including labeling and patient communications, but despite these efforts, “the rates of misuse and abuse, and of accidental overdose of opioids, have risen over the past decade.”

Reformulations under consideration
Coincidentally, the week before the announcement, a clinical research organization called LifeTree Clinical Research (Salt Lake City, UT) presented a study at the American Academy of Pain Medicines conference (Honolulu, Jan 27-31). Under a grant from King Pharma, LifeTree has been devising an “abuse quotient” for oxycodone formuations based on a ratio between maximum blood concentration of the drug (Cmax) and the time to maximum concentration (Tmax). The ratio puts a numerical value on euphoria drug abusers experience. By reformulating painkillers to stretch out Tmax (or, conceivably, by lowering Cmax), the level of euphoria might be better controlled without affecting the pain-killing effects of such drugs.

Opioids continue to be problematic for the pharmaceutical supply chain. Besides the eventual REMS requirement, manufacturers, distributors and physicians already have to comply with the Controlled Substance Ordering System (CSOS) of the Drug Enforcement Administration (DEA), and distributors have had repeated instances of failing to meet DEA recordkeeping requirements.