Commentary- FDA, REMS, and ESAs

In the current issue of NEJM an article by Jerry Avorn is worth a read. Dr. Avorn is a Professor of Medicine at Harvard Medical School and Chief of the Division of Pharmacoepidemiology. Here is a quote from the article:

“Since all active compounds have some potential for harm, we are trying to learn how best to regulate, prescribe, and monitor the use of medications in ways that maximize their benefit while reducing the likelihood and severity of adverse effects. The concept of Risk Evaluation and Mitigation Strategies, also mandated in the 2007 legislation, is an attempt to move therapeutics in this direction.”

The Food and Drug Administration Amendments Act of 2007 gave FDA the authority to require a Risk Evaluation and Mitigation Strategy (REMS) from manufacturers to ensure that the benefits of a drug or biological product outweigh its risks. There are now nearly 200 drugs that are covered by REMS. 

Both erythropoiesis stimulating agents (ESAs) in the US, Aranesp (darbepoetin) and epoetin alfa are now covered by REMS, and various elements have to be implemented by dialysis providers and care-givers. Those elements include a medication guide, a communication plan, and elements to assure safe use (e.g., a restrictive distribution program).  Additionally, all REMS must include a timetable for assessments with assessments at 18 months, 3 years and 7 years after approval of the REMS. 

In 2010, I published an editorial in CJASN about REMS and ESAs. I argued that REMS for ESAs is a start but is not enough and that additional studies are needed on the safety of ESAs.

“the FDA should …consider exercising its statutory authority under Title IX “Enhanced Authorities Regarding Postmarket Safety of Drugs” to require additional studies to be conducted by the manufacturers of ESAs. The FDA's authority accrues from an amendment to section 505 of the Federal Food, Drug, and Cosmetic Act (21 USC 355) contained within the FDAAA legislation. The FDA would be well within its rights to ask for these studies. This is because the amendment was incorporated into the FDAAA precisely for instances when safety becomes an issue after approval of a drug. Under the new law, the FDA can mandate a clinical trial or trials of a drug to assess risk. And, certainly the billions of dollars in profit made by industry in ESA sales should easily accommodate a program to rigorously test the long-term safety of ESAs. The FDA should also provide guidance to the ESA manufacturers on design and timing of the trial(s).”

Some have argued that REMS for ESAs in dialysis patients only serves to alarm patients. However, this has not been the experience across the country. Most dialysis providers have taken this program into their stride. For example, in speaking with senior leadership at Satellite Dialysis in Northern California there did not seem to be any undue alarm among patients, and the staff do not seem to be encumbered with additional work.

Dr. Avorn’s article points out that 50 years have elapsed since FDA regulations were beefed up triggered by the thalidomide debacle. REMS is the latest attempt by the FDA to scrutinize drugs after they have been launched. Epoetin and it’s analogue darbepoetin are 2 of nearly 200 drugs to be a part of REMS and this relatively new safety program will hopefully provide reassurance to patients that we have struck the right balance in weighing risk versus benefits. But for ESAs REMS is not enough. We need more studies evaluating the risk of ESAs and we need these to start soon.