In briefing materials posted on FDA’s website today, the agency lays out the issues it wants the committee to discuss, including the possibility of removing the indication for use of the drugs in the cancer setting. (EPO products are also used to treat anemia in other indications, primarily kidney disease.)
The possibility of FDA withdrawing the approval of what has been a standard component of chemotherapy regimens for almost 15 years is truly astonishing to consider. But it is by no means surprising that the committee will be asked to discuss that possibility. When FDA announced the latest ODAC visit for EPO in January, the agency made very clear that it would be at least raising the possibility of withdrawing that indication altogether. (You can read our analysis of the issues at stake March 13 here.)
The more interesting reading for biopharma executives trying to make sense of the new drug safety climate comes in an appendix to the briefing materials, containing the review of potential risk management options for EPO by FDA’s Office of Surveillance and Epidemiology.
Assuming the committee supports leaving at least some oncology indications in place for EPO, the discussion will quickly turn to risk management options. And, as of the end of this month, FDA is armed with the power to make those programs mandatory.
The FDA Amendments Act, signed into law in September, spells out a series of tools that FDA can require as part of Risk Evaluation & Mitigation Strategies. What it does not do is spell out how, in practice, FDA will choose which tools to apply—and how to determine what is or is not an effective strategy.
That is where Appendix 2 in the briefing documents comes in.
To us, it reads like a case study in how the agency will define the metrics for success in REMS.
The message it sends is unmistakable: "success" for a sponsor facing a serious safety question looks an awful lot like failure in a commercial context. When FDA wants to know if a REMS is working, it will look at market data or other commercial tracking statistics for evidence that use is declining—either overall or in submarkets of concern.
The analysis is filled with market research statistics. The agency uses retail prescription data to look at how use of the drugs has been affected by risk management steps taken so far. The review acknowledges reimbursement changes by the Centers for Medicare & Medicaid Services as an important factor as well (though we would argue that CMS’ policy probably is the biggest reason for reduced use of EPO.)
But the agency drills down much deeper, looking into metrics like settings of use. Aranesp, FDA finds, is used most commonly in outpatient clinics (54% of vials sold), while Procrit’s largest in non-federal hospitals (39%). Outpatient pharmacies are relatively small markets for each brand, FDA notes. “Interestingly, the long-term care channel accounted for approximately 10% and 5% of sales distribution for Procrit and Aranesp, respectively.”
The agency also looks at indications associated with use of the drugs. “The top two diagnoses or indications associated with the use of Procrit and Aranesp as reported by office-based physician practices were ‘other and unspecified anemias’ (ICD-9285), and ‘chronic kidney disease’ (ICD-9 585), each accounting for roughly 60% and 12% of use during year 2007.”
FDA and the committee will discuss options ranging from informed consent procedures to “voluntary” limits on advertising to restricted distribution programs—including programs that would restrict use by setting of care or by indication. So data on prescription trends, settings of use and indications will be useful for determining what types of risk management tools might work—and, more importantly, for future assessments of whether the programs are in fact working.
And, let’s be blunt: until FDA has better measures it will be looking for less use of a product with safety considerations. That is one of the uncomfortable new realities of the era of REMS: investing in marketing campaigns that intended to produce overall reductions in prescriptions, reductions in off-label indications, or reductions in vials shipped to “interesting” submarkets, like long-term care.