With the passage of the long-awaited 21st Century Cures legislation, we saw Senator Mike Lee (R-UT) vote “no” because the bill did not include language that would allow generic pharmaceutical companies to obtain samples of products under the Risk Evaluation and Mitigation Strategies (REMS) program. Senator Lee an others, including Senator Chuck Grassley (R-IA) and Patrick Leahy (D-VT) had supported an amendment to Cures based on a legislative proposal that would improve the REMS process as a method to control drug prices. This is why it is interesting to review a draft guidance from FDA that tries to further explain the application of REMS regulatory paradigm, which can ultimately delay generic drug competition. A REMS can be a medication guide or package insert or communication plan that is required by FDA to ensure that the benefits of a drug outweighs the risks.
40 percent of FDA approvals are subjected to REMS
In a 2014 report, the Generic Pharmaceutical Association (GPhA) wrote that nearly 40 percent of new FDA approvals are subject to REMS, and brand manufacturers have also begun imposing distribution restrictions on non-REMS products. “Government, consumers, and private payors are already missing out on sizeable health care savings from misuse of these programs. Specifically, REMS and non-REMS strategies to restrict access to brand drug samples represent lost savings on small-molecule drugs of at least $5.4 billion annually,” said the GPhA.
The 14-page draft, “FDA’s Application of Statutory Factors in Determining When a REMS Is Necessary,” offers some explanation for how it tries to address the burden of the REMS program.
The FDAAA requires FDA to consider the following six factors in making a decision about whether to require a REMS:
- The seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug;
- The expected benefit of the drug with respect to the disease or condition;
- The seriousness of the disease or condition that is to be treated with the drug;
- Whether the drug is a new molecular entity;
- The expected or actual duration of treatment with the drug;
- The estimated size of the population likely to use the drug.
These six factors influence FDA’s decisions with respect to both whether a REMS is required for a particular drug and what type of REMS might be necessary (i.e., what specific elements or tools should be included as part of the REMS). FDA makes decisions about requiring a REMS as part of a benefit-risk determination for a drug after an evaluation that includes integrated consideration of each of the statutory factors. No single factor, by itself, is determinative as to whether a REMS is necessary to ensure that the benefits of a drug outweigh its risks.
The more serious a drug’s known or potential associated risks relative to its benefits, the more likely it is that a REMS will be necessary to ensure a favorable benefit-risk balance, without which the drug could not be approved. In determining whether to require a REMS, FDA considers the source, nature and reliability of available scientific evidence about the adverse events as well as the characteristics of the risks, including the severity, frequency, temporality, preventability, reversibility, background incidence, and likelihood of occurrence of the adverse events.
When assessing a drug’s expected benefits with respect to a specific disease or condition in considering whether a REMS is necessary, FDA may evaluate information about the drug’s effectiveness, whether the drug treats a serious disease or condition, whether it fills an unmet medical need, and whether it can cure the disease or alleviate its symptoms. FDA may also consider the extent to which new dosage forms enhance convenience of administration and/or improve adherence to prescribed regimens, and whether new formulations or delivery mechanisms may extend treatment to patient populations who were formerly unable to use the drug. A drug’s expected benefits, however, are not considered in isolation. In determining whether a REMS is necessary, FDA’s assessment of a drug’s benefit is balanced against consideration of the risks associated with its use.
In the conclusion of its guidance, the agency writes, “FDA understands that REMS, particularly those with ETASU, may impose some measure of burden on patients and/or health care providers. When considering this burden on patient access and the health care delivery system, FDA takes into account existing REMS elements for other drugs with similar risks and whether the REMS under consideration can be designed to be compatible with established medical drug distribution, procurement, and dispensing systems.”
The FDA also looks at patients for whom the drug is indicated currently access health care and whether the REMS may impose additional access difficulties. FDA also takes into account the consequences of potential treatment interruption or delays, particularly where patients have serious or life-threatening conditions and/or have difficulty accessing health care. In such circumstances, FDA claims it takes steps, to the extent possible, to ensure that REMS are designed to minimize delays or interruptions in drug therapy that may have untoward clinical impact.