The documents issued by the US Food and Drug Administration on shared system risk evaluation and mitigation strategies signal the FDA’s willingness to grant waivers from the shared program requirement, but that may complicate matters for the companies trying to negotiate them and the healthcare providers trying to navigate them.

The US Food and Drug Administration (FDA) issued two draft guidance documents on May 31 related to shared system risk evaluation and mitigation strategies (REMS). A REMS is a required risk management plan for drugs associated with serious risks. When a generic drug applicant seeks approval to copy a reference listed drug (RLD) that has a REMS associated with it, the generic and RLD drug manufacturers are required to develop a single shared system (SSS) REMS program. One guidance provides information on developing an SSS REMS, and the other provides information on how generic drug applicants can request a waiver from the shared program.

FDA did not provide any concrete steps to assist drug manufacturers with the challenging task of working cooperatively with market competitors on these drug safety programs. Instead, FDA chose to emphasize the fact that generic companies can submit their own separate REMS program without working with the sponsor of the existing REMS program. Only time will tell whether the healthcare marketplace and consumers will be well-served by the proliferation of separate brand and generic REMS programs for the same drug product.

Background

A REMS is a risk management strategy designed to ensure that the benefits of a drug outweigh its risks. It may require, for example, a medication guide to provide risk information to patients and prescribers, or elements to assure safe use (ETASU), such as particular training or experiences for prescribers of the drug, or monitoring of patients using the drug. An SSS REMS is a REMS that encompasses multiple prescription drug products and is implemented jointly by two or more applicants. It uses a single REMS document, supporting document, and REMS materials that have been agreed to by all applicants and approved for each drug or biologic application.

Although FDA Commissioner Scott Gottlieb issued a statement on the two draft guidance documents sharing his concern that RLD sponsors may have “exploited” the SSS REMS process to delay generic drug approval, FDA took a more measured tone, acknowledging that the “formation of a SSS between an RLD holder and an ANDA applicant can be a complex and time-consuming process.”

Development of a Shared System REMS

The draft guidance document, Development of a Shared System REMS, provides an overview of REMS and shared system REMS, and also distinguishes between required and recommended use of a shared REMS. With regard to the latter, only the holder of an abbreviated new drug application (ANDA) is required to use a shared system REMS (unless FDA waives the requirement). Yet, FDA recommends that certain other product applicants develop shared system REMS where applicable, specifically applicants of products submitted under 505(b)(2) of the FD&C Act or 351(a) or (k) of the Public Health Services (PHS) Act, and applicants for classes of products with similar risk profiles.

The guidance also explains how to develop and submit a shared REMS. In keeping with the current process, FDA will initiate discussions about the formation of an SSS REMS and facilitate contact between the RLD sponsor and the generic applicant. The drug applicants can consider forming a working group to handle negotiations and agreements on developing the program, such as on issues of governance, voting structure, cost-sharing, and confidentiality. While FDA will set forth deadlines for certain development milestones, it does not advise on the business arrangements between the applicants. FDA states that it should be notified, however, if obstacles arise that impede development of the shared system REMS.

FDA also discusses the situation where an ANDA has received only a tentative approval (TA). FDA states that the SSS REMS will be approved at the time of the TA, but will not become operational until after the first ANDA receives final approval, calling it a “bifurcated” REMS.

Waivers of the Single Shared System REMS Requirements

The second guidance, Waivers of the Single Shared System REMS Requirements, describes how FDA intends to consider granting a waiver of the SSS REMS requirement discussed above. FDA repeats the statutory language, stating that it may grant a waiver to the SSS REMS requirement—so long as the generic manufacturer’s separate REMS includes the same ETASU—in the following circumstances:

  • The burden of creating a shared system REMS outweighs the benefit of a single system
  • An aspect of the REMS ETASU is protected by patent or is a trade secret and the ANDA applicant certifies that it sought a license to that aspect and was unable to obtain one

In determining whether the burden of creating the SSS REMS outweighs the benefit, FDA expands a little bit on the statutory factors of the impact on healthcare providers, patients, the ANDA applicant, and the holder of the RLD. Other relevant factors include specifics related to the drug product at issue, the nature of the existing REMS program, and circumstances in the healthcare delivery system. In footnote 2, FDA also points to the three waivers it has granted previously, noting that it considered “the amount of time taken to negotiate a SSS” REMS.

FDA states that it will consider a waiver at any time. The ANDA applicant may either submit an SSS REMS (as agreed upon with the RLD holder), or a proposed separate REMS with a request for a waiver. FDA will review either submission as part of the ANDA. A waiver request should include information on

  • how the burden of forming an SSS REMS outweighs the benefits of such a program;
  • the ANDA applicant’s plans to include additional future applicants in its REMS program;
  • how the proposed separate program is different from the RLD program, including explanations of how aspects of the required ETASU are comparable to those of the RLD REMS;
  • if applicable, attempts made by the ANDA applicant to obtain a license to a protected aspect of the ETASU; and
  • the parties’ attempts at negotiation of the SSS REMS.

Takeaways

There are both efficiency benefits and competitive disadvantages for the brand and generic drug makers with regard to implementing an SSS REMS. In an attempt to minimize perceived obstacles to generic drug market entry, FDA has provided industry with insight into a previously under-defined area of FDA regulation by issuing these two new draft guidance documents. Although much of the information merely restates the statutory language and describes FDA’s years-old internal policies, the impetus for publishing the guidance documents at this time signals that FDA may be more willing than ever before to grant waivers. This willingness could backfire, however, causing what are now difficult negotiations between competing manufacturers to be all but useless conversations. Unless the economic efficiencies inherent in a shared program are sufficient to spur the parties’ agreement, FDA’s current pro-waiver attitude, and the 10-month ANDA user fee review timeline, may completely undermine the very programs that FDA asked Congress to create in 2007.