On May 31, 2018, the FDA announced two new guidances designed to help generic drug manufacturers to obtain access to shared Risk Evaluation and Mitigation Systems programs, thereby promoting competition and access.
The first guidance, “Development of a Shared REMS” (the “Shared REMS Guidance”) describes principles and recommendations to help sponsors with developing shared REMS programs with their generic competitors to improve the clarity and efficiency for developing these programs to enable timelier market entry for additional products under the shared REMS. The second guidance, “Waivers of the Single, Shared System REMS Requirement” (the “Shared REMS Waiver Guidance”) describes when and how the FDA will waive a single, shared REMS requirements, and allow an alternative shared REMS elements or program.
As the FDA explained in the press release accompanying the two guidances:
We believe that by making the process for developing a shared system REMS more efficient, we’ll discourage brand drug makers from using REMS as a way to block generic entry and help end some of the tactics that can delay access. We’re also going to be clearer about the circumstances when we’ll issue waivers to let the generic firms develop their own REMS program. Our safety programs shouldn’t be leveraged as a way to forestall generic entry after lawful IP has lapsed on a brand drug. Our market-based system for rewarding innovation is dependent on this kind of legal competition.
The Shared REMS Guidance explained that a shared REMS uses a single REMS document agreed to by all new drug applications (NDAs) (or biologics license applications (BLAs) and abbreviated new drug applications (ANDAs) (or BLAs submitted under 351(k) (also known as biosimilars) that is implemented jointly by two or more applicants. The FDA views a shared REMS as administratively more convenient and efficient, which is required only for ANDAs and their reference listed drugs (RLDs) for REMS with certain Elements to Assure Safe Use (ETASU) under section 501-1(i)(1)(B) of the Food, Drug, and Cosmetic Act (the “FD&C Act”). ETASU typically involved more restrictive elements, such as requirements for health care providers who prescribe to have special training or experience, special patient monitoring or tests, or restricted distribution or administration. At times, the FDA has also required shared REMS for a class of products with a similar risk profile, e.g. long-acting opioid drugs.
What is new under the Shared REMS Guidance is that the FDA will now initiate discussions for a shared REMS prior to approval of a pending NDA or ANDA and will set expectations for applicants to develop a shared REMS, including timeframes for certain milestones. The FDA may also facilitate collaborations or host teleconferences to encourage communication between applicants. The FDA will identify an agency point of contact (POC) for a shared REMS under development and will provide this to the Industry Working Group (IWG), if formed, to help facilitate negotiations and agreements. Some of the anticipated topics in previous shared REMS have included confidentiality, governance, voting structure, cost-sharing, changes to the distribution model, and whether to use a third-party vendor to implement or manage the shared REMS. The FDA will not, however, advise on the business arrangements being negotiated or arbitrate substantive disputes in terms of the contracts.
The Shared REMS Waiver Guidance explained that while the FDA will consider on a case-by-case basis whether to waive the requirement for a single, shared REMS for ANDAs and their RLDs. Generally, the FDA can grant a waiver for a single, shared REMS only if the burden of creating a single, shared system (“SSS”) outweighs the benefit of a single system or if an aspect of the ETASU is protected by a patent or trade secret entitled to protection, and the ANDA applicant has certified that it has sought and failed to obtain a license. The Shared REMS Waiver Guidance discussed the specific factors the FDA will consider whether to grant a waiver, recognizing that negotiations for shared REMS may be difficult between competitors, who are often also adversaries in patent litigation leading up to an ANDA’s approval. This Guidance further acknowledged that FD&C Act provisions that created REMS also required in section 501-1(f)(8):
No holder of an approved covered application shall use any element to assure safe use required by the Secretary under this subsection to block or delay approval of an application under section 355(b)(2) or (j) of this title or to prevent application of such element under subsection (i)(1)(B) to a drug that is the subject of an abbreviated new drug application.
An ANDA applicant is now directed to submit either a single shared REMS (if agreed to with the RLD holder) or a proposed separate REMS with a request for a waiver of single, shared REMS requirement by the midpoint of a pending review cycle. This Guidance now includes information that the FDA expects to be included in the associated waiver request, including information to support an aspect of an ETASU that is comparable (but perhaps not identical) to that of the RLD REMS and achieves the same level of safety. In general, however, the FDA expects a separate ANDA ETASU to be the same.