As we discussed last summer, FDA has recognized that negotiations surrounding the development of a Single, Shared System REMS may fail, and, to that end, issued a guidance detailing the Agency’s waivers process. Now, the market has borne the fruits of that labor in the form of a “Parallel System (PS)” REMS. Just last week, FDA approved the first Parallel System REMS when it approved several generic versions of Letairis (ambrisentan) for the treatment of pulmonary arterial hypertension with two separate REMS programs.
For the unfamiliar, section 505-1 of the Food, Drug, and Cosmetic Act provides FDA the authority to require a Risk Evaluation and Mitigation Strategy, known as a REMS, when necessary to ensure that the benefits of a drug outweigh its risks. Section 505-1 also requires that an ANDA referencing a drug with a REMS with Elements to Assure Safe Use implement a “single, shared system” with the RLD for any such REMS. FDA may waive the requirement if FDA determines that the burden of creating a single shared system outweighs the benefit of the single shared system or the RLD’s system is covered by a patent or other trade secret protection.
In this instance, FDA explained that one generic manufacturer of ambrisentan would not join with other manufacturers to enter into a shared REMS system because doing so would prevent the use of retail pharmacies for product distribution. Three other generic manufacturers of ambrisentan formed a single, shared system with Gilead, the RLD sponsor, adopting the same methods of distribution under the Letairis REMS, which dispenses to female patients only through specialty pharmacies. The announcement of the two separate REMS systems occurred in conjunction with FDA’s announcement of the four generic approvals. FDA has emphasized that the separate REMS program “achieves the same level of safety as the REMS for the brand-name ambrisentan.”
FDA has exercised its authority to waive a shared system before. For example, for sodium oxybate oral solution, FDA found that both the burden of creating a shared system outweighed the benefit and that aspects of the Elements to Assure Safe Use in the RLD REMS, Xyrem, were protected by patent to which the ANDA applicants were not able to obtain a license. FDA issued this waiver determination days before approval of the relevant ANDAs. Similarly, FDA made a similar determination in April 2015 to waive the single shared system requirement for alosetron hydrochloride products referencing Lotronex. There, FDA determined that the burden of creating a share system outweighs the benefits after several failed rounds of negotiations (and a refusal to participate in any further negotiations by the RLD sponsor given an ongoing FTC inquiry into its conduct during REMS negotiations). Again, the waiver decision was released days before the relevant ANDA approval.
The ambrisentan single shared REMS waiver is the first since the June 2018 publication of the waiver guidance. It’s still too early to tell what impact the guidance has had on waiver requests, particularly because no waiver decision has been issued yet – and it’s not even clear that a formal decision will be issued. But it is exemplary of FDA’s ongoing commitment to working with ANDA holders on expediting generic entry, particularly when hurdles arise in the negotiation of a shared REMS, which may suggest anticompetitive motives. While unrelated, it’s also interesting that the necessity of the separate waiver arises from a difference in the preferred distribution chain, indicating that the use of a specialty pharmacy may be more restrictive than necessary; however, given that three other generic manufacturers have signed on to the Letairis version of the REMS, it stands to reason that FDA has not viewed the restrictive distribution as implemented for anticompetitive reasons.
The tinkering with the REMS system isn’t quite done yet even with this exercise of the June 2018 guidance. Congress is still looking at the single shared REMS system too with a new version of the CREATES Act, last discussed here in 2016. The Act, re-introduced in the Senate in February 2019 and in the house in March 2019, aims to address the use of REMS and related to distribution restrictions as “reasons to not sell quantities of a covered product to generic product developers, causing barriers and delays in getting generic products on the market.” CREATES Act of 2019 § 2(6). It permits a product developer to bring civil action against an RLD or reference product (biologic) sponsor alleging that the sponsor has declined to provide sufficient quantities of the covered product on commercially reasonable, market-based terms. The Creates Act will also amend section 505-1 of the FDC Act to allow an ANDA holder to use “a different comparable aspect of the elements to assure safe use,” which by definition is a “Separate REMS” under the Act. The Act has bipartisan support, but a similar bill made no progress last year in Congress.