Industry Trend Analysis - FDA Focus On REMS Is A Substantial Victory For Generic Industry - JAN 2018

BMI View: C oncerns over potential Risk Evaluation and Mitigation Strategies (REMS) programme abuses have been gaining traction in 2017 at a regulatory and political level. Having already accepted that the REMS programme is potentially open to abuse to delay generic competition, the FDA is somewhat duty-bound to find solutions, and the draft guidance now issued is a first step towards addressing that , and represents a substantial victory for the generic industry. It is especially important given the likelihood that legislative action on the issue will not succeed.

The FDA has unveiled draft guidance that aims to improve its review of shared Risk Evaluation and Mitigation Strategies (REMS) in order to improve generic drug access. REMS are used to ensure that the benefits of a drug outweigh its risks, and can contain various tools, such as a Medication Guide or patient package insert with information for patients, and various 'Elements to Ensure Safe Use' (ETASU). These elements may include requirements for prescriber training or patient counselling.

However, there has been growing concern that REMS programmes have been open to potential abuse to delay generic competition. The Association for Accessible Medicines (AAM) has argued for some time that REMS and restricted access drug programmes have been used to deny generic drug firms access to samples of branded drug products. These samples are needed to conduct generic drug product development and bioequivalence studies necessary for FDA approval. Without access to these samples, which traditionally have been purchased by generic drug applicants through wholesalers, appropriate testing and subsequent approval of generics cannot occur. The AAM has added that as the biosimilar market begins to develop, the inability of biosimilar manufacturers to obtain samples of brand biologics for early development testing purposes will also cause delayed access. The organisation has previously alleged that branded companies have expanded these practices outside of the REMS programme, citing what the AAM claims are unsubstantiated safety concerns as a means to extend their monopolies.

In a statement, FDA Commissioner Scott Gottlieb noted that, as part of the Agency's Drug Competition Action Plan, it needs to ensure that REMS programmes '...maintain their role in serving public health and don't become a tool companies can use to delay or block competition from generic products entering the market.' To address this, the FDA has unveiled a two-pronged approach to addressing shared REMS issues. The first part is to continue to find ways to encourage the use of shared system REMS (SSR) between all innovator and generic companies producing a drug; and the second is to explore new steps that the Agency can take to reduce the likelihood of branded drug companies using the existence of REMS as a way to slow the entry of generic competition.

Gottlieb noted that current law requires that branded and generic companies try to reach agreement on the implementation of a single, shared system REMS rather than maintaining separate REMS for the branded drug and its generic competitor. Any generic drug application referencing a branded drug with a REMS with ETASU must use a single, shared system REMS with the innovator, unless the FDA waives that requirement and permits the generic drug to use a separate, comparable REMS programme. However, Gottlieb acknowledged that negotiations to reach agreement on an SSR can take a long time, which in itself can block the entry of generic competition. Significantly, Gottlieb stated: 'I believe branded firms sometimes use these negotiations strategically, as a way to slow generic competitors.'

To further streamline the submission and review process for SSRs for any REMS that include more than one medication, the FDA has released draft guidance for industry, entitled 'Use of a Drug Master File for Shared System REMS Submissions', that describes how applicants can submit collective sets of files to the FDA that represent all participating firms. Under the existing system for SSRs, multiple applicants need to coordinate the submission of identical REMS-related documents for their respective applications. The draft guidance explains the Agency's current thinking that the use of a single Drug Master File (DMF) for SSR submissions will allow manufacturers with products in SSR programmes to submit one collective set of files to the FDA. Gottlieb noted that this is a first step toward additional action the FDA plans to take to make sharing a single REMS easier. The new process will eliminate the need for each involved manufacturer to submit files individually. It eliminates duplicative paperwork for sponsors, and will decrease the volume of forms the FDA's reviewers must assess. While submitting shared system REMS files this way is not a requirement, given the efficiency gains to both sponsors and the FDA, the Agency is encouraging applicants to use the DMF for SSR submissions.

Gottlieb added that the Agency will also be looking more specifically at how it can address situations where innovator firms may leverage the single SSR requirement to block or delay generic competition, noting that: '...the requirement that the brand and generic sponsor use a single shared system to implement REMS with ETASU necessitates discussion and negotiation between two potential competitors. Because of the impact of generic entry on a brand company's market share, brand companies often have an incentive to prolong these negotiations or refuse to agree to a single, shared system REMS. In addition to delaying generic drug approval, these negotiations are time- and resource- intensive for both industry and the FDA. This is not in the best interest of public health. Not only is the approval of a generic competitor delayed, but also the drug approval process is less efficient.' To address this, the FDA plans to provide information about how and when it intends to consider waiving the requirement that an innovator and generic utilise an SSR, freeing generic entrants from being required to reach agreement with the relevant branded company. These new policy steps will include information on how and when generic drug applicants can request a waiver and the factors that the Agency will consider. Gottlieb commented: 'We believe that addressing this problem will allow for the more efficient approval of generic drugs while maintaining the safety controls sought by the REMS.'

Congress Has Also Looked At Issue

The issues surrounding REMS and generic access to the marketplace have been raised in Congress. In 2016, Senators Charles Grassley (R-IA), Patrick Leahy (D-VT), Amy Klobuchar (D-MN) and Mike Lee (R-UT) introduced the Creating and Restoring Equal Access to Equivalent Samples (CREATES) Act to Congress. The legislation has been reintroduced for the current session of Congress, as House bill HR 2212 (sponsor: Tom Marino, R-PA), complemented by Senate Bill S 974 (sponsor: Patrick J Leahy, D-VT). This proposed legislation seeks to reduce incentives for regulatory abuse with regard to both obtaining samples for generic development and problems with shared REMS programmes.

The bill would create a cause of action in federal court for a generic applicant to obtain sufficient product samples from the branded manufacturer. It also amends the law to make it easier for a generic drug to gain FDA approval for a separate REMS programme. The proposed legislation would not compel the branded company to share its REMS programme with the generic, but instead removes the strategic advantage that currently exists in not sharing it. It will allow both companies to determine whether they will share a REMS programme and the commercial terms for that arrangement on their own.

However, just as the 2016 bill languished in Congress, the same fate has so far befallen the reintroduced legislation. The last action for both HR 2212 and S 974 occurred in April 2017. For HR 2212, this was a referral to the Subcommittee on Health, whilst for S 974 this was a referral to the Committee on the Judiciary. It consequently remains unlikely that this legislation will become law.