1. Amy Speros Latham & Watkins LLP
REMS and Citizen Petitions: FDA Background and Competition Concerns AIPLA Spring Meeting 2017
Amy Speros
Latham & Watkins LLP

2. REMS
Risk Evaluation and Mitigation Strategies

3. REMS Background
Section of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. § 355-1) was enacted in 2007 to give FDA authority to require a REMS for certain drugs if FDA determines that a REMS is “necessary to ensure that the benefits of the drug outweigh the risks of the drug.”
For the majority of drugs, routine risk mitigation measures are sufficient to preserve benefits while minimizing risks.
FDA will require a REMS if it believes that that additional interventions beyond FDA-approved labeling are necessary to maintain the drug’s risk-benefit profile.
The REMS statute is applied to biologics via a separate provision in the Public Health Service Act, which governs FDA authority over biologics.

4. REMS Background (cont’d)
Before the REMS statute, FDA typically used sponsor commitments called Risk Minimization Action Plans (RiskMAPs) to ensure the safety of particularly risky products.
Following enactment of the REMS statute, FDA declared that several product RiskMAPs became “deemed REMS” subject to the new REMS requirements.
Under the statute, FDA must consider certain specific criteria in deciding whether to require a REMS:
The estimated size of the patient population for the drug;
The seriousness of the disease or condition the drug is intended to treat;
The expected benefit of the drug with respect to such disease or condition;
The expected or actual duration of treatment with the drug;
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 patient population for the drug; and
Whether the drug is a new molecular entity.

5. REMS Background (cont’d)
Since 2007, FDA has approved more than 100 new REMS, with 71 currently active REMS programs (excluding products “released” from the REMS requirement).
A 2014 study found that nearly 40% of new FDA approvals are subject to a REMS.
To date, FDA has approved 9 “shared system” REMS with multiple applicants for a particular drug or drug type:
Alosetron REMS
Buprenorphine Transmucosal Products for Opioid Dependence (BTOD) REMS
Clozapine REMS
Extended-Release and Long-Acting (ER/LA) Opioid REMS
Isotrentin iPLEDGE REMS
Mycophenolate REMS
Sodium Oxybate REMS
Transmucosal Immediate-Release Fentanyl (TIRF) Rems
Vigabatrin REMS

6. What Makes a REMS?
All REMS programs must include a timetable for assessments to periodically monitor the REMS effectiveness and the need for potential modification.
In addition, a REMS must include one or more of the following elements:
A Medication Guide and/or Patient Package Insert;
A communication plan for health care providers; and/or
Additional elements to assure safe use (ETASU).
FDA has authority to take enforcement action against companies that fail to comply with statutory REMS requirements.

7. REMS Elements to Assure Safe Use (ETASU)
ETASU are the most stringent type of REMS requirements and typically involve significant time and financial investment for manufacturers to develop, implement, and maintain.
ETASU can include:
A requirement that health care providers who prescribe the drug have particular training or experience, or be specially certified;
A requirement that pharmacies that dispense the drug be specially certified;
A requirement that the drug be dispensed to patients only in certain health care settings (e.g., hospitals), or only with evidence of safe-use conditions (e.g., laboratory test results); and/or
A requirement that each patient using the drug be subject to certain monitoring or enrolled in a registry.

8. REMS ETASU (cont’d)
Given the increased burdens of ETASU on manufacturers, patients, and the health care system, the statute requires FDA to make additional findings before requiring ETASU:
First, the chosen ETASU must be connected to a specific serious risk listed in the labeling of the drug and the ETASU must be commensurate with that risk;
Second:
For new drugs, FDA must find that it would not approve the drug unless the specific ETASU are required, or
For approved drugs, FDA must find that it would withdraw the drug from the market unless the specific ETASU are required, and that other REMS elements are insufficient to mitigate the risk.

9. REMS Goals

10. REMS Competition Concerns
Access to Samples

11. Access to Samples
Generic and biosimilar developers need access to samples of innovator products in order to conduct the comparative testing necessary to support an application (e.g., bioequivalence studies).
An increasing number of REMS programs with ETASU have restricted distribution systems that can prevent access to samples.
By preventing access to samples, brands can hinder follow-on product development and delay competition.
Non-REMS products have also become less available as brands self-impose restricted distribution systems to control access.

12. Access to Samples (cont’d)
The REMS statute specifically prohibits sponsors from using any ETASU to block or delay approval of a follow-on application.
This has not stopped brands from refusing to provide samples to follow-on developers in the REMS context.
FDA has taken the position that it lacks authority to force a brand company to sell its product to a follow-on developer for any reason, including research and development of generic and biosimilar products.

13. Access to Samples (cont’d)
To address the sample access issue, FDA released a guidance in 2014, stating:
FDA is aware of instances in which an RLD sponsor has refused to sell drug product to a prospective ANDA applicant seeking to conduct the testing needed to obtain approval, and the RLD sponsor has cited the REMS ETASU as justification.
Under the guidance, FDA will, upon request:
Review a generic sponsor’s bioequivalence study protocols and materials to assess whether they provide safety protections comparable to the REMS ETASU, and
If comparable protections exist, issue a letter to the RLD sponsor sating that FDA will not consider it a REMS violation to provide drug product to the generic sponsor.

14. Access to Samples (cont’d)
The guidance has not provided a complete solution:
The guidance makes clear an FDA letter is not a legal requirement and the guidance framework is purely optional, but brand companies now routinely request a letter from FDA before even considering whether to provide samples.
The guidance also contemplates that FDA will issue a letter after reviewing human study protocols, but companies often need brand samples prior to that point in order to develop a generic or biosimilar product in the first place.
The guidance also does not address self-imposed restricted distribution systems for non-REMS drugs.

15. REMS Competition Concerns
Shared REMS Negotiations

16. Shared REMS Negotiations
The REMS statute requires that a generic drug and a brand drug must use a single shared system of ETASU unless FDA finds the criteria for a waiver are met.
This single shared REMS requirement necessitates that brands and generics work together in implementing a shared program.
The first shared REMS systems involved negotiations between brands and generics that were already on the market – negotiation delays could not delay generic competition.
Now, most shared REMS involve negotiations between brands and pending generics – negotiation delays have the direct impact of delayed generic approval.
Because FDA cannot approve generic products without the REMS in place, brands can slow-walk negotiations, buying more time alone on the market.

17. Shared REMS Negotiations (cont’d)
Under the statute, FDA may grant a waiver from the single shared REMS requirement and permit ANDA applicants to use different, comparable ETASU if FDA finds that:
The burden of creating a single shared system outweighs the benefit; or
An aspect of the ETASU is protected by patents or trade secrets and ANDA applicants could not obtain a license.
To date, FDA has granted 3 waivers, each based on FDA findings that the burden of a single shared system outweighed the benefit due to prolonged negotiations that impeded patient access to generic alternatives.
1 of the 3 waivers was also based on the additional finding that the ANDA applicants were unable to obtain a license to use patented ETASU.
FDA recently approved the only shared REMS by a brand and a pending generic.

18. REMS Current State of Play
Given FDA’s enforcement stance, there have been several failed attempts over the years to address REMS abuses with legislation.
Two REMS-focused bills have been re-introduced in the current session, the FAST Generics Act and the CREATES Act, which attempt to address REMS abuses by:
Mandating access to samples for both REMS-covered and non-REMS-covered drugs;
Codifying an authorization requirement for REMS-covered drugs similar to the FDA guidance; and
Making it easier to obtain a waiver from the single shared REMS requirement.
Although both bills are bipartisan, neither has been incorporated into pending user fee legislation; however, recent committee hearings have highlighted the issue in connection with the drug pricing debate.

19. Citizen petitions
Section 505(q)

20. Citizen Petition Background
FDA regulations have long permitted any person to petition the agency to take or refrain from taking any form of administrative action.
In 2007, section 505(q) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. § 355(q)) was enacted to address a specific type of petition – citizen petitions requesting that FDA take an action that could delay approval of a pending follow-on application.
Under the statute, FDA can delay approval of an application if, based on its review of a 505(q) petition, FDA determines that the delay is necessary to protect the public health.
FDA can also deny a 505(q) petition outright if it determines that the petition was submitted with the primary purpose of delaying approval of a follow-on application and the petition does not, on its face, raise valid scientific or regulatory issues.

21. 505(q) Competition Concern
Intent to Delay

22. Intent to Delay
FDA’s annual reports to Congress on 505(q) issues show that very few follow-on applications are formally delayed due to a 505(q) petition.
However, 505(q) petitions typically cause informal, de facto delays on account of the time and resources FDA must take to review and answer them while simultaneously reviewing pending follow-on applications.
505(q) petitions can be used to delay approval of competing products regardless of the ultimate petition outcome – in 2015, only 5% of 505(q) petitions were granted in full.
505(q) petitions can also be used to impact public discourse and patient preferences against generic or biosimilar products.

23. Intent to Delay (cont’d)
Although the statute explicitly permits FDA to deny a 505(q) petition on its face, FDA rarely (if ever) does so.
FDA has stated that most petitions raise colorable arguments that the agency must address, even if the petition’s ultimate goal is to stall competition.
As a result, FDA has stated that section 505(q) does not appear to be discouraging the types of petitions it is intended to discourage.
Originally, the statute required that FDA take final action on a 505(q) petition within 180 days of submission, but a 2012 amendment reduced the timeframe to 150 days.
FDA has stated that the hard deadline takes agency time and resources away from completing other work in a more timely manner.

24. Current State of Play
FDA recently promulgated regulations implementing section 505(q) alongside its existing citizen petition regulations, but the regulations are largely consistent with the statutory text.
One notable regulation implements the 505(q) certification requirement, under which petitioners must provide the approximate date on which they became aware of the information and issues raised in the petition.
Although this certification was always required under the statute, some have speculated that FDA’s regulation could indicate increased enforcement against petitions that are untimely and clearly intended to delay.
The impact of the regulations remains to be seen but is ultimately unlikely to deter strategic petitions under the 505(q) framework.

25. Intersections
Shared REMS Negotiations and 505(q) Petitions

26. The Buprenorphine Transmucosal Products for Opioid Dependence (BTOD) REMS

27. The BTOD REMS
In January 2012, FDA notified all ANDA applicants referencing Subutex and Suboxone that they would be required to develop a single shared REMS with the brand, Reckitt Benckiser.
In September 2012, after 9 months of stalled negotiations, Reckitt submitted a 505(q) petition requesting that FDA refrain from approving any follow-on buprenorphine product that lacked certain post-market safety precautions.
At the same time, Reckitt announced that it was withdrawing its Suboxone tablet product from the market in favor of the film version, and in the petition, Reckitt claimed that this was for safety reasons – if FDA agreed, ANDA applicants would not be able to reference the tablet product as the RLD.
In October 2012, the ANDA applicants submitted a waiver request to FDA in order to implement a separate, generics-only shared REMS system distinct from the Reckitt program.
The applicants cited Reckitt’s 505(q) petition and its behavior in shared REMS negotiations as evidence of an intent to delay generic competition, arguing that the burden of requiring a single shared REMS outweighed the benefits.

28. The BTOD REMS (cont’d)
In February 2013, FDA denied Reckitt’s petition and granted the ANDA applicants a waiver from the single shared system requirement, the first such waiver granted under the REMS statute.
Although the ANDA applicants requested that FDA deny the petition on its face for being submitted with the primary purpose of delay, FDA declined to do so, deciding instead to deny the petition on the merits.
However, FDA did note the claims that Reckitt’s petition was part of a pattern of anticompetitive behavior by Reckitt and referred the matter to the FTC.
The FTC later opened an investigation into whether Reckitt abused public regulatory processes, including citizen petition and REMS processes, to maintain its monopoly on the market for Suboxone.

29. The Alosetron REMS

30. The Alosetron REMS
In May 2013, Prometheus Laboratories submitted a 505(q) petition requesting that FDA:
Promulgate rules to establish standards and processes for single shared REMS systems; and
Refrain from granting a waiver for ANDA applicants referencing Prometheus’s Lotronex (alosetron) until FDA granted Prometheus notice and opportunity to participate in the process.
In October 2013, FDA responded to the petition, granting the first request, stating FDA would consider regulations or guidance in the future, but denying the second request, stating that the statute did not provide for notice or participation by brands in the waiver process.
In May 2015, FDA approved an ANDA submitted by Roxane Laboratories referencing Lotronex and granted a waiver from the single shared REMS requirement.
Prometheus promptly sued FDA, alleging that the waiver violated the law and put patients at risk; among other things, Prometheus argued that the separate system was not “comparable” to the brand REMS, as required by the REMS statute.

31. The Alosetron REMS (cont’d)
Roxane intervened in support of FDA, and its opposition brief described “Prometheus’s deliberate frustration of the parties’ negotiations in connection with efforts to develop a single, shared system of ETASUs.”
FDA’s opposition brief likewise cited Prometheus for “dragging its feet for more than three years rather than collaborate with Roxane,” further burdening “patients who were being deprived of access to generic alosetron.”
The court denied Prometheus’s request for a Temporary Restraining Order to prevent FDA from approving Roxane’s generic drug, after which Prometheus quietly dismissed the suit rather than proceed to summary judgment on the merits.

32. Takeaways
REMS and 505(q) Petitions

33. Product Strategy and Timeline Considerations
REMS and citizen petitions are important regulatory frameworks to keep in mind when formulating business plans alongside IP strategies for both brand and generic products.
On the brand side:
Sponsors of REMS-covered products must be mindful of increased FDA requirements associated with heightened safety risks and plan for shared REMS negotiations down the road.
Brands should also be mindful of any product-specific scientific or regulatory issues that could warrant timely, substantive discourse with the agency and the public via the citizen petition process.
On the generic/biosimilar side:
Sponsors should calculate potentially longer development and launch timelines depending on whether a product is covered by a REMS.
Generic/biosimilar sponsors should also consider whether to address citizen petitions via submitting substantive comments to the public docket or via direct discussion with the agency in the context of the application review.