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REMS and Citizen Petitions:
FDA Background and Competition Concerns
AIPLA Spring Meeting 2017
Amy Speros
Latham & Watkins LLP
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REMS
Risk Evaluation and Mitigation Strategies
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REMS Background
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Section 505-1 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.”
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For the majority of drugs, routine risk mitigation measures are sufficient to
preserve benefits while minimizing risks.
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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.
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REMS Background (cont’d)
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Before the REMS statute, FDA typically used sponsor commitments called Risk
Minimization Action Plans (RiskMAPs) to ensure the safety of particularly risky
products.
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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:
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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.
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REMS Background (cont’d)
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Since 2007, FDA has approved more than 100 new REMS, with 71 currently active REMS
programs (excluding products “released” from the REMS requirement).
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A 2014 study found that nearly 40% of new FDA approvals are subject to a REMS.
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To date, FDA has approved 9 “shared system” REMS with multiple applicants for a particular
drug or drug type:
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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
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What Makes a REMS?
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All REMS programs must include a timetable for assessments to periodically
monitor the REMS effectiveness and the need for potential modification.
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In addition, a REMS must include one or more of the following elements:
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A Medication Guide and/or Patient Package Insert;
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A communication plan for health care providers; and/or
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Additional elements to assure safe use (ETASU).
FDA has authority to take enforcement action against companies that fail to
comply with statutory REMS requirements.
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REMS Elements to Assure Safe Use (ETASU)
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ETASU are the most stringent type of REMS requirements and typically involve
significant time and financial investment for manufacturers to develop, implement,
and maintain.
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ETASU can include:
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A requirement that health care providers who prescribe the drug have particular training or
experience, or be specially certified;
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A requirement that pharmacies that dispense the drug be specially certified;
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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
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A requirement that each patient using the drug be subject to certain monitoring or enrolled in
a registry.
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REMS ETASU (cont’d)
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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:
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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;
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Second:
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For new drugs, FDA must find that it would not approve the drug unless the specific ETASU are
required, or
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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.
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REMS Goals
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REMS COMPETITION CONCERNS
Access to Samples
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Access to Samples
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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).
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An increasing number of REMS programs with ETASU have restricted
distribution systems that can prevent access to samples.
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By preventing access to samples, brands can hinder follow-on product
development and delay competition.
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Non-REMS products have also become less available as brands self-impose
restricted distribution systems to control access.
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Access to Samples (cont’d)
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The REMS statute specifically prohibits sponsors from using any
ETASU to block or delay approval of a follow-on application.
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This has not stopped brands from refusing to provide samples to follow-on
developers in the REMS context.
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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.
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Access to Samples (cont’d)
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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.
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Under the guidance, FDA will, upon request:
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Review a generic sponsor’s bioequivalence study protocols and materials to assess
whether they provide safety protections comparable to the REMS ETASU, and
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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.
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Access to Samples (cont’d)
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The guidance has not provided a complete solution:
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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.
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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.
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The guidance also does not address self-imposed restricted distribution systems
for non-REMS drugs.
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REMS COMPETITION CONCERNS
Shared REMS Negotiations
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Shared REMS Negotiations
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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.
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This single shared REMS requirement necessitates that brands and generics
work together in implementing a shared program.
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The first shared REMS systems involved negotiations between brands and generics that
were already on the market – negotiation delays could not delay generic competition.
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Now, most shared REMS involve negotiations between brands and pending generics –
negotiation delays have the direct impact of delayed generic approval.
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Because FDA cannot approve generic products without the REMS in place, brands can
slow-walk negotiations, buying more time alone on the market.
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Shared REMS Negotiations (cont’d)
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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:
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The burden of creating a single shared system outweighs the benefit; or
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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.
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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.
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REMS Current State of Play
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Given FDA’s enforcement stance, there have been several failed attempts over the
years to address REMS abuses with legislation.
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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:
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Mandating access to samples for both REMS-covered and non-REMS-covered drugs;
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Codifying an authorization requirement for REMS-covered drugs similar to the FDA guidance;
and
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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.
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CITIZEN PETITIONS
Section 505(q)
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Citizen Petition Background
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FDA regulations have long permitted any person to petition the agency to
take or refrain from taking any form of administrative action.
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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.
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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.
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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.
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505(Q) COMPETITION CONCERN
Intent to Delay
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Intent to Delay
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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.
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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.
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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.
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505(q) petitions can also be used to impact public discourse and patient
preferences against generic or biosimilar products.
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Intent to Delay (cont’d)
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Although the statute explicitly permits FDA to deny a 505(q) petition on its
face, FDA rarely (if ever) does so.
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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.
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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.
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FDA has stated that the hard deadline takes agency time and resources away from
completing other work in a more timely manner.
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Current State of Play
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FDA recently promulgated regulations implementing section 505(q)
alongside its existing citizen petition regulations, but the regulations are
largely consistent with the statutory text.
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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.
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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.
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The impact of the regulations remains to be seen but is ultimately unlikely to
deter strategic petitions under the 505(q) framework.
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INTERSECTIONS
Shared REMS Negotiations and 505(q) Petitions
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The Buprenorphine Transmucosal Products for Opioid
Dependence (BTOD) REMS
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The BTOD REMS
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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.
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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.
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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.
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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.
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The BTOD REMS (cont’d)
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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.
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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.
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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.
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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.
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The Alosetron REMS
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The Alosetron REMS
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In May 2013, Prometheus Laboratories submitted a 505(q) petition requesting that FDA:
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Promulgate rules to establish standards and processes for single shared REMS systems; and
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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.
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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.
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In May 2015, FDA approved an ANDA submitted by Roxane Laboratories referencing
Lotronex and granted a waiver from the single shared REMS requirement.
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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.
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The Alosetron REMS (cont’d)
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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.”
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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.”
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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.
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TAKEAWAYS
REMS and 505(q) Petitions
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Product Strategy and Timeline Considerations
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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.
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On the brand side:
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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.
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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:
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Sponsors should calculate potentially longer development and launch timelines depending on whether a
product is covered by a REMS.
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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.
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