FDA Largely Denies Citizen Petition on Single, Shared REMS System, But Outlines Agency Standards and Processes

By Kurt R. Karst –       

Now that the shutdown of the U.S. Federal Government is over and FDA’s Dockets Management Branch is open again, the backlog of docket submissions is rolling in on regulations.gov, including Citizen Petiton responses issued during the shutdown.  One petition response we’ve been waiting patiently to read is FDA’s response to a May 2013 Citizen Petition (Docket No. FDA-2013-P-0572) submitted by Prometheus Laboratories, Inc. (“Prometheus”) concerning Risk Evaluation and Mitigation Strategy (“REMS”) systems shared among sponsors of brand-name drugs approved under NDAs and generic drug manufacturers whose generic equivalents are approved under ANDAs, and specifically with respect to Prometheus’ LOTRONEX (alosetron hydrochloride) Tablets approved under NDA No. 021107.

FDC Act § 505-1 provides FDA with the authority to require a proposed REMS from an NDA sponsor if the Agency determines that such a strategy “is necessary to ensure that the benefits of the drug outweigh the risks of the drug.”  A REMS may include various elements, such as a Medication Guide, patient package insert, and/or communication plan.  In addition, under FDC Act § 505-1(f), FDA may require that a REMS “include such elements as are necessary to assure safe use of the drug, because of its inherent toxicity or potential harmfulness.”  The Elements To Assure Safe Use (“ETASU”) of such a drug include, among other things, certain restricted distribution, procurement, and dispensing systems.  (In addition, we understand that if the brand-name RLD has an approved REMS, an authorized generic version of that RLD must have an approved REMS prior to distribution, such that the brand-name REMS must be modified to account for the authorized generic.) 

ANDAs for generic versions of RLDs with an approved REMS must have the same Medication Guide (if there is one) and the same or a comparable ETASU REMS.  Specifically, FDC Act § 505-1(i)(1)(B) states:

A drug that is the subject of an [ANDA] and the listed drug shall use a single, shared system under [FDC Act § 505-1(f)].  The Secretary may waive the requirement under the preceding sentence for a drug that is the subject of an [ANDA], and permit the applicant to use a different, comparable aspect of the elements to assure safe use, if the Secretary determines that—

(i) the burden of creating a single, shared system outweighs the benefit of a single, system, taking into consideration the impact on health care providers, patients, the applicant for the [ANDA], and the holder of the [RLD]; or

(ii) an aspect of the [ETASU] for the applicable listed drug is claimed by a patent that has not expired or is a method or process that, as a trade secret, is entitled to protection, and the applicant for the [ANDA] certifies that it has sought a license for use of an aspect of the [ETASU] for the applicable listed drug and that it was unable to obtain a license.

ETASU REMS have been particularly controversial.  In June 2009, Dr. Reddy’s Laboratories, Inc. submitted a Citizen Petition (Docket No. FDA-2009-P-0266) to FDA requesting that the Agency “establish procedures to facilitate the availability of generic versions of drug products subject to a [restricted distribution REMS] and enforce the FDC Act to prevent companies from using REMS to block or delay generic competition.”  ETASU REMS can limit the availability of a drug such that ANDA sponsors are unable to procure supply to conduct required bioequivalence testing.  In August 2013, FDA granted in part and denied in part the Dr. Reddy’s petition, saying that the Agency would issue clarifying guidance on the procedures generic applicants can follow for conducting studies of products under an ETASU REMS, and that FDA would refer certain matters to the Federal Trade Commission (“FTC”).  And last year, Actelion Pharmaceuticals Ltd. and Actelion Clinical Research, Inc. preemptively sued generic drug manufacturers over REMS and biostudy product availability issues (see our previous posts here, here, and here).  A written decision on a pending motion in that case is expected soon. 

LOTRONEX is approved with a REMS consisting of a Medication Guide and ETASU with certain prescribing and dispensing elements, and is not yet subject to generic competition.  Prometheus in its May 2013 Citizen Petition requested that FDA: (1) complete notice and comment rulemaking on the standards and processes for establishing a single, shared REMS; and (2) refrain from granting a waiver of the single, shared system requirement for LOTRONEX without providing Prometheus with adequate notice that a waiver request was submitted and an opportunity to participate in the process of determining whether the waiver should be granted. 

“To the extent that Prometheus’ Petition takes issue with the FD&C Act’s requirement that brand and generic companies work together to implement single, shared REMS systems, we note that this requirement is statutorily mandated by Congress,” writes FDA in the Agency’s petition response denying this request.  “As FDA gains experience with single, shared system development, the Agency is considering whether regulations or guidance in this area would assist industry with the development and implementation of these systems.”  Nevertheless, FDA goes on to describe how single, shared REMS systems have been successfully developed in the past.  Among other things, FDA outlines the following procedures:

• When a generic application for a product subject to a REMS with ETASU has been found to be acceptable for filing, FDA has notified the ANDA applicant ofthe requirement for a single, shared system through a REMS notification letter, which has directed the ANDA applicant to contact the sponsor of the RLD regarding the development ofa single, shared system REMS.  FDA has expected that negotiation of the single, shared REMS would begin promptly thereafter, and would proceed concurrently with the review ofthe ANDA application.
• In cases where several companies were impacted by the single, shared REMS requirement, many companies have chosen to form what is commonly referred to as an “industry working group” (IWG) that has worked together to develop a proposal for the single, shared REMS. . . .  FDA has typically monitored the IWG’s progress on developing a REMS through regular teleconferences and face-to-face meetings on an as-needed basis.  In addition to monitoring the IWG's progress on developing a REMS, FDA has acted to help ensure that sponsors were cooperating and that there were no obstacles to developing a single, shared system.
• Once developed, the single, shared REMS proposal has been submitted by the brand and generic companies to the Agency for review.  The proposed single, shared REMS developed by the brand and generic sponsors was then reviewed as part ofthe overall ANDA review process (and,where appropriate, approved as part of the overall ANDA approval).
• To help reduce the burden on the healthcare system, FDA has previously required that all components of a REMS program be shared by the participating sponsors in a shared system REMS.  That is, NDA and ANDA application holders in a single, shared system REMS have been subject to the same ETASU, implementation system, and assessments.  In addition, participating sponsors have worked together to establish a common REMS document and REMS materials (for example, common forms, training materials, and a common REMS Web site and database to capture entities enrolled in the REMS, such as hospitals, pharmacies, and healthcare professionals).
• Unlike the elements of the REMS, which are reviewed and approved by FDA, cost-sharing, governance, and other business issues relating to the implementation of single, shared REMS are left to the discretion of the sponsors.
• Thus far, once a single shared REMS is approved, FDA has required changes proposed by a sponsor affecting common content be agreed to by the other participating sponsors in the REMS and then submitted to each of the individual applications.  Generally, for product-specific changes (such as the addition of a new indication), the change has first been approved under the individual application, after which the other participating sponsors in the REMS have been notified that a change to their REMS was necessary.  When a new product has been added to a single, shared system, the participants in the REMS generally each have submitted the modification (adding the new product) to their individual applications once the new product was approved.

With respect to Prometheus’ request that FDA refrain from granting a waiver of the single, shared REMS system requirement for LOTRONEX without providing the company with notice that a waiver request was submitted and an opportunity to participate in the waiver process, FDA says that the Agency welcomes Prometheus’ input on the topic at any time (and thus grants the petition in this respect), but otherwise denied this petition element.  According to FDA, the Agency:

welcomes input from brand companies at any point on whether the burdens of creating a single, shared system outweigh the benefits for their drug product.  In the past, through its facilitation of single, shared system negotiations between brand and generic companies, FDA has received general information about brand companies’ views on burdens to the companies involved and other single, shared system issues.  Brand companies are also free to provide FDA with input about the appropriateness of a single, shared system for their product’s REMS outside of the negotiation process, and have done so.  In certain circumstances, if FDA believes additional information from the brand company is necessary to complete its evaluation of the burdens and benefits of creating a particular single, shared system, FDA may also solicit input from the brand company on this topic.  Moreover, the Agency may determine on its own that waiver of the single, shared system requirement is appropriate for a particular product without having received a waiver request from one of the parties.

One of the stated reasons Prometheus sought from FDA greater clarification of the single, shared REMS process is concern over antitrust risk.  According to the company, “[a] rulemaking by FDA providing clear direction on what must be included in single shared REMS and how the innovator and genetic companies must interact in the development, implementation, and maintenance of single shared REMS is needed to assure innovator companies that they can comply with the single shared REMS requirement without undue antitrust risk.”  FDA decided not to wade into these waters in its response.  Instead, FDA recommends that “[t]o the extent that Prometheus believes there may be antitrust issues associated with establishing single, shared systems, . . .  it [should] consult with the FTC.”