Regulatory Focus™ > News Articles > Prometheus Slams FDA for Lack of REMS Clarity as Agency Shows Signs of Conceding

Prometheus Slams FDA for Lack of REMS Clarity as Agency Shows Signs of Conceding

Posted 29 May 2013 | By Alexander Gaffney, RAC

A Citizen Petition filed by Prometheus Laboratories in May 2013 slams the US Food and Drug Administration (FDA) for failing to establish "standards and processes" for single shared Risk Evaluation and Mitigation Strategies (REMS), explaining that the current process is unprecedented, unclear and potentially raises anti-trust issues that could leave companies open to litigation.


In 2007, Prometheus Laboratories purchased Lotronex (alosetron hydrochloride), a treatment for Irritable Bowel Syndrome, from GlaxoSmithKline. The drug was first approved in February 2000, but was later temporarily withdrawn after FDA began to receive reports of obstructed or ruptured bowels.

To reintroduce the drug back into the marketplace, GSK developed a risk management plan, then known as a RiskMAP, which succeeded in allaying FDA's concerns about the drug and allowed it to return to the market in June 2002. The entire process, Prometheus explains, was both lengthy and costly to GSK.

Then, with the 2007 passage of the FDA Amendments Act (FDAAA), that RiskMAP started the process of becoming a REMS, a set of safety plans meant to ensure that a risky product is used appropriately. In the case of Lotronex, its REMS includes prescriber controls, patient education and acknowledgement requirements, pharmacy distribution of educational materials and program monitoring. FDA signed off on the company's REMS in 2010.

Then, in January 2011, Roxane Laboratories submitted an abbreviated new drug application (ANDA) to FDA and filed Paragraph IV certification claiming that Prometheus' patent protection on the drug was no longer valid. Prometheus counter-sued, alleging infringement. The lawsuit would later include Cipla, which also filed an ANDA to FDA for the same claim.

Prometheus: Unprecedented and Unclear Process

In the meantime, Prometheus said it "has begun discussions with Roxane over developing a single shared REMS system that would apply to both Lotronex and Roxane's generic form of Lotronex." The ability to do so was required by FDAAA, with the carve-out that FDA could waive that requirement if it felt that it would be too burdensome on companies, patients or healthcare providers. This protects generic manufacturers from being delayed by patented aspects of REMS plans, for example.

The problem, Prometheus said, is that it has been unable to understand or address a lengthy set of issues, leaving it to conclude that FDA should issue a regulation to clarify what the requirements are for shared REMS under the law.

For example, the statute fails to actually define what is meant by a "single shared REMS," leaving much of the negotiation to fall to the innovative and generic manufacturers-a time-consuming and expensive process. It's also a process that Prometheus called "unprecedented among federal laws."

"To our knowledge, no other federal law requires one party to negotiate and reach an agreement with a specific identified competitor and work together as business partners for the foreseeable future," it wrote in its Citizen Petition. This raises a number of potential anti-trust issues, the company said, potentially raising legal liability issues with the Federal Trade Commission (FTC).

To boot, FDA has not issued any guidance regarding the desired qualities of a single shared REMS or waivers from the requirement in the five years subsequent to the passage of FDAAA, leaving the company with no answers to a considerable number of questions.

For example, it wrote that it has no clarity regarding the timeline for entering into negotiations with the ANDA applicant (parallel to the review process, or subsequent to approval?), whether the costs of the process should fall entirely on the generic manufacturer or be shared, the collection of adverse events under a shared system, how a shared system should be modified in the future as additional generic companies seek approval, and what factors constitute a "block or delay" of an ANDA under FDAAA (behavior which would violate statute).

"FDA's failure to provide meaningful direction to industry … has likely contributed to the scarcity of single shared REMS approved" under the law, Prometheus charged.  Because of this, Prometheus complained that it is unable to even look to existing precedent to inform its decision-making process since only six drugs operate under a single shared REMS, and none of those have been negotiated between companies.

FDA Indicating a Favorable Response?

Prometheus' petition appears to have been the driving force behind a recent FDA meeting notice in which the agency said it wants to begin standardizing the REMS process.

"FDA may be able to establish standards to reduce unnecessary variation and to make REMS more predictable and simpler to understand, implement, and measure," FDA explained. "The establishment of standards also presents the opportunity to improve upon the design of REMS elements and associated tools and assessment methodologies in the future."

FDA's Federal Register notice says it has a number of questions for industry, including:

  • Can some prescriber training materials, approaches and assessments be standardized?
  • Are prescriber certification forms easy enough for prescribers and patients to understand, and can they be streamlined or otherwise simplified?
  • How can prescriber- and patient-directed REMS tools be standardized, made more efficient, and more useful?
  • What other technologies and tools should FDA consider using in the future for REMS?
  • What should the process of standardization look like?
  • What would make written educational materials more effective for patients?
  • Could the provision of patient information be made easier? What about the counseling process?

These questions are similar to ones quoted by Prometheus in its Citizen Petition, which was filed with FDA just 10 days before the publication of the meeting announcement.

And, perhaps to the satisfaction of Prometheus, FDA's meeting announcement indicates that the intent of the meeting is to generate a guidance document regarding the assessment of REMS products. Whether or not that guidance will address the negotiation process between companies and subsequent standardization, however, is yet to be determined.

Prometheus Citizen Petition

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