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February 03, 2011

Risk Evaluation and Mitigation Strategies (REMS) Summary

Medguide 2 
According to a recent assessment by the Tufts Center for the Study of Drug Development (CSDD), “drug developers, healthcare providers, insurance companies, and others involved in the delivery of healthcare in the United States are uncertain about the benefits of a risk evaluation program introduced three years ago by the Food and Drug Administration (FDA).”

Key findings of Tufts CSDD’s assessment of the Risk Evaluation & Mitigation Strategy (REMS) program, the first systematic look at the initiative since the FDA introduced it in 2008, were reported in the January/February Tufts CSDD Impact Report, and released this week.

Christopher-Paul Milne, associate director at Tufts CSDD, who conducted the assessment, explained the findings and noted that “A majority of the organizations told us they felt the REMS program needs a major overhaul, and said that a REMS is a poor substitute for other improvements needed system-wide in drug education, communication, use monitoring, patient access, and delivery of care."

According to Milne, "Most respondents said it is virtually impossible to measure the benefits of a REMS, compared to its burdens on patient access and cost of health care delivery, for a newly approved drug, and that even for an already-approved drug, it would likely require two years or more to effectively conduct such an assessment." Among other findings developed by the survey were the following:

  • Three-quarters of respondents said the REMS program needs a major overhaul.
  • 68% said that REMS are a poor substitute for other improvements needed system-wide in drug education, communication, monitoring of use, patient access and delivery of care.
  • 86% felt that under current guidelines, risk and benefit information was not well balanced in REMS communications.
  • Only 22% of respondents thought the REMS program has been an improvement over the existing risk management system.

Milne noted that the REMS program will likely impact a growing number of healthcare stakeholders as the number of products with REMS expands in coming years.

Background of REMS

In September 2007, the Food and Drug Administration Amendments Act (FDAAA) was signed into law providing the FDA with expanded authority. One of the new provisions gave FDA the authority to require that companies submit Risk Evaluation and Mitigation Strategies (REMS) when deemed necessary to ensure that a drug or biological product’s benefits outweigh the risks.

FDA may now require REMS for any New Drug Application (NDA), Abbreviated New Drug Application (ANDA), or Biologic License Application (BLA) at any stage of the product lifecycle when the FDA determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks.

If the FDA requires a REMS, the manufacturer has 120 days to submit a proposed REMS if it is for a marketed drug. For a new drug, the manufacturer must include the proposed REMS as part of its NDA submission.  Once approved, the REMS creates enforceable obligations for the manufacturer and the FDA.

REMS Requirements

To assist manufacturers in developing REMS, the FDA issued a guidance for industry in September 2009. The draft guidance for industry:

  • Provides FDA’s current thinking on the format and content that industry should use for submissions of proposed REMS
  • Describes each potential element
  • Includes preliminary information on the content of assessments and proposed modifications of approved REMS
  • Describes REMS policies for certain regulatory situations
  • Informs industry about who to contact within FDA about a REMS
  • Indicates FDA Web sites where documents about approved REMS will be posted
  • Provides an example of what an approved REMS might look like for a fictitious product.

Additionally, FDA has outlined the specific elements that should be included in the proposed document. FDA recommended that the proposed REMS should be concise and specific and include the goal(s) along with the explicit components that will be developed to ensure that the drug will be used safely and appropriately. The manufacturer should also describe how it intends to evaluate whether the REMS is meeting its goal(s) and objective(s) at various time points from the time of launch and beyond.

Failure to comply with FDA REMS requirements can render the company’s drug misbranded and result in substantial penalties (e.g., $250,000 to $1 million cap per violation; $1 million to $10 million cap per proceeding). Proposed REMS may contain any of the following elements:

  • Medication Guide – Document written for patients highlighting important safety information about the drug; this document must be distributed by the pharmacist to every patient receiving the drug.
  • Communication Plan – Plan to educate healthcare professionals on the safe and appropriate use of the drug and consists of tools and materials that will be disseminated to the appropriate stakeholders.
  • Elements to Assure Safe Use (EASU) – These are strictly controlled systems or requirements put into place to enforce the appropriate use of a drug. Examples of EASUs include physician certification requirements in order to prescribe the drug, patient enrollment in a central registry, distribution of the drug restricted to certain specialty pharmacies, etc.
  • Implementation Plan – A description of how certain EASUs will be implemented.
  • Timetable for Submission of Assessments – The frequency of assessment of the REMS performance with regard to meeting the goal(s) and objective(s). FDA requires that assessments be conducted at 18 months, 3 years, and 7 years post-launch, at a minimum. Results of these evaluations must be reported to the FDA and will determine whether additional actions or modifications to the REMS program are required.

A drug’s REMS program may not require the provision of all the components above, as the specific components a REMS program employs will vary based on the severity of the risks, the population likely to be exposed, and other factors. Most common REMS only require the provision of a medication guide. While REMS components are not uniform, some do and will contain new provisions and requirements for physicians and other certified health care providers.  

As of today, the FDA has approved 166  REMS since the implementation of FDAAA.


Consequently, FDA’s Office of New Drugs Director John Jenkins discussed a draft proposal to standardize and integrate REMS into the healthcare system last month at an FDA-Industry PDUFA V Reauthorization Meeting. This proposal includes developing draft criteria for determining the need for a REMS and a series of public meetings to explore strategies to standardize REMS and better integrate them into the existing and evolving healthcare system. While further discussion of this proposal will take place in an FDA-Industry Working Group, according to the FDA Lawyers Blog, Dr. Jenkins outlined FDA's vision of "plug-and-play" REMS elements that could be standardized for specific drugs.

According to their coverage of the meeting, Dr. Jenkins explained that "Plug-and-play doesn't mean that everything's the same, it means that it's compatible . . . its interoperable." The FDA Lawyers Blog noted that based on these reports, Jenkins appears to believe that FDA currently does not have much control over what risk management elements are selected by new drug application ("NDA") holders, when a product is first approved. Following approval, moreover, FDA can ask a company to impose certain risk management elements but can only withdraw a product from the market, if an NDA holder does not want to comply with FDA's wishes.

According to the blog, “Jenkins further said that FDA wants to be able to mandate a single, shared risk management program across a class of drugs, such as what FDA has been working towards for the opioid drug class, which is preferable to the other option of about 20-30 different REMS for the current opioid products on the market.” Dr. Jenkins “indicated that there are pharmacy payment computer systems that may be helpful in the REMS standardization effort to facilitate payments and REMS program information for specific products. FDA also plans to reduce the number of Medication Guide-only REMS to reduce some of the REMS workload for pharmacists, who have a spotty record for distributing the mandated information.”

The blog noted that members of industry, such as Robert Clark, Pfizer Vice President of Worldwide Regulatory Strategy, “voiced support for a standardized REMS system at the summit, citing to benefits for not having to design a REMS from scratch. But Jenkins also seemed to acknowledge that while FDA has successfully negotiated some shared systems, it has been difficult to create a shared system for both innovator and generic companies.”

Analyzing Dr. Jenkins comments, the FDA Lawyers Blog noted that in the past, innovator companies, such as Celgene, “have voiced concern that they will be responsible for an increased workload once generic "share" their system, and some risk management program elements may be protected by patents listed in the Orange Book.” On the other hand, they also noted generic companies, such as Dr. Reddy's Laboratories, Inc. ("Dr. Reddy's"), who “have asked FDA to prevent innovators from using their REMS as a shield to deny reference listed drug to generic companies, which prevents generic applicants from conducting required bioequivalence studies for filing generic drug applications.”

To date however, the blog states that “both Celgene's and Dr. Reddy's petitions remain unanswered by FDA.” The blog predicted that “Even with FDA's vision for standardized REMS elements, it may prove difficult for FDA to prevent innovator companies from using REMS to block or discourage generic competition.”


Ultimately, with three-quarters of respondents from the Tufts CSDD assessment thinking that the REMS program needs a major overhaul, Dr. Jenkins comments about a REMS proposal to standardize the REMS process for specific drugs will be important to address industry concerns.

Since over two-thirds of respondents believed that REMS are a poor substitute for other improvements needed system-wide and because 86% felt that under current guidelines, risk and benefit information was not well balanced in REMS communications, it is clear that Dr. Jenkins proposal must create solutions to these problems. Industry’s input in this process, along with other stakeholders such as patient advocacy and consumer groups will play a significant role in the future of REMS.

Finally, those stakeholders involved in continuing medical education (CME) should also play an active role in addressing industry concerns of REMS, as they have done in the past and currently with opioids.

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