September 2009

The decision to approve a drug is highly dependent on the answer to the following question: “Do the benefits of the drug outweigh the risks?” Both pharmaceutical manufacturers and the Food and Drug Administration (FDA) continually evaluate the potential benefits of a drug versus its potential risks. Many factors are taken into consideration, some of which include:

  • Seriousness of the disease or condition to be treated
  • Size of the patient population
  • Expected benefit of the drug
  • Expected duration of treatment
  • Seriousness of the known or potential adverse events

These evaluations are performed not only prior to the approval of a new drug, but also throughout the entire life cycle of the drug. This serves as a means to continuously assess the safety and efficacy of existing drugs based on adverse event reports and results from post-marketing clinical studies.

For every drug approved by the FDA, the risks associated with its use are communicated through the product package insert. In some cases, however, the manufacturer and/or the FDA may determine that a Risk Evaluation and Mitigation Strategy (REMS) is necessary to go beyond product labeling to manage risks and thereby ensure that the benefits outweigh the risks.

Despite what we may think of the current flurry of activities to develop and implement REMS -- the latest trend in risk management – the concept of risk management isn’t new.

Early Risk Management

In 1960, FDA instituted a policy of full disclosure. Manufacturers were required (and still are) to provide complete information about the product’s indication, dosing, side effects, etc. to healthcare professionals. This information is included in the product labeling. The Controlled Substances Act (CSA) of 1970 is the first glimpse of what many consider to be the initial effort in modern-day pharmaceutical risk management. The CSA regulates manufacturers, prescribers, dispensers, product labeling, warnings, and drug scheduling by providing additional indicators of risk and tools to manage those risks beyond those established under the Federal Food, Drug, and Cosmetic Act (FD&C Act)[1]. Common tools included boxed warnings and “Dear Healthcare Provider” letters.

The safe and effective use of drugs was the reason that the FDA endorsed the requirement in the late 1970s to distribute Patient Package Inserts (PPIs) with oral contraceptives and estrogen replacements to patients. Prior safety communications were geared toward healthcare professionals. Since oral contraceptives and estrogens were considered elective medications, FDA insisted that patients (consumers) be provided with written information about the benefits and risks of taking these products to assist in their decision about birth control methods.

Special programs that extended beyond labeling and PPIs to restrict access to certain risky products were instituted between 1988 and 1998. Three products -- Accutane® (isotretinoin), Clozaril® (clozapine), and thalidomide, for example, had specifically-designed programs to detect or prevent serious adverse events.

Accutane is indicated for the treatment of severe recalcitrant nodular cystic acne. To mitigate the risk of teratogenicity, the manufacturer, Roche, developed a series of three programs in an effort to continuously improve patient outcomes:

  • Pregnancy Prevention Program (1988),
  • Targeted Pregnancy Prevention Program (1999), and
  • S.M.A.R.T.[2] (2001)

Clozaril®, an atypical antipsychotic, was found to increase the risk of agranulocytosis. Clozaril’s “no blood, no drug” program was instituted in 1990. Registered physicians were required to submit weekly complete blood cell counts (CBCs) before receiving authorization to prescribe the product. The program required physicians, pharmacists, and patients to be enrolled in a registry to monitor compliance.

In 1998, thalidomide, for the treatment of complications of leprosy, was approved with The System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.™). The program required all patients, pharmacists, and physicians be registered and for patients to be tested for pregnancy – again, to avoid the potential for birth defects.

Medication Guides were introduced in the late 1990s for products perceived to pose “serious and significant public health concerns”.[3] It was mandatory for pharmacists to distribute them at the time of drug dispensing.

Today, more than 70 prescription medicines have associated Medication Guides. FDA requires that Medication Guides be issued when the Agency determines that:

  • Certain information is necessary to prevent serious adverse effects,
  • Patient decision-making should be informed by information about a known serious side effect with a product, or
  • Patient adherence to directions for the use of a product is essential to its effectiveness[4]

Risk Minimization Action Plans (RiskMAPs)

After several products (e.g., Lotronex®, Rezulin®) were removed from the market because of safety concerns, the FDA came under increased scrutiny. FDA formed working groups that developed three risk management concept papers and draft guidances in May 2004. Final risk minimization guidances were issued in March 2005 to address safety monitoring and interventions:

  • Premarketing Risk Assessment
  • Development and Use of Risk Minimization Action Plans
  • Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment

The guidance for RiskMAPs gave manufacturers specific direction about how to address product risk-related goals with tools or interventions to mitigate the risks and ensure strict adherence to product labeling. Products considered risky by the FDA were approved only if an appropriate RiskMAP was instituted by the manufacturer.

Despite Roche’s earlier efforts to communicate the risks associated with the use of Accutane® via the S.M.A.R.T. program, which included branded and generic products, product use among women of childbearing potential continued. This led to collaboration in 2006 among Roche, generic manufacturers, and the FDA to launch a shared RiskMAP program for isotretinoin – iPLEDGE.

Other examples of products with RiskMAPs included:

  • Tikosyn® (dofetilide) – T.I.P.S.[5]
  • Tracleer® (bosentan) – T.A.P.[6]
  • Plenaxis® (abarelix) – PLUS[7]

Elements of these programs varied from the highest level of restricted distribution systems (e.g., performance-linked access systems) to educational materials to mitigate known or potential risks.


In September 2007, the Food and Drug Administration Amendments Act (FDAAA) was signed into law providing the FDA with expanded authority. Some of the new provisions gave FDA the authority to:

  • Require post-approval studies or clinical trials to assess a known or serious risk, or to learn more about a hypothetical serious risk,
  • Require that new safety information be added to the product labeling, and
  • Require that companies submit Risk Evaluation and Mitigation Strategies (REMS) when deemed necessary to ensure that the product’s benefits outweigh the risks

FDA may now require REMS for any NDA, ANDA, or BLA[8] at any stage of the product lifecycle. 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 New Drug Application (NDA) submission. Once approved, the REMS creates enforceable obligations for the manufacturer and the FDA.

The FDA requested that 16 selected products with current RiskMAPs transition into REMS by September 2008. Because of this expanded FDA authority beyond what was previously called RiskMAP, REMS have superseded the regulatory authority of RiskMAPs, making use of the term RiskMAP obsolete.

REMS Requirements

To assist manufacturers in developing REMS, the FDA has issued an outline of specific elements that should be included in the proposed document. 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 MM cap per violation; $1 MM to $10 MM cap per proceeding).

REMS Elements

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.

At this date, over 88 REMS have been approved by the FDA since the implementation of FDAAA. Final FDA guidance is anticipated by the end of 2009.


  1. Leiderman, D. 2008.  Risk Management of Pharmaceutical Products at FDA – A Historical Perspective
  2. S.M.A.R.T. – System to Manage Accutane-Related Teratogenicity
  3. 21 CFR 208, June 1999
  4. U.S. Food and Drug Administration. Medication Guides.
  5. T.I.P.S. – Tikosyn in Pharmacy System
  6. T.A.P. – Tracleer Access Program
  7. PLUS – Plenaxis User Safety Program
  8. NDA – New Drug Application
    ANDA – Abbreviated New Drug Application
    BLA – Biologic License Application
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