REMS Timeline

2017 marks the tenth anniversary of the legislation that created the safety protections called Risk Evaluation and Mitigation Strategies (REMS). Yet, recognition of the need to mitigate the risks of prescription drugs dates back almost 50 years.

Initial Drug Safety Efforts: 1970s – 1990s

Long before REMS, the Food and Drug Administration (FDA) endorsed the requirement in the late 1970s to distribute Patient Package Inserts (PPIs) with oral contraceptives and estrogen replacements so patients would have written information about the benefits and risks of these drugs. Then, starting in the late 1980s, FDA recognized the need to restrict access to certain potentially dangerous medicines and in the late 1990s, the agency began to require pharmacists to distribute medication guides to patients when there were potentially serious health concerns.

Setting the stage for REMS

By the early 2000s, a series of high-profile drug withdrawals caused FDA to develop a systems approach to risk management called Risk Minimization Action Plans (RiskMAPs), which laid out specific actions to mitigate the ensure the safe prescribing and use of medicines known to cause adverse effects. However, the widely publicized withdrawal of the pain killer Vioxx in 2004 exposed some fundamental weaknesses with RiskMAPs, setting the stage for Congress to authorize the REMS program in 2007.

Below are the milestone moments leading up to the introduction of the REMS program and the evolution of this program today.

Rems Milestones

November 2000

Lotronex, the only available treatment for severe diarrhea-predominate irritable bowel syndrome (IBS), is withdrawn from the market due to rare but serious gastrointestinal adverse events. This causes thousands of patients and many physicians to call on the FDA to find a solution to reintroduce the drug with safety controls.

August 2001

Baycolm, a widely used cholesterol-lowering drug is withdrawn from market after the fatal risk of muscle wasting is determined.

September 2004

Vioxx, a popular pain medication is withdrawn from the market, following reports of serious cardiovascular risks.

September 2007

Congress passes the Food and Drug Amendments Act (FDAAA) which authorizes the REMS program.

November 2007

Trasylol, a drug used to reduce bleeding after surgery is withdrawn from the market after the risk of death is identified.

March 2008

Provisions of FDAAA go into effect; REMS begin to be required.

September 2009

FDA issues “Draft Guidance on the Format and Content of a Proposed REMS,” giving manufacturers a blueprint for how to implement a REMS program.

July 2010

FDA holds a public meeting to hear from stakeholders on standardizing and evaluating REMS, including best-practice solutions for designing and measuring REMS programs.


FDA creates the REMS Integration Initiative to improve standardization and assessments of REMS and to integrate REMS into the healthcare system.

June 2012

FDA holds a public workshop to discuss survey methodologies and instruments that can be used to evaluate patients’ and health care providers’ knowledge about the risks of drugs marketed with an approved REMS.

July 2012

The Food and Drug Administration Safety and Innovation Act (FDASIA), enacted on July 9, 2012, amends FDA’s REMS authorities and strengthens the agency’s ability to safeguard and advance public health. Among other things, FDASIA reauthorized the Prescription Drug User Fee Act (known as “PDUFA V”) with new commitments for FDA to measure the effectiveness of REMS, develop techniques to standardize REMS, and seek stakeholder input on ways to integrate REMS into the existing and evolving health care system.

July 2013

FDA holds a public meeting attended by more than 30 stakeholder organizations to explore approaches for designing and measuring the impact of REMS, including evidence-based “best practice” solutions that still retain flexibility in an evolving health care environment.

September 2013

FDA participates with stakeholders in an expert workshop held at the Brookings Institution, “Strengthening Risk Evaluation and Mitigation Strategies (REMS) Through Systematic Analysis, Standardized Design, and Evidence-Based Assessment.” The workshop identifies limitations with existing methods for the design of REMS programs, and existing approaches to identify, evaluate, and mitigate risks that can inform REMS design.

September 2014

FDA issues a report, “Standardizing and Evaluating Risk Evaluation and Mitigation Strategies (REMS),” with the findings of the 2013 public meeting, which identifies priorities for action, including updating the REMS website and make information more accessible to stakeholders.

December 2014

FDA issues draft guidance laying out the process by which generic manufacturers can obtain samples of REMS drugs from the branded manufacturer. If the brand drug is subject to a REMS with ETASU, a generic manufacturer can request a letter from the FDA clarifying that the brand manufacturer will not violate its product’s REMS by providing drug samples to a generic manufacturer for bioequivalence testing.

April 2015

FDA issues “Risk Evaluation and Mitigation Strategies: Modifications and Revisions. Guidance for Industry” explaining how the agency will define and process submissions for modifications and revisions to existing REMS programs.

June 2015

FDA introduces REMS@FDA, a news REMS website with searchable and sortable tables to provide stakeholders, researchers and others with access to convenient, up-to-date REMS information.

October 2015

FDA hosts a public meeting on understanding, evaluating, and minimizing REMS burden on the health care delivery system.

May 2016

FDA convenes a joint meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee to discuss results from assessments of the extended-release and long-acting (ER/LA) Opioid Analgesics REMS. The committees provide comments as to whether the REMS assures safe use and how to minimize the burden to the health care delivery system.

September 2016

FDA issues draft guidance, “FDA’s Application of Statutory Factors in Determining When a REMS Is Necessary,” to clarify how the agency determines that a REMS is necessary. The guidance states that FDA makes decisions about requiring a REMS after an evaluation that includes integrated consideration of the factors that may pose a burden on patients and/or health care providers.

December 2016

FDA tentatively approves a generic version of Aveed (testosterone undecanoate) with a single shared system REMS for the branded and generic versions.

April 2017

FDA approves a generic version of Sabril (vigabatrin) with a single shared REMS for the branded and generic versions. The agency also removes the REMS requirements for the use of epoetin alfa and darbepoetin to treat patients with anemia from associated myelosuppressive chemotherapy.

June 2017

FDA approves the generic version of the HIV drug Truvada (emtricitabine and tenofovir disoproxil fumarate) ahead of schedule with a single shared system REMS for the brand and generic versions.

September 2017

FDA is able to approve the first gene therapy in the U.S., Kymriah (tisagenlecleucel), by requiring a rigorous REMS program to manage the potentially life-threatening side effects of treatment. Kymriah is a first-of-its-kind therapy for children and young adults with a form of acute lymphoblastic leukemia (ALL) who have not responded to treatment or the ALL has returned when the prognosis is poor.

October 2017

FDA approves axicabtagene ciloleucel (Yescarta) as the second in a new class of CAR-T cell therapies to treat adult patients with certain types of large B-cell lymphoma, the most common type of non-Hodgkins lymphoma. Because Yescarta can cause neurological toxicities and a potentially fatal immune reaction called cytokine release syndrome (CRS), FDA approved the therapy with a REMS program with elements to assure safe use, such as requiring hospitals and clinics that dispense the drug to be specially certified.

February 2018

FDA approves benzhydrocodone and acetaminophen (Apadaz) for the short-term (no more than 14 days) management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

April 2018

FDA approves tolvaptan (Jynarque) as the first treatment to slow kidney function decline in adults with rapidly progressing Autosomal dominant polycystic kidney disease (ADPKD). One of the most common, life-threatening genetic diseases, ADPKD results in the development of fluid-filled cysts in both kidneys, eventually leading to kidney failure. The disease affects over 12 million people worldwide and impacts families across multiple generations.