Do the Benefits of REMS Programs Outweigh the Risks?


The intention of risk evaluation and mitigation strategy programs is to ensure that the patient gets potentially dangerous drugs that are monitored appropriately.

When choosing any drug therapy, consideration needs to be taken about whether the benefits of the therapy outweigh the risks. The job of the FDA is to determine the safety and efficacy of every drug they approve.

When certain drugs become riskier, only to be offset by benefits not attainable by safer alternatives, rather than removing those drugs from the market or not approving the drug at all, a program is implemented to approve the drug conditionally. The risk evaluation and mitigation strategy (REMS) program provides this cautionary function.

History of REMS

  • In the 1960s, the FDA "Full Disclosure Policy" required that the agency was informed of everything pertaining to the drug.
  • In the 1970s, the Controlled Substance Act resulted in the creation of the "Patient Package Insert,” containing additional regulations surrounding labeling, warnings, scheduling beyond the Food, Drug & Cosmetic Act.
  • In 1988, the Pregnancy Prevention Program was created for Accutane with several iterations since then.
  • In 1990, the “no blood, no drug” program was initiated for Clozaril due to the potential for agranulocytosis.
  • In 1998, the System for Thalidomide Education and Prescribing program was created to prevent Thalidomide use in pregnancy.
  • In late 1999, a medication guide was required for risky medications meant to educate patients on how to prevent adverse events, instructions on how to take the medication, and directions to ensure efficacy of the medication. It was up to the manufacturer to set up the format of the guide that needed to be dispensed with every prescription.
  • In 2004, RiskMAPS were introduced by the FDA for drugs deemed risky following the removal from the market of several medications due to safety issues (ex: Vioxx) for the following drugs:

  • Accutane- iPledge 2006 Tikosyn- TIPS (Tikosyn in Pharmacy System) Tracleer- TAP (Tracleer Access Program) Plenaxis- PLUS (Plenaxis Users Safety Program)

It was up to the manufacturer to devise RiskMAPs programs to present to the FDA for approval.

  • In September 2007, modern day REMS were introduced as the FDA Amendments Act expanding the authority of the FDA to: Require post-approval studies or clinical trials to assess known/serious risk or hypothetical risk as needed. Require new information surrounding safety added to label as needed. Require REMS to ensure benefit outweighs risk as needed. Require REMS for an NDA, ANDA, or BLA at any stage of drug development, including drugs already marketed. If a REMS was required by the FDA, the manufacturer had 120 days to submit the REMS as an enforceable obligation for the manufacturer. The 16 drugs that had RiskMAPs were transitioned to REMS programs and the RiskMAPs became obsolete. Failure to comply with the REMS requirement meant the drug was misbranded and subject to severe financial penalties ranging from $250,000 to $1 Million per violation and $1 million to $10 Million per legal proceeding.

REMS Outline

The REMS outline has to contain the following:


What is the purpose of the REMS and the safety issue with the medication that the REMS is meant to avert, example: The goal of the Adasuve REMS is to mitigate the risk of Adasuve induced bronchospasm by dispensing it in a setting where trained personnel are present to manage acute bronchospasm with access to emergency response services.

Elements of the REMS

Med guide or package insert: Highlights drug safety information which is meant to be dispensed each time the medication is dispensed.

Communication plan and outline for all parties: Contains the training materials for all health care professionals regarding safe and appropriate use of the medication and documentation collected on what and how the training has been performed.

Elements to assure safe use (ETASU): Not all REMS programs have an ETASU. This is a component where patients are expected to be enrolled in a registry and there is a limited distribution plan for the medication, example: Tracleer had been limited to 4 pharmacies as part of the REMS program and each prescription was dispensed following a negative pregnancy test.

Implementation plan: A description of the ETASU implementation and a system to collect data to determine whether a REMS program was successful or if a modification was required. For example, data collected at 18 months, 3 years, and 7 years post-launch are submitted to the FDA to determine whether REMS modifications are needed.

Current specialty drugs with REMS programs

Currently, there are 58 drugs listed on the FDA website requiring a REMS program, the majority of these are drugs only available through a specialty pharmacy. REMS requirements range anywhere from educational programs with training for health care professionals to registries requiring patients to have monthly pregnancy tests before a drug can be dispensed.

Are REMS effective? When good intentions get in the way of patient care

The majority of the REMS drugs that have an ETASU are more appropriate to be dispensed in a specialty pharmacy with more resources and time to navigate the complexities of the REMS program. There has been pushback on REMS requirements, causing hurdles and delaying treatment.

In an article in the Journal of Food and Drug Law, in 2011 the authors concluded after surveying representatives from biopharmaceutical companies, payers, health care providers, pharmacists, and patient advocacy organizations, that the program is burdensome and not an improvement over previous risk management programs.

Specialty pharmacy in ideal position to perform REMS requirements

Along the same lines, in a 2016 article in the Journal of Pharmacy and Therapeutics, author Stephen Barlas wrote, “The difficulty some patients experience obtaining critical REMS drugs, whether at the hospital or in their homes, is just one of the criticisms that has buffeted the program since Congress authorized it in 2007.”

According to JoAnn Stubbings, BS Pharm, assistant director of Specialty Pharmacy Services at the University of Illinois Hospital and Health Sciences System, “we have been denied access to some drugs with REMS,” she said, meaning the pharmacy has to leave the patient’s electronic health record and independently contact an outside specialty pharmacy that the manufacturer has designated.

“That leads to fragmentation in the patient’s care and delay in getting the patient his or her medication,” she explained.

Specialty pharmacies and manufacturers believe there are good reasons to keep some REMS drugs—mostly those with ETASU—out of the hands of hospital and retail pharmacies. Melissa Schulman, senior vice president for Government and Public Affairs at CVS Health, said the FDA should label some REMS drugs as “specialty only” so they are handled appropriately.

CVS Health believes that the specialty pharmacies will fill gaps beyond the scope of the retail pharmacies, since they already dedicate the necessary educational and administrative time.

REMS programs such as those developed by Celgene for lenalidomide (Revlimid), pomalidomide (Pomalyst), and thalidomide (Thalomid) are not conducive to the retail environment and fit better in the specialty environment due to burdensome, time-consuming requirements. These include:

  • Providing patient or caretaker consultation for every fill.
  • Obtaining and maintaining confirmation and authorization numbers.
  • Tracking each dispensing to adhere to quantity restrictions.
  • Ensuring appropriate documentation is received.

Paul Sheehan, head of REMS for Celgene, noted:

To satisfy this REMS obligation in a manner that optimizes both patient safety and access, Celgene has adopted a limited distribution network of specialty pharmacies, hospitals, and clinics that are authorized to dispense each of these three products. Including additional providers into the limited distribution networks could unnecessarily weaken the operation and effectiveness of our REMS and could make the certification, training, auditing, and monitoring requirements of the REMS infeasible.


The intention of REMS programs is to ensure that the patient gets potentially dangerous drugs that are monitored appropriately; however, if they require weeks of paperwork and back and forth communications due to a lack of understanding about the requirements, this is also dangerous for the patient. This would support the argument that REMS drugs with complex requirements be handled in a specialty pharmacy setting to ensure proper handling and the opportunity to become an expert in each of the REMS requirement medications.

About the Author

Nivedita Kohli earned her Bachelor of Pharmacy degree from the Bouvé College of Health Sciences at Northeastern University and is currently enrolled in the Master of Pharmacy Business Administration (MPBA) program at the University of Pittsburgh, a 12-month, executive-style graduate education program designed for working professionals striving to be tomorrow’s leaders in pharmacy business. She spent the past 20 years developing and implementing drug safety initiatives for a health plan and pharmacy benefit management provider serving Western New York. Over the past decade, she spearheaded educational programs for healthcare practitioners around appropriate opioid prescribing in addition to supporting the Erie County Opioid Epidemic Task Force with multi-faceted programs to improve the outcomes and reduce the impact of the opioid epidemic in Western New York. More recently, she is focusing on opportunities to provide high quality, sustainable healthcare in the current US market, employing her skillset in managed care and business.

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