How to REMS – A Practical Regulatory Guide

This week in the Guardrail, we look at mastering the FDA’s toughest safety oversight protocols -REMS.  As scrutiny intensifies, your team must move beyond simple checkboxes to build a truly resilient system.

Written by Michael Bronfman

Risk Evaluation and Mitigation Strategies, or REMS, are required by the FDA for certain drugs with serious safety concerns. The goal of a REMS program is to ensure that the benefits of a drug outweigh its risks. REMS programs can be complex and highly visible to regulators. Companies must be prepared not only to design and implement a REMS but also to demonstrate that it works.

REMS inspections are increasing in depth and frequency. Being prepared requires a clear understanding of regulatory expectations, strong operational controls, and a culture of compliance.

When a REMS Is Required

The FDA may require a REMS at the time of approval or after a drug is on the market. This decision is based on known or potential risks associated with the product.

REMS may be required when labeling alone is not enough to manage risk. Examples include drugs with serious side effects, high misuse potential, or risks related to pregnancy or long-term use Understanding when and why a REMS is required helps sponsors plan early and avoid delays.

FDA information on REMS

Key Components of a REMS Program

Not all REMS programs are the same. Some are simple, while others are complex and involve multiple stakeholders.

Common REMS components include:

• Medication guide – information provided to patients about risks
  

• Communication plan – educational outreach to healthcare providers
  

• Elements to assure safe use – such as prescriber certification, pharmacy certification, patient enrollment, or monitoring requirements
  
  

Each component must be clearly defined and supported by procedures and training.

The FDA provides REMS guidance .

Regulatory Expectations for REMS Inspections

During a REMS inspection, FDA investigators focus on whether the program is implemented as approved and whether it effectively manages risk.

Inspectors will review policies, procedures, training records, and systems used to support the REMS. They may also interview staff responsible for REMS operations.

Key expectations include clear role definitions, documented processes, and evidence of oversight. Sponsors must show that they monitor compliance and address issues promptly.

Failure to meet REMS requirements can lead to warning letters, fines, or other regulatory actions.

Documentation Is Critical

Documentation is one of the most important aspects of REMS readiness. Every part of the program must be supported by written procedures.

This includes how prescribers are certified, how patients are enrolled, how data is collected, and how compliance is monitored.

Inspectors often ask to see examples of records. Missing or inconsistent documentation is a common inspection finding.

Companies should ensure that records are complete, accurate, and easy to retrieve.

Training and Accountability

Training is a core regulatory expectation for REMS programs. Staff involved in REMS activities must understand their responsibilities.

Training records should show who was trained, when training occurred, and what content was covered. Refresher training should be provided when procedures change.

Accountability is equally important. Roles should be clearly assigned, and oversight should be documented.

Strong training programs reduce the risk of errors and inspection findings.

Monitoring and Auditing REMS Performance

Sponsors are expected to monitor REMS performance on an ongoing basis. This includes tracking compliance with program requirements and identifying trends.

Regular audits help identify gaps before they become regulatory issues. Audit findings should be documented, and corrective actions should be implemented and tracked.

FDA guidance emphasizes the importance of continuous evaluation of REMS effectiveness

Inspection Readiness Best Practices

REMS inspection readiness should be built into daily operations. Waiting for an inspection notice is too late.

Best practices include:

• Maintaining up-to-date procedures
  

• Conducting mock inspections
  

• Ensuring staff can confidently explain the program
  

Centralized documentation systems help ensure consistency and access. Leadership involvement reinforces the importance of REMS compliance.

Evolving REMS Inspection Trends

REMS inspections are becoming more detailed. Inspectors increasingly focus on how data is used to evaluate effectiveness.

They may ask how the sponsor determines whether the REMS is meeting its goals. They may also review how changes to the program are assessed and implemented.

Technology systems used to support REMS are also under greater scrutiny. Data accuracy, security, and access controls are key areas of focus.

Sponsors should be prepared to explain system validation and oversight.

Managing Third-Party Vendors

Many REMS programs rely on third-party vendors. These vendors may manage call centers, data systems, or training.

While vendors perform the work, the sponsor remains responsible. Inspectors will review vendor oversight and contracts.

Clear agreements, regular performance reviews, and documented oversight are essential. Vendor issues are a common source of REMS inspection findings.

REMS Modifications and Updates

REMS programs may need to be modified over time. Changes may be driven by new safety information or operational challenges.

Regulatory expectations for REMS modifications are strict. Changes must be reviewed and approved by the FDA before implementation unless otherwise permitted.

Sponsors should maintain clear change control processes and documentation.

Preparing for the Inspection Day

On the day of a REMS inspection, preparation makes a difference. Staff should know who will interact with inspectors and where documents are stored.

Responses should be clear and factual. If information is not immediately available, it is better to follow up than to speculate.

A calm and organized approach supports a positive inspection outcome.

Looking Ahead

REMS programs are a critical tool for managing drug safety. Regulatory scrutiny in this area will continue to increase.

Companies that invest in strong REMS design, clear documentation, and continuous monitoring are better positioned to meet expectations.

REMS compliance is not just a regulatory requirement. It is a commitment to patient safety and public trust.

Is your safety strategy ready for the spotlight? Don’t wait for a knock at the door—Contact  Metis Consulting Services to sharpen your oversight and secure your path to market

RIC, REMS, and the REMarkable Dr. Frances Oldham Kelsey

Dr Francis Oldham Kelsey - image from Library of Congress

Written by Li-Anne Rowsell Mufson

METIS' CEO and Founder Michelleanne is finishing up with the SQA Conference and is headed to the REMSIndustry Consortium (RIC) to Convene on March 22nd and 23rd. 

The promised second half of our blog on REMS and The history of Thalidomide is below. I wound up becoming even more fascinated with Dr. Frances Oldham Kelsey and her heroism, and it is particularly appropriate to celebrate her during Women's History Month. If you want to hear more about REMS, listen to Ep. 6 Of the "Queens of Quality Podcast."

 if you'd like to know more about how our consultants can help your company with REMS programs, drop us a line at Hello@metisconsultingservices.com

Frances Kelsey: A Woman Who Made a REMarkable Difference in the World of Medicine

Who is Dr. Frances Oldham Kelsey?

Frances Oldham Kelsey was a Canadian-born physician who fought big pharma companies and a tremendous amount of pressure to do her job. In the process, she saved lives and heartbreak for thousands of Americans. She was born in 1914 and received her bachelor of science and master of science degrees from McGill University, Montreal, in 1934 and 1935. In 1938 she earned her Ph.D. from the University of Chicago and married and had two children while teaching and earning her medical degree there. She began her career at the Food and Drug Administration (FDA) in 1960 at the age of 46. At the FDA, Kelsey worked in the Division of New Drugs and was responsible for reviewing and approving new drugs for the American market. During her time at the FDA, Kelsey became a vocal advocate for rigorous testing and regulation of new drugs. She also believed in ensuring the safety and efficacy of new medicines before they were approved for sale.

What did Frances Kelsey do that was so remarkable?

In 1961, during her first month at the FDA, Kelsey began her very first significant project, reviewing a new drug called Thalidomide. It was a sedative being marketed as a safe and effective treatment for morning sickness in pregnant women, among other sedative uses. As other countries began approving the drug for sale, Kelsey was skeptical about its safety. Dr. Kelsey knew that drugs could cross the placental barrier and harm an unborn baby. So she asked for evidence of trials on pregnant animals and requested that the company submit more data about its safety and efficacy, but they were reluctant to do so. These were never provided. 

In fact, that company resubmitted the NDA several times without ever providing the information she sought. Dr. Kelsey's insistence on more testing and regulation saved thousands of lives. When other countries began approving the drug for sale, thousands of babies were born with congenital disabilities. However, the drug was never approved for sale in the United States due to Kelsey's diligence and attention to detail.  Despite all her efforts, and even though the drug was not approved in the United States, as many as 20,000 Americans were given Thalidomide in the 1950s and 1960s. These individuals were part of two clinical trials operated by the American drug makers Richardson-Merrell and Smith, Kline & French. The Sales manuals even assured doctors that the new drug had been "shown to be absolutely harmless" in pregnant women and children. 

And if not for Dr. Kelsey, that number would have grown exponentially. 

She was eventually awarded the President's Award for Distinguished Federal Civilian Service by John F. Kennedy for her efforts to ensure the safety of drugs prescribed to pregnant women.

How did Kelsey's work impact the regulatory landscape?

Kelsey's story has been told in films, books, and documentaries. She is a powerful symbol of achievement through dedication, hard work, and determination. Her story highlights the importance of rigorous testing and regulation in the world of medicine. The FDA strengthened and improved its regulations due to Kelsey's work. The 1962 Kefauver-Harris Amendment required more data to be collected about the safety and efficacy of new drugs before they were approved for sale. The amendment also allowed the FDA to issue sanctions against pharmaceutical companies that did not comply with the regulations.

 Kelsey's work also had a global impact. Organizations like the World Health Organization (WHO) and the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use were formed to coordinate and facilitate the regulation and testing of drugs among different countries. And the FDA would never have created the REMS program.

What’s REMS again? 

As we have mentioned, REMS (Risk Evaluation and Mitigation Strategy) is a drug safety program that the U.S. Food and Drug Administration (FDA) has implemented for medications to help ensure the benefits of the medication outweigh the risks. The key participants in the Risk Evaluation and Mitigation Strategy (REMS)are patients, healthcare providers, pharmacists, and healthcare settings that dispense or administer the drug. There are four pieces to REMS:

1. Risk piece-there are serious risks identified

2. Evaluation- through trials, analysis, etc.

3. Mitigation piece- what can be done to reduce that risk 

4. Strategy piece - how that mitigation is done

When was REMS started?

Risk Evaluation and Mitigation Strategies (REMS) are programs instituted by the FDA to monitor medications with a high potential for serious adverse effects. REMS applies only to specific prescription drugs but can apply to brand-name or generic drugs. The REMS program was formalized in 2007. REMS programs are designed to reinforce medication use behaviors and actions that support the safe use of that medication. While all medications have labeling that informs healthcare stakeholders about medication risks, only certain medications require a REMS. REMS are not designed to mitigate all the adverse events of a medication; Rather, REMS focus on preventing, monitoring, and/or managing specific serious risks by informing, educating, and reinforcing actions to reduce the frequency and/or severity of the event. 

According to the FDA's website, there are three major components to the strategy for each REMS.

1. Communication to Patients-REMS may require the drug manufacturer to develop materials for patients like medication guides(these would be in addition to the medication guides all drugs must include.) These handouts contain FDA-approved information in patient-friendly language that can help inform patients about the safest way to use the medication.

2. Communication to Health Care Providers, Pharmacists, and Health Care Settings-

The REMS may include communicating directly to health care providers, pharmacists, nurses, or other participants involved in the delivery of these medications. In some cases, the communications may also target medical professional societies or state licensing boards to inform them of the REMS' particular safety concerns and/or to support conveying this information to their members.  They may provide information about a specific risk and steps to take to reduce it.  

3. Required Activities or Clinical Intervention-Sometimes these activities are referred to as "elements to assure safe use (ETASU)."

Sometimes, participants are required to conduct activities that support the safe use of the medication. These activities must be undertaken before the drug can be prescribed, dispensed, or received.   

The storied history of Thalidomide was one of the critical elements in the regulations that eventually led to the institution of the REMS programs. 

Dr. Frances Kelsey's story can be an inspiration to us all. She was a woman who rose to prominence during a time when women were not taken seriously in the world of medicine. Despite this, she was determined to ensure that the drugs on the market were safe and effective. Kelsey's story highlights the importance of Quality assurance and regulatory oversight in the pharmaceutical and medical device world. Dr. Kelsey's story is also a reminder that change is possible. By questioning the status quo and challenging the accepted standard, she brought about positive change in how drugs are regulated and tested. 

Her story should remind us all of the importance of insisting on evidence, putting patient health first, doing the work, and, of course, standing up for what is right. 

Cited research

The Story of Thalidomide in the U.S., Told Through Documents. https://www.nytimes.com/2020/03/23/health/thalidomide-fda-documents.html

What's in a REMS? | FDA. https://www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/whats-rems

Risk Evaluation and Mitigation Strategies | REMS | FDA. https://www.fda.gov/drugs/drug-safety-and-availability/risk-evaluation-and-mitigation-strategies-rems

What is this Alphabet Soup?

What is this alphabet soup?

Written by Li-Anne Rowswell Mufson

REMS- RISK EVALUATION AND MITIGATION STRATEGY. 

RIC- REMS Industry Consortium

Although it is reasonably well understood conceptually, the REMS program is relatively new - it started in 2007- and is still in the process of being operationally understood. The reality of multiple Sponsor and Vendor organizations sharing a REMS program can lead to breakdowns in Communication, Collaboration, and Consensus among the different organizations and even the departments within those organizations. With help from Metis' Consultants and with the tools provided by RIC, organizations can work to identify potential issues before they start and prevent communication siloing along departmental and organizational lines; by fostering collaboration and consensus with shared REMS sponsors and vendors. 

Evaluation within the REMS program is used to mitigate risks, and the strategy for the Mitigation piece is presented to the FDA. The FDA evaluates for both tactics and strategies. 

Because of all the complexities and even some unnecessary complications, staying current and having specialists in this manner is essential. That is the reason the  RIC was started. 

The REMS Industry Consortium provides education and learning tools to help and standardize the successful execution of an REMS program. Metis is a very enthusiastic supporter of the Consortium as it kicks off. 

What is RIC?

The REMS Industry Consortium, Inc. (RIC) is a nonprofit organization made up of industry experts. According to the RIC website, it " brings together the perspectives of organizations that sell—or anticipate selling—prescription drugs or biologics subject to Risk Evaluation and Mitigation Strategies (REMS).”

The RIC seeks to:

• Foster and encourage two-way communication between manufacturers/REMS sponsors and FDA

• Discuss and clarify challenges faced by industry sponsors and the FDA

• identify best practices for REMS throughout the development, review, and management lifecycle

• Provide the FDA with a "sounding board" to solicit feedback on REMS

• collectively explore vendor participation and capabilities in REMS."

The emphasis is mine. In these areas, in particular, having knowledgeable and experienced consultants from Metis will be invaluable to pharmaceutical manufacturers subject to REMS.

What is REMS?

The U.S. Food and Drug Administration (FDA) introduced the Risk Evaluation and Mitigation Strategies (REMS) program in 2007 to ensure that the benefits of particular drugs outweigh their risks. REMS is a comprehensive strategy pharmaceutical manufacturers must develop and implement to manage known or potential serious risks associated with a specific drug while ensuring continued patient access to the medication.

One key aspect of REMS is the Risk Identification and Analysis (RIA) process, which involves identifying potential risks associated with a drug and analyzing the likelihood and severity of those risks. Based on the RIA, pharmaceutical manufacturers develop a REMS program that includes various strategies to manage and mitigate the identified risks.

REMS programs typically include a combination of elements such as medication guides, communication plans, training and certification programs for healthcare providers, patient registries, and restricted distribution programs. These elements aim to ensure that healthcare providers and patients have access to the information they need to make informed decisions about the pharmaceutical's use and minimize the risks associated with its use.

Pharmaceutical manufacturers must submit a proposed REMS program to the FDA for review and approval before marketing the drug. The FDA reviews the proposed REMS program to ensure that it includes appropriate risk management strategies and is feasible to implement.

Once the REMS program is approved, pharmaceutical manufacturers must implement and maintain the program as authorized. The FDA monitors the implementation and effectiveness of REMS programs through various means such as inspections, audits, and assessments.

Pharmaceutical manufacturers must understand and comply with REMS requirements to ensure that their drugs are safe and effective for patient use. Failure to comply with REMS requirements can result in enforcement action by the FDA, including fines, product seizures, and injunctions.

In summary, REMS is a critical program that pharmaceutical manufacturers must comply with to ensure the safe use of their drugs. REMS requires manufacturers to identify and mitigate potential risks associated with their drugs and implement various risk management strategies to minimize those risks. Pharmaceutical manufacturers should work closely with the FDA throughout the REMS process to ensure that their REMS programs meet regulatory requirements and effectively protect patient safety. 

Coming up

In our next blog post, we will discuss the history of thalidomide, the heroic work of Frances Kelsey, and how that eventually led to the institution of REMS.

Metis' CEO, Michelleanne Bradley, has been involved with REMS programs since they began in 2007. For more information about RIC and REMS, listen to Episode 6 of the "Queens of Quality" Podcast. You can also drop us a line at Hello@metisconsultingservices.com or check us out on LinkedIn.