REMS Programs: Understanding FDA Risk Evaluation and Mitigation Strategies for High-Risk Medications

When a drug can save your life-but also kill you if used wrong-how do you make sure it’s safe? That’s the problem the FDA solved with REMS programs. These aren’t just extra labels or warnings. They’re legally required safety systems built into the way certain high-risk medications are prescribed, dispensed, and monitored. If you’ve ever waited days to get a prescription filled because your pharmacy needed special clearance, or your doctor had to complete training before writing a script, you’ve run into a REMS program.

What Exactly Is a REMS Program?

REMS stands for Risk Evaluation and Mitigation Strategies. It’s a formal system created by the U.S. Food and Drug Administration in 2007 under the Food and Drug Administration Amendments Act (FDAAA). The goal? To allow life-saving drugs with serious risks to stay on the market-while making sure those risks don’t get out of control.

Think of it this way: Most drugs come with a warning label. That’s standard. But for some medications, the label alone isn’t enough. Maybe the side effect is rare but deadly. Maybe it affects unborn babies. Maybe it requires blood tests every week. That’s where REMS steps in. It adds layers of control-beyond the label-to make sure the right people get the right drug, under the right conditions.

The FDA doesn’t use REMS for every drug. Only about 5% of approved medications need one. But those 5% include some of the most critical treatments: cancer drugs, antipsychotics, immunosuppressants, and medications that can cause birth defects. As of October 2023, there were 78 active REMS programs covering around 150 drugs. That’s more than double the number from 2015.

How REMS Works: The Three Key Elements

Not all REMS programs are the same. Each one is custom-built for the specific danger a drug poses. But they all include at least one of these three core components:

• Medication Guides: These are printed handouts given to patients when they pick up their prescription. They explain the risks in plain language-no medical jargon. For example, the guide for isotretinoin (Accutane) clearly warns that pregnancy during treatment can cause severe birth defects.
• Communication Plans: These are directed at doctors and pharmacists. They include training materials, emails, webinars, and alerts to make sure providers understand the risks and how to manage them. For drugs like clozapine, which can wipe out white blood cells, doctors must be trained on when and how to order weekly blood tests.
• Elements to Assure Safe Use (ETASU): This is the strictest layer. It can mean:

• Only certified prescribers can write the script.
• Patients must enroll in a registry.
• Drugs can only be dispensed in certain settings-like a hospital or specialized clinic.
• Patients need lab results before getting the next dose.

Take Zyprexa Relprevv, a long-acting shot for schizophrenia. Because it can cause sudden drowsiness or confusion right after injection-even leading to coma-the FDA requires it to be given only in certified clinics. After the shot, patients must sit and be watched for at least three hours. No exceptions.

Why REMS Programs Exist: Real Risks, Real Stories

The history of REMS goes back to drugs that caused disasters because their risks weren’t properly managed.

Thalidomide, used in the 1950s and 60s for morning sickness, caused thousands of babies to be born with missing limbs. When it was revived decades later to treat leprosy and multiple myeloma, the FDA didn’t take chances. They created the S.T.E.P.S. program-the first REMS-which required strict pregnancy prevention, regular testing, and signed consent forms. That program is still active today.

Isotretinoin (Accutane) is another example. It’s incredibly effective for severe acne-but it’s also a known teratogen. If a woman gets pregnant while taking it, the baby has a high chance of serious birth defects. The iPLEDGE REMS program requires two negative pregnancy tests, two forms of birth control, monthly counseling, and a 30-day waiting period between prescriptions. It’s frustrating for patients. But it works: birth defects from isotretinoin have dropped by over 95% since iPLEDGE started.

Clozapine, used for treatment-resistant schizophrenia, can cause agranulocytosis-a dangerous drop in white blood cells. Without weekly blood tests, patients can die from infections. The clozapine REMS requires pharmacies to verify lab results before dispensing. It’s a bottleneck, but it saves lives.

Who Runs REMS Programs? The Pharmaceutical Companies

Here’s something most people don’t realize: The FDA doesn’t run REMS programs. The drugmakers do.

Pharmaceutical companies must design, pay for, and maintain each REMS. They build the websites, train the providers, manage the registries, and report data to the FDA. The FDA just approves the plan and checks in to make sure it’s working.

That means REMS costs money-big money. A simple program with just a medication guide might cost $500,000 a year. A complex one with patient registries, certified clinics, and real-time monitoring can cost over $15 million annually. The entire U.S. pharmaceutical industry spends about $1.2 billion each year on REMS.

And if a company messes up? The FDA hits them hard. In 2022, the agency issued 17 warning letters for REMS failures. One generic drugmaker paid a $2.1 million fine for not properly managing clozapine’s blood test requirements.

The Downside: Delays, Burdens, and Access Problems

REMS saves lives-but it also slows things down.

A 2019 study in JAMA Internal Medicine found that REMS drugs took an average of 5.4 days longer to get to patients than non-REMS drugs. For someone with a rare disease who needs treatment fast, that’s a lifetime.

Doctors report delays too. A 2022 survey of 1,250 U.S. physicians found that 68% had to wait longer to start REMS medications. Nearly half said those delays hurt patient outcomes.

Pharmacists are stuck in the middle. One hospital pharmacist told Pharmacy Times they spend 2-5 extra hours a week just verifying REMS paperwork. For isotretinoin, the iPLEDGE system requires multiple logins, date checks, and confirmations. On Reddit, pharmacists call it a “nightmare.”

And it’s worse for rural patients. A 2023 report from the National Organization for Rare Disorders said many rare disease patients have to drive hours to a certified clinic just to get their medication. If they miss an appointment, they lose their dose. No one’s accounting for transportation, childcare, or time off work.

Is REMS Working? Experts Are Divided

Supporters say REMS made the impossible possible.

Dr. Robert Temple, former FDA deputy director, said REMS allowed life-saving drugs to be approved that otherwise would’ve been banned. Without REMS, drugs like thalidomide and clozapine wouldn’t be available today.

Critics say some REMS are outdated and unnecessary.

Dr. Aaron Kesselheim from Harvard testified in 2021 that the REMS for long-acting opioids required doctors to take training-but didn’t require patient monitoring. The result? More paperwork, no better safety. He called it “administrative burden without benefit.”

The FDA agrees. In 2022, former Acting Commissioner Dr. Janet Woodcock said, “Not all REMS programs have been equally effective.” That’s why they’ve started sunsetting old ones. In August 2023, the FDA officially ended the REMS for thalidomide after 20 years-because better practices and education made it redundant.

What’s Changing in 2025?

REMS isn’t frozen in time. It’s evolving.

The FDA’s 2024-2026 plan includes modernizing REMS with digital tools. Pilot programs are testing smartphone apps that let patients log blood pressure, heart rate, or symptoms in real time. That could replace weekly clinic visits for some drugs.

The REMS Integration Initiative has already brought 22 of the 78 programs onto a single platform. That means fewer logins, less confusion, and less time wasted.

And now, every REMS proposal must include a formal assessment: “Does this program create unnecessary access barriers?” Especially for rare diseases, low-income patients, or those in rural areas.

The goal isn’t to remove safety. It’s to make safety smarter.

What This Means for You

If you’re a patient: You might face delays. You might need to do extra paperwork. But you’re also getting a drug that’s been tightly controlled to protect you. If your doctor says you need a REMS medication, ask: What’s the risk? What do I have to do? Is there a simpler option?

If you’re a prescriber or pharmacist: You’re on the front lines. Use the FDA’s REMS Dashboard to check which programs are active. Know your responsibilities. Push back when a REMS feels outdated. The FDA listens.

If you’re in the industry: REMS is expensive, complex, and under scrutiny. But it’s also your legal responsibility. Don’t treat it as a checkbox. Make it a system that works-for patients, not just regulators.

REMS in the Bigger Picture

REMS is a uniquely American solution. In Europe, all new drugs have a Risk Management Plan (RMP)-a lighter, more general version. The U.S. goes further, only applying REMS to the riskiest drugs. That makes it more targeted-but also more fragmented.

As cancer drugs get more powerful-and more dangerous-the number of REMS programs will keep rising. Evaluate Pharma predicts that by 2027, 45% of new oncology drugs will need one.

The challenge isn’t whether REMS should exist. It’s whether we can make it faster, fairer, and smarter.

Right now, we’re still balancing two things: saving lives and not making access harder than the disease itself.