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

When a drug can save your life-but also seriously harm you if used wrong-how do you make sure it’s used safely? That’s the exact problem the FDA solved with REMS programs. These aren’t just extra labels or warnings. They’re legally required safety systems built into the use of certain high-risk medications. If you’ve ever waited days to fill a prescription for isotretinoin, had your doctor jump through hoops to prescribe clozapine, or seen a pharmacist spend 20 minutes verifying paperwork before handing over a shot of Zyprexa Relprevv, you’ve seen REMS in action.

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 isn’t to block access to dangerous drugs-it’s to make sure the benefits outweigh the risks. Some medications are too risky to be sold without extra safeguards. REMS ensures those safeguards are in place.

Think of it this way: most drugs come with a label that lists side effects. That’s standard. REMS kicks in when those side effects are severe enough that the label alone isn’t enough. For example, isotretinoin (Accutane) can cause life-threatening birth defects. Clozapine can wipe out white blood cells, leaving patients vulnerable to deadly infections. Thalidomide, once infamous for causing severe birth defects in the 1950s, is still used today to treat leprosy and multiple myeloma-but only under strict controls.

REMS doesn’t apply to every drug. Only about 5% of FDA-approved medications require one. But for those that do, it’s non-negotiable. The FDA can require a REMS at the time a drug is approved-or years later, if new safety data emerges. It’s not a one-size-fits-all system. Each REMS is custom-built for the specific risks of the drug.

How REMS Programs Work: The Key Elements

Every REMS program includes at least one of three core components, and often a mix of them:

• Medication Guides: Printed handouts given to patients explaining the risks in plain language. These are the most common element and required for drugs like isotretinoin and clozapine.
• Communication Plans: Letters, emails, or training materials sent to doctors and pharmacists to make sure they understand the risks and how to manage them.
• Elements to Assure Safe Use (ETASU): These are the heavy-duty controls. They’re only used when the risk is serious and preventable only through direct intervention.

ETASU can include:

• Prescriber certification: Doctors must complete training and register before they can prescribe.
• Pharmacy certification: Only certain pharmacies can dispense the drug.
• Patient enrollment: Patients must sign up in a registry so their use can be tracked.
• Special dispensing: The drug can only be given in a hospital or clinic, not a regular pharmacy.
• Lab monitoring: Blood tests, imaging, or other checks before each dose.

Take Zyprexa Relprevv, an injectable antipsychotic. Because it can cause sudden sedation or delirium right after injection, the FDA requires it to be administered only in certified clinics. Patients must be monitored for at least three hours after each shot. That’s not a suggestion-it’s a legal requirement. Skip it, and the pharmacy can’t legally fill the prescription.

Who’s Responsible for Running REMS Programs?

The FDA sets the rules, but the drugmaker pays for and runs the program. That means pharmaceutical companies must build and maintain the systems: training portals, registries, verification websites, and reporting tools. For example, the iPLEDGE program for isotretinoin is managed by a third-party contractor hired by the manufacturer. Doctors and pharmacists log in to verify patient eligibility, confirm birth control use for women of childbearing age, and submit monthly reports.

This puts a heavy burden on companies. The FDA estimates that REMS programs cost the industry about $1.2 billion a year. Simple programs with just medication guides can cost $500,000 annually. Complex ones with registries, certified providers, and monitoring-like those for clozapine or certain cancer drugs-can cost over $15 million per year.

And it’s not just about money. Compliance is monitored closely. In 2022, the FDA issued 17 warning letters to drugmakers for failing to meet REMS requirements. One generic manufacturer paid a $2.1 million settlement for not properly managing clozapine’s blood monitoring system.

Why REMS Programs Are Controversial

REMS saves lives. But it also delays care.

A 2019 study in JAMA Internal Medicine found that REMS drugs took an average of 5.4 days longer to be prescribed for the first time compared to non-REMS drugs. For patients with rare diseases who live far from specialty clinics, that delay can mean worsening symptoms or hospitalization.

Doctors report the same thing. A 2022 survey by the American Medical Association found that 68% of physicians experienced delays in starting REMS-required medications. Forty-two percent said those delays hurt patient outcomes.

Pharmacists are on the front lines. One hospital pharmacist told Pharmacy Times they spend 2-5 extra hours a week just on REMS paperwork. For clozapine, patients need weekly blood tests for the first six months. Each result must be checked, logged, and verified before the next prescription can be filled. That’s a lot of calls, faxes, and portal logins.

On Reddit’s r/pharmacy community, pharmacists share stories of patients waiting 3-7 days just to get isotretinoin because of iPLEDGE’s multiple verification steps. Some patients give up. Others end up with worse acne, scarring, or depression.

Even the FDA admits the system isn’t perfect. Former Acting Commissioner Dr. Janet Woodcock said in 2022, “Not all REMS programs have been equally effective.” In response, the agency launched the REMS Integration Initiative in 2023, standardizing 22 of the 78 active programs onto a single platform to reduce duplication and paperwork.

REMS vs. Other Safety Systems

REMS isn’t the only way the world manages drug risks. The European Union requires all new drugs to have a Risk Management Plan (RMP). That’s broader and more routine. In the U.S., REMS is only used for drugs with the most serious, preventable risks.

Also, REMS is different from post-market surveillance. Most drugs are monitored through voluntary adverse event reports from doctors and patients. That’s how we catch rare side effects after approval. REMS is proactive-it stops problems before they happen.

And unlike drug recalls, which pull a medication off the market entirely, REMS keeps it available-just under tighter control. It’s a middle ground between banning a drug and letting it go unchecked.

What’s Changing in REMS Today?

The system is evolving. The FDA now requires drugmakers to prove that their REMS isn’t creating unnecessary barriers-especially for patients with rare diseases or those in rural areas.

In August 2023, the FDA made history by lifting the REMS for thalidomide after 20 years. Why? Because better education, safer alternatives, and improved prescribing practices made the old system redundant. That’s the goal: to remove REMS when it’s no longer needed.

Technology is also changing the game. Pilot programs are testing smartphone apps to monitor patients taking anticoagulants in real time. Instead of requiring monthly blood draws, patients might use a connected device that sends lab results automatically to their doctor. If successful, this could cut down on visits and delays.

By 2027, experts predict 45% of new cancer drugs will need REMS-up from 38% in 2023. As drugs get more targeted and powerful, the risks increase. REMS is becoming more common, not less.

But there’s still a big gap: 63% of current REMS programs don’t have clear metrics to measure if they’re actually improving safety-or just adding bureaucracy. The FDA and drugmakers are working together to fix that.

What This Means for Patients and Providers

If you’re prescribed a REMS drug:

• Expect delays. The system is slow by design.
• Ask your doctor: “Is this drug under REMS? What do I need to do?”
• Keep your paperwork organized. Registration numbers, lab results, and certification codes matter.
• If you’re having trouble getting your medication, contact the REMS program’s patient support line. Most have one.

If you’re a provider:

• Know which drugs in your practice require REMS. Keep a list.
• Don’t assume your EHR system automatically handles REMS. Only 35% of REMS programs integrate with electronic health records.
• Use the FDA’s REMS Dashboard to check the latest requirements. It’s updated monthly.

REMS isn’t perfect. It’s clunky, expensive, and sometimes frustrating. But for drugs that could kill you if used carelessly, it’s the best tool we have to keep people safe without taking away access.

Next Steps for Patients and Providers

If you’re a patient: Don’t let REMS delays discourage you. Contact the REMS program’s patient support line. Most have dedicated staff to help navigate the system. Keep copies of every form, test result, and certification code.

If you’re a provider: Know your REMS drugs. Keep a printed or digital list in your office. Train your staff on how to handle verification. Don’t rely on your EHR to do it all-most REMS systems still work separately.

REMS isn’t going away. As drugs get more powerful, the need for precision safety will grow. The goal isn’t perfection-it’s balance. Keeping life-saving drugs available while preventing avoidable harm. That’s what REMS is for.