Risk Evaluation Mitigation Strategies: The Evolution of Risk Management Policy

Abstract

The United States Food and Drug Administration (FDA) has the primary regulatory responsibility to ensure that medications are safe and effective both prior to drug approval and while the medication is being actively marketed by manufacturers. The responsibility for safe medications prior to marketing was signed into law in 1938 under the Federal Food, Drug, and Cosmetic Act; however, a significant risk management evolution has taken place since 1938. Additional federal rules, entitled the Food and Drug Administration Amendments Act, were established in 2007 and extended the government's oversight through the addition of a Risk Evaluation and Mitigation Strategy (REMS) for certain drugs. REMS is a mandated strategy to manage a known or potentially serious risk associated with a medication or biological product. Reasons for this extension of oversight were driven primarily by the FDA's movement to ensure that patients and providers are better informed of drug therapies and their specific benefits and risks prior to initiation. This article provides an historical perspective of the evolution of medication risk management policy and includes a review of REMS programs, an assessment of the positive and negative aspects of REMS, and provides suggestions for planning and measuring outcomes. In particular, this publication presents an overview of the evolution of the REMS program and its implications. (Population Health Management 2013;16:132–137)

Introduction

T he United States Food and Drug Administration (FDA) has the primary regulatory responsibility for ensuring medications are safe and effective, both prior to drug approval and while medications are being actively marketed by manufacturers. The Pure Food and Drug Act of 1906 forbade the manufacture, sale, or transportation of poisonous patient medicines. The Act required that certain drugs, including heroin, cocaine, morphine, and cannabis, be labeled with contents and dosage.¹ The responsibility for safe medications prior to marketing was signed into law in 1938 under the Federal Food, Drug, and Cosmetic (FD&C) Act.² This law came into effect when more than 100 patients died in 1937 after consuming Elixir Sulfanilamide, an antibiotic syrup manufactured by the S. E. Massengill Pharmaceutical Company of Bristol, Tennessee. The antibiotic was mixed with diethylene glycol, a known toxin. The company reportedly only tested the elixir for appearance and palatability before distribution. The catastrophic event led to the passage of the FD&C Act.³ However, a significant risk management evolution has taken place since 1938. Additional federal rules, entitled the Food and Drug Administration Amendments Act (FDAAA), were established in 2007 and extended the government's oversight through the addition of a mandated Risk Evaluation and Mitigation Strategy (REMS) for certain drugs.⁴

It is useful to understand the medication risk management evolution because it impacts the drug development process by adding a layer of complexity and cost. The goal of REMS is to ensure that patients and providers will be better informed of a specific drug therapy and its benefits and risks prior to initiation. As a result of FDAAA, the FDA has enforcement power to ensure that manufacturers and health care providers inform patients of specific risks related to certain drug therapies prior to initiation.⁴ Outcome studies would provide insight into the level of value REMS provides to patients, providers, and payers in the health care system.

Methods

A literature review was conducted to develop this historical perspective utilizing MEDLINE with the following search criteria: Risk Evaluation Mitigation Strategies, FDA REMS, risk FDA regulations, drug safety, opioid risks, medication guides, elements to assure safe use, FDA RiskMAP, and thalidomide. In addition, the FDA Web site (www.fda.gov) was used extensively.

FDA and Drug Safety: An Historical Perspective

The history of drug safety legislation and risk management policies by the FDA are listed in Figure 1. After 1938, the largest change in United States drug legislation occurred as a result of the thalidomide teratogen tragedy. Thalidomide, which was introduced in a number of countries in 1957 to treat morning sickness of pregnancy, was found to cause significant birth defects, including malformations of the limbs, ears, and internal organs.^5
–7 Following these findings, Frances Kelsey of the FDA refused to allow thalidomide into the US market.⁵ Further, Congress enacted legislation to establish more rigorous testing requirements before a drug can be approved in the United States. The 1962 Kefauver-Harris drug amendment to the FD&C Act was passed to ensure drug efficacy and greater drug safety. The amendment required drug manufacturers to prove the effectiveness and safety of their products to the FDA before marketing them.^6,7

FIG. 1.

Historical overview of risk management policies for medications.

A second significant safety-related FDA milestone occurred in 1976 when the patient information leaflet or the patient package insert was introduced for mandatory distribution with oral contraceptives.⁸ Unlike package inserts, which provide comprehensive product information to health care professionals, the patient package insert was a new tool designed to communicate information about medication risks and key safety issues directly to patients.⁸

The FDA has continued to expand its role in assessing risk and assuring the safe use of medications. In 1990, the FDA developed guidelines for risk minimization action plans (RiskMAPs), which are implemented by pharmaceutical and biotechnology companies. RiskMAPS are safety programs designed to minimize the risk to patients who are taking certain prescribed medications that have known associated risks, while at the same time optimizing the drug's benefits.⁹ FDA recommends that RiskMAP goals be translated into specific and measurable tools.⁹ Examples of RiskMAP tools include:

• Targeted education and outreach to communicate risks to health care practitioners or patients.¹⁰

• Reminder systems or forms to foster reduced-risk prescribing and use.¹⁰

• Performance-linked access systems that guide prescribing, dispensing, and use of the product for targeted populations and conditions.¹⁰

The FDA statutory authority to impose these types of safety programs as a condition of approval was limited to products that received accelerated approval. (“Mindful of the fact that obtaining data on clinical outcomes can take a long time, in 1992 FDA instituted the Accelerated Approval regulation, allowing earlier approval of drugs to treat serious diseases, and that fill an unmet medical need based on a surrogate end point. A surrogate end point is a marker—a laboratory measurement or physical sign—that is used in clinical trials as an indirect or substitute measurement that represents a clinically meaningful outcome, such as survival or symptom improvement. The use of a surrogate end point can considerably shorten the time required prior to receiving FDA approval.”)¹¹

In September of 2007, FDAAA was signed by President Bush with an effective date of March 25, 2008.⁴ FDAAA, specifically Title IX of the Act, empowers the FDA with significant new responsibilities and authority, including enforcement authority, over the postmarketing assessment and management of medication safety issues.⁴ The FDA now may require manufacturers to conduct postmarketing studies and make safety labeling changes based on the study findings. In addition, a manufacturer may be required to develop a REMS for a medication (although not all drugs have a REMS program). The requirement for a REMS can occur for medications that are currently approved or in development.

RiskMAPs versus REMS

As mentioned, FDAAA gives the FDA the right to mandate that the pharmaceutical and biotechnology industries develop a REMS for specific medications.⁴ The number of approved REMS programs per year are listed in Figure 2. This is in contrast to the former process in which the FDA was limited to negotiating risk management plans with companies. REMS use many of the elements that the earlier RiskMAPs used.^9,12 Examples of REMS elements include:

• Communication Plans: “Dear Health Care Provider” letters highlight important safety, prescribing, and dispensing information on the product and the actions the health care provider can take to help ensure appropriate use. Communication plans also may include letters to the leadership of professional societies and/or Web-based information for health care providers.

• Patient education materials.

• Medication Guide: Medication Guides are printed handouts that are provided with some prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and contain FDA-approved information that can help patients avoid serious adverse events.¹³

• A timetable for assessment at a minimum of 18 months and 3 years after a strategy is approved, as well as in the seventh year after approval.⁴ The required assessments are agreed upon with the FDA, but typically include data on the number of prescribers who have enrolled in the REMS program for a particular medication at a specified time point. If the FDA determines that serious risks of the medication have been identified and appropriately managed by REMS, additional assessments may be eliminated after the 3-year period.⁴

• “Elements to assure safe use”: These may include some or all of the following as defined in Table 1: prescriber and pharmacy certification that documents specific training or experience with a medication; distribution of the drug to patients is restricted to certain health care settings; and/or patient tracking requirements that each patient using a medication is enrolled in a registry.

• Enrollment forms.

• Patient and prescriber agreements.

FIG. 2.

Number of approved REMS and original new drug application approvals by year (2008–2011).¹²

Table 1.

Features of REMS and their Respective Elements ⁴

Elements to Assure Safe Use	Certification
	• Health care providers who prescribe the drug have particular training or experience, or are specially certified
	• Pharmacies, practitioners, or health care settings that dispense the drug are specially certified
	Patient agreement/consent
	Restricted distribution
	• The drug is dispensed to patients only in certain health care settings, such as hospitals
	• The drug is dispensed to patients with evidence or other documentation of safe use conditions, such as lab test results
	Tracking
	• Each patient using the drug is subject to certain monitoring
	• Each patient using the drug is enrolled in a registry

REMS, risk evaluation and mitigation strategy.

However, as compared with RiskMAP tools, the REMS tools are applied to a broader setting of targeted therapies. Specifically, the key difference is that REMS, unlike RiskMAPs, safeguard against potential safety risks not experienced during controlled trials but that may be of concern on the basis of other factors (ie, postmarketing studies, adverse event reporting). REMS also may include fines as an enforcement mechanism. REMS are designed to provide information to ensure that health care professionals have a good understanding of the product label and the evidence of known safety risks; this enables health care professionals to continue to employ sound medical judgment based on evidence. REMS enable medications to enter the market that might not otherwise be approved because of safety concerns. Examples include birth defects (see earlier discussion of thalidomide); overdose and diversion as seen with opioid analgesics used to treat pain (eg, OxyContin); increased tumor progression in cancer patients as seen with erythropoesis stimulating agents, PROCRIT, Epogen, and Aranesp; or irreversible end organ destruction as seen with vigabatrin, a drug used to treat adults with complex partial seizures but that can lead to vision loss.^4,14 Thus, REMS may allow patients access to potentially beneficial medications while ensuring that they are informed of possible adverse events. FDAAA delineates specific factors that should be considered by the FDA when determining whether a medication should be required to have a REMS.⁴ A REMS may be required prior to a medication's approval if the FDA concludes that one is necessary. The FDA may weigh the following factors when making its decision:⁴

• The estimated size of the population.

• The seriousness of the condition treated by the medication.

• The expected benefits of the medication with respect to that condition.

• The duration of treatment with the medication.

• The seriousness of known or potential adverse events associated with the medication and the background incidence of such events in the population.

• Whether the medication is a New Molecular Entity (ie, a drug that contains no active moiety that has been approved by the FDA in any other application submitted under section 505(b) of the FD&C Act.)¹³

Further, REMS may be required if new safety information for a marketed product suggests a need to ensure that the medication's benefits outweigh its risks.⁴ After notification by the FDA of the need for a REMS, the medication's manufacturer has 120 days (or other reasonable time period determined by the FDA) to submit a proposed REMS. New safety information may be derived from a clinical trial, a postapproval study, an adverse event report, the peer-reviewed biomedical literature, the FDA's new active surveillance system, or other scientific data.

Specifically, health care providers who prescribe a medication with a REMS, along with pharmacies or health care settings that dispense the medication, must have specific training or a special certification to either prescribe or dispense the drug. Dispensation of the drug may be limited to a certain setting (eg, hospitals) or restricted to certain patients with evidence or other documentation of safe-use conditions, such as specific laboratory test results. Patient safety may be assessed by imposing mandatory patient monitoring programs or enrolling patients in a safety registry. The FDA also may require that manufacturers take reasonable steps to monitor and evaluate implementation by health care professionals who are responsible for implementing those REMS elements and to work to improve their implementation.

Impact of REMS on Health Care

REMS can potentially provide benefits to patients and health care providers by offering detailed explanations of the risks associated with a medication that can enhance appropriate use and prevention of adverse events related to misuse. For example, the iPLEDGE program for Accutane (isotretinoin) is in place to educate females with childbearing potential about the risk of birth defects and to prevent those who are pregnant or who are not using a proper form of birth control from receiving the medication.¹⁵ (Note: Accutane has been taken off the market; only the generic, isotretinoin, is on the market.) The program requires patients, physicians, and pharmacists to register on a Web site to receive the medication. The iPLEDGE program was initiated on March 1, 2006 as a replacement for the SMART program (System to Manage Accutane-Related Teratogenicity), which was instituted in April 2002. SMART aimed to eliminate isotretinoin-induced birth defects by preventing pregnant women from being prescribed or exposed to the drug. The program required all women of childbearing age seeking an Accutane prescription to have 2 consecutive negative pregnancy tests, birth defect risk counseling, and a pledge to use 2 forms of contraception when engaging in intercourse. A voluntary registration program called “The Accutane Survey” also was put in place. Unfortunately, no effort was made to verify compliance by physicians and pharmacists. Further, only a small percentage of women registered in the survey, and the reputation of Accutane as a highly effective acne drug continued to spur demand for new prescriptions.¹⁵

Although there are benefits to REMS, there also are potential negative impacts. Implementing REMS processes can be burdensome on health care providers. For example, health care professionals may be required to track medication doses, enroll patients in registries, or obtain additional patient information required by the REMS. These tasks are time consuming and are not currently reimbursed by insurance companies.¹⁶ The time required to appropriately comply with REMS (eg, registering health care providers, facilities, and/or patients) often means that time or other resources are taken away from direct patient care and education. In addition, the increasing numbers of unique REMS programs and their requirements may result in health care provider confusion and inconsistencies in compliance. Last, implementing REMS processes has resulted in significant costs, both to the pharmaceutical industry and health care providers.^16,17 Consistently, pharmacy organizations and pharmaceutical companies have urged the FDA to consider more uniformity to REMS requirements and tools.^16,17

REMS Measurement

Part of the requirements associated with REMS programs is to provide assessments to the FDA at specified time intervals. This topic has not been well defined or studied in controlled trials to this point. Certainly a variety of measurements can be established to form these assessments (Table 2). Examples as recognized by the FDA in their guidance document include: surveys for REMS program perceptions about satisfaction, practice, or use characteristics; access to care issues; educational programs; possible improvements; and barriers. Also “process measures,” such as the number and demographics of enrollees (patient, pharmacy/pharmacist, and prescriber), prescriptions, and surrogate measures such as health claims data, spontaneous adverse event reports, and registry safety reports. The difficulty with these assessments is the lack of a control group to evaluate the baseline risks and the changes that are targeted for improvement. For example, how does one measure the change in incidence of opioid abuse, diversion, and misuse that was attributed to the REMS intervention in a prospective fashion? The value of these programs in reducing risk should be measured prospectively against their potential impact on reduced access and rising costs to the health care system.

Table 2.

REMS Measurement Examples

Types	Methods	Targets	Measures/Outcomes
Surveys	• Online/mail• Advisory boards	• Providers• Patients• Pharmacies• Health Plans	• Program satisfaction• Practice pattern perceptions (access to care, resource allocation, barriers, improvements)• Education methods• Administrative logistics
Process measures	• Program measurements (online, fax, mail)	• Providers• Patients• Pharmacies• Health Plans	• Enrollee demographics• Prescription enrollment• Educational compliance• Attestations compliance• Medication Guide delivery
Health outcomes	• Claims analysis	• Providers• Patients• Pharmacies• Health Plans	• Prescription patterns• Procedures• Healthcare costs• Safety/Risk measures• Patient demographics
	• Registries	• Providers• Patients• Pharmacies• Health Plans	• Prescription patterns (access to care)• Safety/risk measures
	• Controlled studies	• Providers• Patients• Pharmacies• Health Plans	• Access to care• Enrollee demographics• Prescription enrollment• Educational compliance• Attestations compliance• Medication Guide delivery• Comparative differences in risk profiles related to REMS interventions

REMS, risk evaluation and mitigation strategy.

Enforcement Authority of the FDA

Under FDAAA, the FDA has authority to impose civil monetary penalties if REMS requirements are not met. Civil penalty fines of up to $250,000 per violation can be imposed, not to exceed $1 million for all violations adjudicated in a single proceeding.⁴ If a violation continues after written notice from the FDA, the FDA will impose penalties of up to $10 million for all violations adjudicated in a single proceeding.⁴

Conclusion

An evolution has taken place with respect to the responsibilities of the FDA to ensure the safe use of medications. REMS programs are a new reality for all key stakeholders involved in the patient treatment paradigm. As of 2011, there are just under 100 REMS programs approved by the FDA.¹⁸ These programs vary by drug and contain different requirements based on the risks and benefits associated with each drug. Reasons for this expansion of oversight were driven primarily by the FDA's movement to ensure that patients and providers are better informed about the specific benefits and risks of a drug prior to initiation.

REMS will continue to be applied to more drug classes in years to come, fines will continue to increase for lack of compliance, and physicians' responsibility to disclose will expand to ensure that patients truly understand the benefits and risks of therapy prior to initiation. The impact of REMS is already far reaching, and the need for standardization of program requirements and consideration of health care provider time and costs are areas yet to be addressed.¹⁷ In addition, outcome studies measuring the value of REMS interventions should be conducted to evaluate their impact on risk mitigation of intended outcomes and overall access to care by patients.

Footnotes

Author Disclosure Statement

Ms. Hollingsworth is Vice President, Strategy and External Innovation, at the Janssen Pharmaceutical Companies of Johnson & Johnson. Dr. Toscani disclosed no conflicts of interest with regard to the research, authorship, and/or publication of this article.

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