“It is simply not possible to identify all the side effects of drugs before they are marketed.”¹

INTRODUCTION

The safety vigilance that a drug manufacturer exercises to obtain approval of a new prescription drug from the United States Food and Drug Administration (FDA) continues through the life of the product.² An ongoing challenge faced by industry involves charting and implementing an effective strategic course for managing risks and enhancing drug safety after product launch. A vigilant, responsive drug safety system that applies the best possible science and technologies to identify and understand the risks of medication use promotes patient safety and fosters public trust and confidence in the drug manufacturer and its products.

A more formalized plan of risk evaluation and mitigation may be required by FDA under legislation added to the Food Drug and Cosmetic Act (FDCA)³ by the FDA Amendments Act of 2007 (FDAAA).⁴ The drug safety provisions of FDAAA strengthen FDA’s authority to regulate the postmarket safety of drugs and mandate that the agency establish novel programs to prevent and detect adverse drug reactions to enhance drug safety.⁵ Under the FDAAA, FDA may require postmarket studies and clinical trials to address safety issues, safety labeling changes, and Risk Evaluation and Mitigation Strategies (REMS) if the agency determines this is necessary to ensure that the benefits of the drug outweigh the risks.⁶

FDA has issued guidance papers to assist industry in developing and implementing effective risk management strategies. This article discusses FDA’s Draft Guidance for Industry, Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications (“REMS Guidance”), September 2009.⁷ FDA’s REMS Guidance provides a useful blueprint for developing important strategies on risk evaluation and mitigation.⁸ The article concludes with recommendations and practical tips for pharmaceutical manufacturers.

FDA REMS Guidance

Overview of REMS

Section 505-1 of the FDCA authorizes FDA to require a Risk Evaluation Mitigation Strategy (REMS).⁹ During the approval process, FDA will determine whether a REMS is required to ensure that the benefits of the drug or biological product outweigh the risks. If so, FDA will require the sponsor of the application to submit a proposed REMS, and the REMS will be approved when the drug is approved. If a product is already approved and FDA becomes aware of new safety information¹⁰ that suggests a REMS is necessary to ensure that the benefits of the drug product outweigh the risks, FDA will require a REMS.¹¹ Among other things, a REMS may include plans for a Medication Guide, Patient Package Insert, a Communication Plan, Elements to Assure Safe Use (ETASU), and an Implementation System. The REMS must include a timetable for assessment.¹²

Examples of drugs that may be subject to REMS are opiate drug products; products that are human teratogens; and products that may call for specialized healthcare skills, training, or facilities to manage the therapeutic or serious side effects of the medication.¹³ As FDA becomes more comfortable with its new power and as more decisions regarding class-wide REMS are finalized, we can expect the number of REMS to grow significantly.

FDA may impose civil monetary penalties for violations of the REMS provisions, or the drug or biological product can be deemed misbranded and FDA could obtain injunctive relief.¹⁴ Section 505-1 of the Act provides that the penalties may not exceed $250,000 per violation, or $1 million for all violations adjudicated in a single proceeding. If a violation continues after the sponsor receives written notice, the penalty is $250,000 for the first 30-day period (or any portion thereof) that the violation continues, not to exceed $1 million for any 30-day period and not to exceed $10 million for all violations adjudicated in a single proceeding. FDA may take into consideration whether the company is making efforts to correct the violation when determining the amount of a civil penalty.

Relationship Between REMS and RiskMAP

Some drug and biological products that previously were approved or licensed with risk minimization action plans (RiskMAPs) will now be deemed to have REMS. More specifically, before the enactment of FDAAA, FDA approved a small number of drug and biological products with RiskMAPs. A RiskMAP is “a strategic safety program designed to meet specific goals and objectives in minimizing known risks of a product while preserving its benefits.”¹⁵ In 2005, FDA issued a Guidance for Industry on Development and Use of Risk Minimization Action Plans that described how to develop RiskMAPs, select tools to minimize risks, evaluate and monitor RiskMAPs and monitoring tools, and communicate with FDA about RiskMAPs.¹⁶

Because FDA now has the authority under the FDAAA to require REMS when necessary to promote drug safety, FDA is seeking to reconcile REMS and RiskMAPs. FDA anticipates that a drug that would previously have been approved with a RiskMAP will instead be approved with a REMS if the statutory requirements for a REMS are met.¹⁷ Further, drugs that would previously have been approved with a Medication Guide or patient package insert that meets the statutory requirements for a REMS will now be required to have a REMS.¹⁸

Many of the principles that were included in the RiskMAP guidance are embodied in Section 505-1 of the FDCA. The RiskMAP guidance continues to apply to products with existing RiskMAPs and to products with new RiskMAPs (e.g., Abbreviated New Drug Applications, or “ANDAs,” for which the reference listed drug has a RiskMAP).¹⁹

Content of REMS

A proposed REMS submission to FDA should have two parts.²⁰ First, the submission should contain a proposed REMS, which is a concise document that describes the goals and elements of the REMS and, once approved, will be the basis for enforcement.²¹ Second, the submission should have a REMS supporting document that expands on information included in the proposed REMS.²²

Proposed REMS

The proposed REMS should include product and contact information, goals, and elements used to achieve goals. A template for the proposed REMS is available on the FDA website.²³

REMS goals should target the achievement of particular health outcomes related to known safety risks, such as patients on X drug should not also be prescribed Y drug.²⁴ In turn, these goals should be translated into pragmatic, specific, and measurable program objectives that result in processes or behaviors leading to the REMS goals.”²⁵ For example, if the goal is the elimination of dangerous concomitant prescribing, then the objectives could consider lowering physician co-prescribing rates or pharmacist co-dispending rates or both.²⁶

Potential REMS elements may include a Medication Guide, package insert, and communication plan to healthcare providers if the plan may support implementation of an element of the strategy.²⁷ These elements target education and outreach. They aim to increase the knowledge and behaviors of key people or groups, such as healthcare providers and consumers.

Medication Guides will be required if FDA determines that one or more of the following circumstances exist: (1) the drug product is one for which patient labeling could prevent serious adverse side effects; (2) the drug product is one that has serious risks (relative to benefits) of which patients should be made aware because information concerning the risks could affect the patients’ decision to use, or to continue to use, the product; and (3) the drug product is important to health, and patient adherence to directions for use is crucial to the drug’s effectiveness.²⁸ The sponsor is responsible for ensuring that the Medication Guide is available for distribution to patients who are dispensed the drug.²⁹ Copies of Medication Guides and patient package inserts that are part of a REMS should be appended to the proposed REMS.³⁰

FDA may determine that a Communication Plan targeted at healthcare providers and/or patients is a necessary element of the REMS.³¹ Communication plans may include sending letters to healthcare providers, disseminating information about REMS elements to encourage implementation by healthcare providers or to explain certain safety protocols such as medical monitoring by periodic laboratory tests, or disseminating information to healthcare providers through professional societies about any serious risks of the drug and any safety protocols.³²

For a drug that has been shown to be effective but which is associated with a serious adverse event, there are elements required to assure safety.³³ Before requiring one or more Elements to Assure Safe Use (ETASU), though, FDA must make a determination that: (1) the drug, which has been shown to be effective but is associated with a serious adverse drug experience, can be approved only if, or would be withdrawn unless, such elements were required; or (2) for a drug initially approved without ETASUs, other possible elements of a REMS are not sufficient to mitigate such serious risk.³⁴

Elements to Assure Safe Use include requiring healthcare providers who prescribe the drug to have particular training or experience or to be specially certified; requiring pharmacies, practitioners, or healthcare settings that dispense the drug to be specially certified; requiring the drug to be dispensed to patients only in certain healthcare hospitals, requiring the drug to be dispensed only to patients with evidence or other documentation of safe-use conditions, such as laboratory results;³⁵ requiring each patient using the drug to be subject to certain monitoring; and/or requiring each patient using the drug to be enrolled in a registry.³⁶ Sponsors are expected to have in place an implementation system to monitor and evaluate healthcare providers, pharmacists and other parties in the healthcare system who are responsible for implementing the elements of the ETASU.³⁷

Further, these REMS elements for an NDA must have a proposed timetable for submission of assessments of the REMS.³⁸ Under Section 505-1(d), each timetable for submission of a REMS must at a minimum include assessments submitted by 18 months, three years and in the seventh year after the strategy is approved, with additional dates if more frequent assessments are necessary to ensure that benefits of the product continue to outweigh the potential risks.³⁹ For drugs with an FDA-approved ETASU, the first assessment period is typically shorter than 18 months. One example is GlaxoSmithKline’s Entereg®, a medication indicated to accelerate the time for upper and lower gastrointestinal recovery following partial large or small bowel resection with primary anastomosis. One of the purposes of the REMS plan for Entereg is to reduce the risks of myocardial infarction observed with long term use. The FDA-approved REMS requires the drug manufacturer to submit assessments of the REMS on a quarterly basis during the first 18 months after REMS approval and annually thereafter.

Proposed REMS Supporting Documents

The REMS supporting document should provide a thorough explanation of the rational for and supporting information about the content of the proposed REMS. A template for a REMS supporting document is available on the FDA website.⁴⁰ The background section should describe what is known about the risk to be minimized by the REMS, such as the magnitude, severity, and frequency of the adverse event; whether there are particular populations at risk; the background incidence of the risk in the population likely to use the product; whether adverse events can be prevented or are reversible; and the benefits that would be preserved by implementation of the REMS.⁴¹ The REMS supporting documents also should include a goals section, supporting information about proposed REMS elements, and other relevant information.⁴²

RECOMMENDATIONS AND PRACTICAL TIPS

FDA REMS Guidance provides a useful blueprint for developing safety strategies and preparing a plan that will satisfy the requirements of Section 505.1 of the FDCA, as well as obtain FDA approval. As of April 15, 2010, FDA has approved 117 REMS.⁴³ Eighty-three REMS include only a Medication Guide. Thirty-four REMS include elements other than a Medication Guide, such as a Communication Plan and/or Elements to Assure Safe Use. Of these 34 REMS, twelve have Elements to Assure Safe Use.

A review of FDA approved REMS indicates what FDA is looking for in a proposed plan. First, it is important that the REMS specifically targets the newly identified potential risk. Second, the nature of the potential new risk determines the scope of the REMS. For instance, if the new risk concerns an increased risk of tendonitis and tendon rupture, then the goal of the REMS would be to inform patients about these potential increased risks, and the REMS elements would include a Medication Guide. If the potential risk includes medication errors because of similarities with other products on the market, then the REMS elements would include not only a Medication Guide, but also a Communication Plan.

The key to any successful plan, whether a REMS or something less formal, is to (1) identify issues and put them into context; (2) assess the risk and assess the benefits; (3) identify and analyze options; (4) select a strategy; (5) implement a strategy; and (6) evaluate results. Through this process the drug manufacturer should be working with FDA as well as keeping lines of communication open with healthcare providers and patients. The accompanying flowchart, taken from a Report to the FDA Commissioner from the Task Force on Risk Management, provides a useful illustration.⁴⁴

Based on this flowchart, consideration should be given to the recommendations below. These are general recommendations only. The author acknowledges that circumstances related to individual drugs and issues to be addressed will vary, as will steps appropriate to addressing these circumstances or issues.

Implement Safety-Related Sections of FDAAA

• Review Framework for Tracking Adverse Experiences
• Evaluate and Improve Framework
• Increase Capacity for Postmarket Safety Monitoring
• Develop and Improve Automated Systems for Managing Adverse Event Reports
• Integrate Pre- and Postmarket Information Systems
  • Provide uniform application of analytical tools, data entry, and editing
  • Make information readily available to every reviewer

Managing the Postmarketing Surveillance

• Multidisciplinary Team-based Approach to Drug Safety
• World Class Project Management
  • Ensures company focuses the same attention on postmarket safety issues as it does on premarket review
  • Creates a culture of safety
• Most Appropriate and Best Qualified Lead Regulatory Decisions
• Ensure that Significant Postmarket Safety Issues are Highest Priority

Strengthen the Science of Drug Safety

• Advance Postmarket Drug Safety Predictions
• Advance Signal Detection and Analysis
  • Identify signals of potential safety problems database of spontaneous reports (Distinguish noise from real concerns)
  • Develop background incidence rates for problems in a population
  • Develop new methodological tools for inference from available datasets
  • Enhance clinical and laboratory studies to develop new methods to improve product safety (e.g., biomarkers).
• Ensure Quality Manufacturing
  • Facilitate increased reliance on quality systems that will continually improve the quality of drugs and drug manufacturing.
  • Integrate enhanced quality management systems into review and inspection processes.
  • Encourage implementation of risk- based approaches that focus on critical areas. Ensure that regulatory review and inspection policies are performed by well-trained staff.

Expanding Communication and Information Flows

• Risk Communication within Company
• Risk Communication with FDA
• Risk Communication with Healthcare Providers
• Risk Communication with Patients

CONCLUSION

The vast majority of prescription drugs are safe and effective when used as labeled. As globalization, emerging areas of science, evolving technologies, and people’s growing interest in managing their health and well-being present the industry with unprecedented challenges and opportunities, risk evaluation and minimization strategies keep pharmaceutical companies one step ahead.

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[1] Wood, et al., “Making Medicines Safer—The Need for an Independent Drug Safety Board,” N. Engl. J. Med., 339: 1851-1854 (1998).

[2] 21 U.S.C. §§355(k), 355 (o), 355-1 (2008).

[3] 21 U.S.C. §§301 et seq.

[4] Pub. L. No. 110-85, title IX, 121 Stat. 823 (Sept. 27, 2007).

[5] See id. §§901-21.

[6] See 21 U.S.C. §§355 (o), 355-1.

[7] The REMS Guidance: (a) provides FDA’s current thinking on the format and content that industry should use for submission of proposed REMS; (b) describes each potential element; (c) includes preliminary information on the content of assessments and proposed modifications of approved REMS; (d) describes REMS policies for certain regulation situations; (e) informs industry about who to contact within FDA about a REMS; (f) indicates FDA websites where documents about approved REMS will be posted; and (g) provides an example of what an approved REMS might look like for a fictitious product. See REMS Guidance <http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf>. Last accessed April 21, 2010.

[8] Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research, FDA News Release dated Sept. 30, 2009. <http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm184399.htm>. Last accessed April 21, 2010.

[9] 21 U.S.C. §355-1.

[10] “New safety information” refers to “information derived from a clinical trial, an adverse event report, a postapproval study, or peer-reviewed biomedical literature; data derived from the postmarket risk identification and analysis system […] or other scientific data deemed appropriate by the Secretary about a serious risk or an unexpected serious risk associated with use of the drug that the Secretary has become aware of (that may be based on a new analysis of existing information) since the drug was approved, since the REMS was required, or since the last assessment of the approved REMS; or the effectiveness of the approved REMS obtained since the last assessment of the strategy.” Id. at §355-1 (b)(3).

[11] Id.

[12] Id.

[13] Fed. Reg. Vol. 73, No. 60 at 16313-14 (March 27, 2008).

[14] 21 U.S.C. §§331-333.

[15] REMS Guidance at 3.

[16] FDA Guidance for Industry, Development and Use of Risk Minimization Action Plans (March 2005), passim. For further discussion of RiskMAPs, see Pro Te: Solutio v.1, no.4, pp. 6-9.

[17] REMS Guidance at 3.

[18] Id.

[19] Id.

[20] Id. at 7.

[21] Id.

[22] Id. at 7.

[23] FDA’s Postmarket Drug Safety Information for Patients and Providers. <www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders>. April 6, 2010. Last accessed April 21, 2010.

[24] REMS Guidance at 9.

[25] Id.

[26] Id.

[27] 21 U.S.C. §355-1(e).

[28] 21 C.F.R. Part 208.

[29] REMS Guidance at 10.

[30] Id.

[31] 21 U.S.C. §505-1(e)(3); REMS Guidance at 10-11.

[32] REMS Guidance at 11.

[33] Id. at §355-1(f).

[34] Id. at §355-1(f)(1).

[35] Because laboratory testing or other documentation may be burdensome and disrupt patient care, this tool should be considered when products have unique benefits but unusual risks, such as irreversible disability or death, and when other measures are known or likely to be insufficient to minimize those risks.

[36] Id. at §355-1(f)(3)(A)-(F).

[37] Id. at §355-1(f)(3)(B),(C) and (D).

[38] 21 U.S.C. §355-1(d).

[39] Id.

[40] FDA’s Postmarket Drug Safety Information for Patients and Providers. <www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders>. April 6, 2010. Last accessed April 21, 2010.

[41] REMS Guidance at 16.

[42] Id. at 17-21.

[43] See FDA Approved RiskEvaluation and Mitigation Strategies. <http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm>. April 15, 2010. Last accessed April 21, 2010.

[44] Task Force on Risk Management, Report on Managing the Risks from Medical Product Use and Creating a Risk Management Framework at 74-75. May 1999. <http://www.fda.gov/Safety/SafetyofSpecificProducts/ucm180325.htm>. April 15, 2010. Last accessed April 21, 2010.

Finis