The FDA published three risk management guidance documents: (1) Premarketing Risk Assessment, (2) Development and Use of Risk Minimization Action Plans, and (3) Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. In issue three of Pro Te: Solutio, we discussed Premarketing Risk Assessment. In this article, we will discuss RiskMAPs.

In 2005, The U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, and Center for Biologics Evaluation and Research published Guidance for Industry: Development and Use of Risk Minimization Action Plans. This guidance provides nonbinding recommendations to develop, implement, and evaluate risk minimization action plans (RiskMAPs) for prescription drug products.

Risk management involves risk assessment and risk minimization and is an ongoing process. A sponsor must assess the prescription drug product’s risk/benefit ratio then implement tools to minimize risks while maintaining the product’s benefits. Once the tools are in place, a sponsor must decide if the product is effective and re-evaluate the risk/benefit ratio. Risk minimization aims to minimize a product’s risk while maintaining its benefits. For more than half of products, routine risk minimization measures are adequate to minimize risk and maintain benefits. However, some products may benefit from a RiskMAP.

I. What is a RiskMAP?

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.”¹ A RiskMAP focuses on one or more safety-related health results or aims and uses certain tools to attain the goals. When developing a RiskMAP, FDA recommends that the goals focus on achieving certain health results related to known risks. FDA recommends that sponsors’ goals be “pragmatic, specific, and measurable program objectives that result in processes or behaviors leading to achievement of RiskMAP goals.”² The objectives are intermediate steps to achieve the goal(s). Different systems or tools can be utilized in RiskMAPs.

Due to risk management’s ongoing process, a RiskMAP may be considered during the premarketing or postmarketing risk assessment. FDA recommends that sponsors utilize appropriate information such as (a) clinical development program data, post marketing surveillance, and Phase 4 studies and (b) the product’s intended population and use to determine if a RiskMAP should be considered. However, FDA may also recommend a RiskMAP based on its own interpretation of a sponsor’s risk information.

A. Risk Minimization Tools

There are three categories of RiskMAP tools:

• Targeted education and outreach
• Reminder systems
• Performance-linked access systems

Targeted education and outreach tools seek to increase awareness and responses of people who may stop or lessen a product’s risk (i.e. physicians or consumers). FDA recommends targeted education and outreach “(1) when routine risk minimization is known or likely to be insufficient to minimize product risks or (2) as a component of RiskMAPs using reminder or performance-linked access systems.”³ Sponsors can use targeted education and outreach in addition to their routine risk minimization programs without implementing a RiskMAP.

Some examples of targeted education and outreach are:

• Healthcare practitioner letters
• Patient package inserts
• Direct-to-consumer advertising emphasizing appropriate patient use.

Another category of tools is reminder systems. Reminder system tools prompt or remind healthcare practitioners and patients in prescribing or using products to minimize risk. FDA recommends reminder system tools in addition to targeted education and outreach “when targeted education and outreach tools are known or likely to be insufficient to minimize identified risks.”⁴ A consent form signed by a patient acknowledging that he/she read the material and agrees to follow instructions is an example of this type of tool.

Performance-linked access systems may disrupt a patient’s care because they link a product’s access to lab results or other documentation. FDA suggests sponsors consider tools in this category only when:

(1) products have significant or otherwise unique benefits in a particular patient group or condition, but unusual risks also exist, such as irreversible disability or death, and

(2) routine risk minimization measures, targeted education and outreach tools, and reminder systems are known or likely to be insufficient to minimize those risks.⁵

Some examples of performance-linked access systems tools include prescription only by specially certified practitioners and product dispensing limited to pharmacies or practitioners who elect to be specially certified.⁶

B. FDA Site to Describe RiskMAP Tools

FDA intends to assist sponsors by developing a RiskMAP website that will offer information for RiskMAP design and describe the current RiskMAP tools. FDA also intends to summarize information regarding the effectiveness of RiskMAP tools.

II. Developing a RiskMAP

FDA recommends sponsors use the tools in each of the three categories that are most appropriate for the product’s goals and objectives. FDA further recommends that sponsors consider factors in choosing the tools for a RiskMAP such as maintaining the broadest possible access to the product with the least burden to the healthcare system, identifying key stakeholders who have the ability to minimize risk and defining the stakeholders’ roles, considering tools based on effectiveness and trying to avoid unintended consequences of a particular tool. It is recommended that the RiskMAP design be:

• Compatible with current technology
• Applicable to both outpatient and inpatient use
• Accessible to patients in diverse locales, including non-urban settings
• Consistent with existing tools and programs or systems that have been shown to be effective with similar products, indications, or risks.⁷

FDA may also require tools to minimize risks for products that present serious risks to public health. Some of the tools that FDA may implement are FDA-requested product recalls, guidance documents, and judicial enforcement procedures.

III. RiskMAP Evaluation Process

FDA recommends that sponsors periodically evaluate their RiskMAP to determine the RiskMAP’s effectiveness. Sponsors are encouraged to use evidence-based performance measures to determine if goals have been achieved. FDA recommends that sponsors use “at least two different quantitative, representative, and minimally biased evaluation methods for each critical RiskMAP goal” to avoid skewing the assessment of the RiskMAP.⁸

FDA also recommends that sponsors go one step further to evaluate the effectiveness of the RiskMAP tools. Sponsors are encouraged to evaluate the effectiveness of tools prior to implementation, if possible. Two factors that play a significant part in tool effectiveness are acceptability and unintended consequences. After evaluating these aspects, a sponsor can improve the use of the tool.

Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research will develop internal manuals and policies for the review of RiskMAPs. Sponsors may submit RiskMAPs to FDA if desired. If a sponsor does so, FDA recommends that the sponsor describe when periodic evaluation results will be submitted to FDA. A sponsor is encouraged to send FDA “data, all analyses, conclusions regarding effectiveness, and any proposed modifications to the RiskMAP.”⁹ FDA would then assess the information provided and discuss the RiskMAP evaluation with the sponsor.

If a sponsor submits a RiskMAP before marketing approval, it will normally be submitted to the new drug application (NDA) or biologics license application (BLA). If a sponsor submits a RiskMAP in the postmarket phase, FDA recommends that the sponsor submit the RiskMAP as a supplement to the appropriate NDA or BLA. However, if a sponsor wants to submit a RiskMAP during Phases 1 to 3 studies, the sponsor can send the RiskMAP to the investigational new drug application.

IV. Conclusion

FDA offers several recommendations to sponsors to develop, implement, and evaluate RiskMAPs. Following these recommendations or implementing RiskMAP tools will help to minimize risks of products and to achieve the intended goals and objective of a product.

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[1] Guidance, at 5.

[2] Id.

[3] Id. at 8.

[4] Id. at 9.

[5] Id. at 10.

[6] Id.

[7] Id. at 11.

[8] Id. at 15.

[9] Id. at 17.

Finis