Guidance for Industry

Development and Use of Risk Minimization Action Plans

#########  {#section .TOC-9}

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**Center for Biologics Evaluation and Research (CBER)**

**March 2005**

**Clinical Medical**

Guidance for Industry

Development and Use of Risk Minimization Action Plans

*Additional copies are available from:*

*Office of Training and Communication*

*Division of Drug Information, HFD-240*

*Center for Drug Evaluation and Research*

*Food and Drug Administration*

*5600 Fishers Lane*

*Rockville, MD 20857*

*(Tel) 301-827-4573*

[*http://www.fda.gov/cder/guidance/index.htm*](http://www.fda.gov/cder/guidance/index.htm)

*or*

*Office of Communication, Training, and*

*Manufacturers Assistance, HFM-40*

*Center for Biologics Evaluation and Research*

*Food and Drug Administration*

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*[http://www.fda.gov/cber/guidelines.htm]{.underline}.*

*(Tel) Voice Information System at 800-835-4709 or 301-827-1800*

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**Center for Biologics Evaluation and Research (CBER)**

**March 2005**

**Clinical Medical**

## 

**TABLE OF CONTENTS**

# I. INTRODUCTION [1](#i.-introduction) {#i.-introduction-1 .TOC-1}

# II. BACKGROUND [2](#ii.-background) {#ii.-background-2 .TOC-1}

## A. PDUFA III's Risk Management Guidance Goal [2](#pdufa-iiis-risk-management-guidance-goal) {#a.-pdufa-iiis-risk-management-guidance-goal-2 .TOC-2}

## B. Overview of the Risk Management Draft Guidance Documents [2](#b.-overview-of-the-risk-management-guidance-documents) {#b.-overview-of-the-risk-management-draft-guidance-documents-2 .TOC-2}

# III. THE ROLE OF RISK MINIMIZATION AND RiskMAPs IN RISK MANAGEMENT [3](#iii.-the-role-of-risk-minimization-and-riskmaps-in-risk-management) {#iii.-the-role-of-risk-minimization-and-riskmaps-in-risk-management-3 .TOC-1}

## A. Relationship Between a Product's Benefits and Risks [4](#relationship-between-a-products-benefits-and-risks) {#a.-relationship-between-a-products-benefits-and-risks-4 .TOC-2}

## B. Determining an Appropriate Risk Minimization Approach [4](#determining-an-appropriate-risk-minimization-approach) {#b.-determining-an-appropriate-risk-minimization-approach-4 .TOC-2}

## C. Definition of Risk Minimization Action Plan (RiskMAP) [5](#definition-of-risk-minimization-action-plan-riskmap) {#c.-definition-of-risk-minimization-action-plan-riskmap-5 .TOC-2}

## D. Determining When a RiskMAP Should Be Considered 6 {#d.-determining-when-a-riskmap-should-be-considered-6 .TOC-2}

# IV. TOOLS FOR achieving RiskMAP goals and objectives [7](#iv.-tools-for-achieving-riskmap-goals-and-objectives) {#iv.-tools-for-achieving-riskmap-goals-and-objectives-7 .TOC-1}

## A. Relationship of RiskMAP Tools to Objectives and Goals [8](#relationship-of-riskmap-tools-to-objectives-and-goals) {#a.-relationship-of-riskmap-tools-to-objectives-and-goals-8 .TOC-2}

## B. Categories of RiskMAP Tools 8 {#b.-categories-of-riskmap-tools-8 .TOC-2}

### 1. Targeted Education and Outreach 9 {#targeted-education-and-outreach-9 .TOC-3}

### 2. Reminder Systems 10 {#reminder-systems-10 .TOC-3}

### 3. Performance-Linked Access Systems  {#performance-linked-access-systems .TOC-3}

## C. Description of RiskMAP Tools 10 {#c.-description-of-riskmap-tools-10 .TOC-2}

## D. Selecting and Developing the Best Tools 10 {#d.-selecting-and-developing-the-best-tools-10 .TOC-2}

## E. Mechanisms Available to the FDA to Minimize Risks 12 {#e.-mechanisms-available-to-the-fda-to-minimize-risks-12 .TOC-2}

# V. RiskMAP Evaluation: Assessing the Effectiveness of Tools and the Plan 12 {#v.-riskmap-evaluation-assessing-the-effectiveness-of-tools-and-the-plan-12 .TOC-1}

## A. Rationale for RiskMAP Evaluation 13 {#a.-rationale-for-riskmap-evaluation-13 .TOC-2}

## B. Considerations in Designing a RiskMAP Evaluation Plan 14 {#b.-considerations-in-designing-a-riskmap-evaluation-plan-14 .TOC-2}

### 1. Selecting Evidence-Based Performance Measures 14 {#selecting-evidence-based-performance-measures-14 .TOC-3}

### 2. Compensating for an Evaluation Method's Limitations 14 {#compensating-for-an-evaluation-methods-limitations-14 .TOC-3}

### 3. Evaluating the Effectiveness of Tools in Addition to RiskMAP Goals 15 {#evaluating-the-effectiveness-of-tools-in-addition-to-riskmap-goals-15 .TOC-3}

### 4. Evaluating RiskMAP Tools Prior to Implementation 15 {#evaluating-riskmap-tools-prior-to-implementation-15 .TOC-3}

## C. FDA Assessment of RiskMAP Evaluation Results 16 {#c.-fda-assessment-of-riskmap-evaluation-results-16 .TOC-2}

## D. Making Information From RiskMAP Evaluations Available to the Public 16 {#d.-making-information-from-riskmap-evaluations-available-to-the-public-16 .TOC-2}

# VI. COMMUNICATING WITH FDA REGARDING RiskMAP DEVELOPMENT AND DESIGN ISSUES 18 {#vi.-communicating-with-fda-regarding-riskmap-development-and-design-issues-18 .TOC-1}

# VII. REcommended Elements of a RISKMAP SUBMISSION TO FDA 19 {#vii.-recommended-elements-of-a-riskmap-submission-to-fda-19 .TOC-1}

## A. Contents of a RiskMAP Submission to FDA 19 {#a.-contents-of-a-riskmap-submission-to-fda-19 .TOC-2}

### 1. Background 19 {#background-19 .TOC-3}

### 2. Goals and Objectives 19 {#goals-and-objectives-19 .TOC-3}

### 3. Strategy and Tools 20 {#strategy-and-tools-20 .TOC-3}

### 4. Evaluation Plan 21 {#evaluation-plan-21 .TOC-3}

## B. Contents of a RiskMAP Progress Report 22 {#b.-contents-of-a-riskmap-progress-report-22 .TOC-2}

### 1. Summary 22 {#summary-22 .TOC-3}

### 2. Methodology 22 {#methodology-22 .TOC-3}

### 3. Data 22 {#data-22 .TOC-3}

### 4. Results 23 {#results-23 .TOC-3}

### 5. Discussion and Conclusions 23 {#discussion-and-conclusions-23 .TOC-3}

#####  {#section-2 .TOC-5 .unnumbered}

**Guidance for Industry**[^1]

**Development and Use of Risk Minimization Action Plans**

This guidance represents the Food and Drug Administration\'s (FDA\'s)
current thinking on this topic. It does not create or confer any rights
for or on any person and does not operate to bind FDA or the public. You
can use an alternative approach if the approach satisfies the
requirements of the applicable statutes and regulations. If you want to
discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA
staff, call the appropriate number listed on the title page of this
guidance.

# 

# 

# I. INTRODUCTION

This document provides guidance to industry on the development,
implementation, and evaluation of risk minimization action plans for
prescription drug products, including biological drug products.[^2] In
particular, it gives guidance on (1) initiating and designing plans
called risk minimization action plans or RiskMAPs to minimize identified
product risks, (2) selecting and developing tools to minimize those
risks, (3) evaluating RiskMAPs and monitoring tools, and (4)
communicating with FDA about RiskMAPs, and (5) the recommended
components of a RiskMAP submission to FDA.

FDA\'s guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe the
Agency\'s current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements
are cited. The use of the word *should* in Agency guidances means that
something is suggested or recommended, but not required.

# 

# II. BACKGROUND

## PDUFA III's Risk Management Guidance Goal

On June 12, 2002, Congress reauthorized, for the second time, the
Prescription Drug User Fee Act (PDUFA III). In the context of PDUFA III,
FDA agreed to satisfy certain performance goals. One of those goals was
to produce guidance for industry on risk management activities for drug
and biological products. As an initial step towards satisfying that
goal, FDA sought public comment on risk management. Specifically, FDA
issued three concept papers. Each paper focused on one aspect of risk
management, including (1) conducting premarketing risk assessment, (2)
developing and implementing risk minimization tools, and (3) performing
postmarketing pharmacovigilance and pharmacoepidemiologic assessments.
In addition to receiving numerous written comments regarding the three
concept papers, FDA held a public workshop on April 9--11, 2003, to
discuss the concept papers. FDA considered all of the comments received
in developing the three draft guidance documents on risk management
activities. The draft guidance documents were published on May 5, 2004,
and the public was provided with an opportunity to comment on them until
July 6, 2004. FDA considered all of the comments received in producing
the final guidance documents:

*1. Premarketing Risk Assessment* *(Premarketing Guidance)*

*2. Development and Use of Risk Minimization Action Plans* *(RiskMAP
Guidance)*

*3. Good Pharmacovigilance Practices and Pharmacoepidemiologic
Assessment (Pharmacovigilance Guidance)*

## B. Overview of the Risk Management Guidance Documents

Like the concept papers and draft guidances that preceded them, each of
the three final guidance documents focuses on one aspect of risk
management. The *Premarketing Guidance* and the *Pharmacovigilance
Guidance* focus on premarketing and postmarketing risk assessment,
respectively. The *RiskMAP Guidance* focuses on risk minimization.
Together, risk assessment and risk minimization form what FDA calls
*risk management*. Specifically, risk management is an iterative process
of (1) assessing a product's benefit-risk balance, (2) developing and
implementing tools to minimize its risks while preserving its benefits,
(3) evaluating tool effectiveness and reassessing the benefit-risk
balance, and (4) making adjustments, as appropriate, to the risk
minimization tools to further improve the benefit-risk balance. This
four-part process should be continuous throughout a product's lifecycle,
with the results of risk assessment informing the sponsor's decisions
regarding risk minimization.

When reviewing the recommendations provided in this guidance, sponsors
and applicants should keep the following points in mind:

-   Many recommendations in this guidance are ***not*** intended to be
    generally applicable to all products.

> Industry already performs risk assessment and risk minimization
> activities for products during development and marketing. The Federal
> Food, Drug, and Cosmetic Act (FDCA) and FDA implementing regulations
> establish requirements for ***routine*** risk assessment and risk
> minimization (see e.g., FDA requirements for professional labeling and
> adverse event monitoring and reporting). As a result, many of the
> recommendations presented here focus on situations in which a product
> may pose a clinically important and unusual type or level of risk. To
> the extent possible, we have specified in the text whether a
> recommendation is intended for all products or only this subset of
> products.

-   It is of critical importance to protect patients and their privacy
    during the generation of safety data and the development of risk
    minimization action plans.

> During all risk assessment and risk minimization activities, sponsors
> must comply with applicable regulatory requirements involving human
> subjects research and patient privacy.[^3]

-   To the extent possible, this guidance reflects FDA's commitment to
    harmonization of international definitions and standards.

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-   When planning risk assessment and risk minimization activities,
    sponsors should consider input from healthcare participants likely
    to be affected by these activities (e.g., from consumers,
    pharmacists and pharmacies, physicians, nurses, and third-party
    payers).

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-   There are points of overlap among the three guidances.

> We have tried to note in the text of each guidance when areas of
> overlap occur and when referencing one of the other guidances might be
> useful.

# III. THE ROLE OF RISK MINIMIZATION AND RiskMAPs IN RISK MANAGEMENT

As described in section II.B, FDA views risk management as an iterative
process encompassing the assessment of risks and benefits, the
minimization of risks, and the maximization of benefits. Specifically,
the premarketing guidance and the pharmacovigilance guidance discuss how
sponsors should engage in evidence-based risk assessment for all
products in development and on the market to define the nature and
extent of a product's risks in relation to its benefits. The goal of
risk minimization is to minimize a product's risks while preserving its
benefits. For the majority of products, routine risk minimization
measures are sufficient to minimize risks and preserve benefits. Only a
few products are likely to merit consideration for additional risk
minimization efforts (see section III.D). Efforts to maximize benefits
to improve the overall balance of risks and benefits can be pursued in
concert with risk minimization efforts and can be discussed with FDA.

## Relationship Between a Product's Benefits and Risks 

The statutory standard for FDA approval of a product is that the product
is safe and effective for its labeled indications under its labeled
conditions of use (see sections 201(p)(1) and 505(d) of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321(p)(1) and 355(d)). FDA's
determination that a product is safe, however, does not suggest an
absence of risk. Rather, a product is considered to be safe if the
clinical significance and probability of its beneficial effects outweigh
the likelihood and medical importance of its harmful or undesirable
effects. In other words, a product is considered safe if it has an
appropriate benefit-risk balance for the intended population and use.

Benefit and risk information emerges continually throughout a product's
lifecycle (i.e., during the investigational and marketing phases) and
can reflect the results of both labeled and off-label uses. Benefits and
risks can result in a range of corresponding positive and negative
effects on patient outcomes that may (1) be cosmetic, symptomatic, or
curative; (2) alter the course of the disease; or (3) affect mortality.
Benefits and risks are difficult to quantify and compare because they
may apply to different individuals and are usually measured and valued
differently. Examples of factors to weigh are (1) population risks and
benefits, (2) individual benefits from treatment, (3) risks of
nontreatment or alternative products, and (4) modest population benefits
in the context of a serious adverse effect that occurs rarely or
unpredictably. Benefits as well as risks are also patient-specific and
are influenced by such factors as (1) the severity of the disease being
treated, (2) the outcome of the disease if untreated, (3) the
probability and magnitude of any treatment effect, (4) existing
therapeutic options, and (5) the individual's understanding of risks and
benefits and the value they attach to each of them. Thus, assessment and
comparison of a product's benefits and risks is a complicated process
that is influenced by a wide range of societal, healthcare, and
individualized patient factors.

## Determining an Appropriate Risk Minimization Approach 

To help ensure safe and effective use of their products, sponsors have
always sought to maximize benefits and minimize risks. FDA believes
that, for most products, routine risk minimization measures are
sufficient. Such measures involve, for example, FDA-approved
professional labeling describing the conditions in which the drug can be
used safely and effectively, updated from time to time to incorporate
information from postmarketing surveillance or studies revealing new
benefits (e.g., new indications or formulations) or risk concerns.
Efforts to make FDA-approved professional labeling clearer, more
concise, and better focused on information of clinical relevance reflect
the Agency's belief that communication of risks and benefits through
product labeling is the cornerstone of risk management efforts for
prescription drugs. [^4] For most products, routine risk management will
be sufficient and a RiskMAP need not be considered.

There are, however a small number of products for which a RiskMAP should
be considered (see section III.D). FDA recommends that RiskMAPs be used
judiciously to minimize risks without encumbering drug availability or
otherwise interfering with the delivery of product benefits to patients.

This guidance focuses on the development, implementation, and evaluation
of RiskMAPs.

## Definition of Risk Minimization Action Plan (RiskMAP)

As used in this document, the term RiskMAP means a strategic safety
program designed to meet specific *goals* and *objectives* in minimizing
known risks of a product while preserving its benefits. A RiskMAP
targets one or more safety-related health outcomes or goals and uses one
or more *tools* to achieve those goals.[^5] A RiskMAP could also be
considered as a selectively used type of Safety Action Plan as defined
in the International Conference on Harmonization (ICH) guidance *E2E:
Pharmacovigilance Planning* (E2E guidance).[^6]

FDA recommends that RiskMAP goals target the achievement of particular
health outcomes related to known safety risks. FDA suggests that
sponsors state goals in a way that aims to achieve maximum risk
reduction. The following are examples of RiskMAP goals: "patients on X
drug should not also be prescribed Y drug" or "fetal exposures to Z drug
should not occur." FDA recommends that goals be stated in absolute
terms. Although it might not be possible to ensure that absolutely no
one on X drug receives Y drug, FDA believes that a *goal,* as the term
implies, is a statement of the ideal outcome of a RiskMAP.

FDA recommends that RiskMAP goals be translated into pragmatic,
specific, and measurable program *objectives* that result in processes
or behaviors leading to achievement of the RiskMAP goals. Objectives can
be thought of as intermediate steps to achieving the overall RiskMAP
goal. A RiskMAP goal can be translated into different objectives,
depending upon the frequency, type, and severity of the specific risk or
risks being minimized. For example, a goal may be the elimination of
dangerous concomitant prescribing. The objectives could include lowering
physician co-prescribing rates and/or pharmacist co-dispensing rates. As
described in greater detail in section IV, many processes or systems to
minimize known safety risks are available or under development for use
in RiskMAPs. These systems include:

-   targeted education and outreach to communicate risks and appropriate
    safety behaviors to healthcare practitioners or patients

-   reminder systems, processes, or forms to foster reduced-risk
    prescribing and use

-   performance-linked access systems that guide prescribing,
    dispensing, and use of the product to target the population and
    conditions of use most likely to confer benefits and to minimize
    particular risks

For certain types of risks (e.g., teratogenicity of category X drug
products), it may be possible to develop systems with similar processes
and procedures that can be used industrywide.

The use of these systems can occur outside of a RiskMAP. For example,
while most drugs do not need a RiskMAP, many would still benefit from a
program of physician and patient education and outreach. At times,
communication of potential product risks may be warranted before a
sponsor agrees to do a RiskMAP or an agreed upon RiskMAP is completed.

## Determining When a RiskMAP Should Be Considered[^7] 

As described in the premarketing guidance and pharmacovigilance
guidance*,* evidence-based risk identification, assessment, and
characterization are processes that continue throughout a product's
lifecycle. Therefore, a risk warranting the consideration of a RiskMAP
could emerge during premarketing or postmarketing risk assessment.[^8]
The Agency recommends that the appropriate information for consideration
in making such a determination include, as applicable, (1) data from the
clinical development program, postmarketing surveillance, and phase 4
studies, and (2) the product's intended population and use.

Although it is expected and hoped that sponsors will determine when a
RiskMAP would be appropriate, FDA may recommend a RiskMAP based on the
Agency\'s own interpretation of risk information.

Decisions to develop, submit, or implement a RiskMAP are always made on
a case-by-case basis, but several considerations are common to most
determinations of whether development of a RiskMAP may be desirable:

-   Nature and rate of known risks versus benefits: Comparing the
    characteristics of the product's adverse effects and benefits may
    help clarify whether a RiskMAP could improve the product's
    benefit-risk balance. The characteristics to be weighed might
    include the (1) types, magnitude, and frequency of risks and
    benefits; (2) populations at greatest risk and/or those likely to
    derive the most benefit; (3) existence of treatment alternatives and
    their risks and benefits; and (4) reversibility of adverse events
    observed.

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-   Preventability of adverse effects: Serious adverse effects that can
    be minimized or avoided by preventive measures around drug
    prescribing are the preferred candidates for RiskMAPs.

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-   Probability of benefit: If factors are identified that can predict
    effectiveness, a RiskMAP could help encourage appropriate use to
    increase benefits relative to known risks.

Consider the following examples:

-   Opiate drug products have important benefits in alleviating pain but
    are associated with significant risk of overdose, abuse, and
    addiction. The Agency recommends that sponsors of Schedule II
    controlled substances, including Schedule II extended release or
    high concentration opiate drug products, consider developing
    RiskMAPs for these products.

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-   Drugs that provide important benefits, but that are human teratogens
    would often be appropriate for a RiskMAP to minimize in utero
    exposure.

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-   Some drugs may warrant RiskMAP consideration because safe and
    effective use call for specialized healthcare skills, training, or
    facilities to manage the therapeutic or serious side effects of the
    drug.

Involving all stakeholders during the initial phases of considering
whether a RiskMAP is appropriate allows input and buy-in by all parties
who will later have roles in implementing the RiskMAP. If a RiskMAP is
appropriate, stakeholders can help shape the RiskMAP to foster its
success in the healthcare delivery environment. Therefore, we recommend
public discussion about the appropriateness of a RiskMAP through the FDA
advisory committee process. Such public advisory committee meetings can
also be used to address (1) whether a RiskMAP is appropriate, (2) what
the goals and objectives of the RiskMAP could be (see footnote 6), (3)
the circumstances under which a RiskMAP tool might be revised or
terminated, and (4) whether a RiskMAP itself is no longer appropriate.
The FDA advisory committee structure and processes are well suited to
foster such discussions as they arise on a case-by-case basis.

# IV. TOOLS FOR achieving RiskMAP goals and objectives 

A risk minimization tool is a process or system intended to minimize
known risks. Tools can communicate particular information regarding
optimal product use and can also provide guidance on prescribing,
dispensing, and/or using a product in the most appropriate situations or
patient populations. A number of tools are available; FDA encourages and
anticipates the development of additional tools.

## Relationship of RiskMAP Tools to Objectives and Goals 

Risk minimization tools are designed to help achieve one or more RiskMAP
objectives that are directed at the overall RiskMAP goal or goals. One
or more tools can be chosen to achieve a particular objective. For
example, a goal might be that patients with condition A should not be
exposed to product B. An objective for achieving this goal might be to
communicate to patients that if they have condition A, they should not
take product B. Depending on the likelihood and severity of the adverse
event associated with product B in a patient with condition A, a variety
of tools could be applied to achieve this objective. One possible tool
would be patient labeling explaining that a patient with condition A
should not take product B. On the other hand, if the potential harm to a
patient with condition A is severe and/or likely to occur, a more active
tool may be appropriate. For example, the sponsor could choose to
develop a patient agreement where, before receiving the product, the
patient formally acknowledges their understanding and/or agreement not
to take product B if he or she has condition A.

## Categories of RiskMAP Tools 

A variety of tools are currently used in risk minimization plans. These
fall within three categories: (1) targeted education and outreach, (2)
reminder systems, and (3) performance-linked access systems. A RiskMAP
might include tools from one or more categories, depending on its risk
minimization goals. FDA notes that the use of tools in different
categories does not imply greater or lesser safety risks, but rather
indicates the particular circumstances put in place to achieve the
objectives and goals.

> *1. Targeted Education and Outreach*

### 

FDA recommends that sponsors consider tools in the targeted education
and outreach category (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 (see sections IV.B.2 and 3 below).

Tools in this category employ specific, targeted education and outreach
efforts about risks to increase appropriate knowledge and behaviors of
key people or groups (e.g., healthcare practitioners and consumers) that
have the capacity to prevent or mitigate the product risks of concern.

FDA acknowledges that tools in this category are occasionally used for
products where the benefit/risk balance does not necessarily warrant a
RiskMAP. Educational efforts by sponsors might include one or more of
the tools described below without a RiskMAP being in place. Sponsors are
encouraged to continue using tools, such as education and outreach, as
an extension of their routine risk minimization efforts even without a
RiskMAP.

Examples of tools in this category are as follows:

-   healthcare practitioner letters

-   training programs for healthcare practitioners or patients

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-   continuing education for healthcare practitioners such as
    product-focused programs developed by sponsors and/or
    sponsor-supported accredited CE programs

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-   prominent professional or public notifications

-   patient labeling such as Medication Guides and patient package
    inserts

-   promotional techniques such as direct-to-consumer advertising
    highlighting appropriate patient use or product risks

-   patient-sponsor interaction and education systems such as disease
    management and patient access programs

In addition to informing healthcare practitioners and patients about
conditions of use contributing to product risk, educational tools can
inform them of conditions of use that are important to achieve the
product's benefits. For example, a patient who takes a product according
to labeled instructions is more likely to achieve maximum product
effectiveness. On the other hand, deviations from the labeled dose,
frequency of dosing, storage conditions, or other labeled conditions of
use might compromise the benefit achieved, yet still expose the patient
to product-related risks. Risks and benefits can have different
dose-response relationships. Risks can persist and even exceed benefits
when products are used in ways that minimize effectiveness. Therefore,
educational tools can be used to explain how to use products in ways
that both maximize benefits and minimize risks.

### 

### 2. Reminder Systems

We recommend that tools in the reminder systems category be used in
addition to tools in the targeted education and outreach category when
targeted education and outreach tools are known or likely to be
insufficient to minimize identified risks.

Tools in this category include systems that prompt, remind, double-check
or otherwise guide healthcare practitioners and/or patients in
prescribing, dispensing, receiving, or using a product in ways that
minimize risk. Examples of tools in this category are as follows:

-   Patient education that includes acknowledgment of having read the
    material and an agreement to follow instructions. These agreements
    are sometimes called *consent* forms.

-   Healthcare provider training programs that include testing or some
    other documentation of physicians\' knowledge and understanding.

-   Enrollment of physicians, pharmacies, and/or patients in special
    data collection systems that also reinforce appropriate product use.

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-   Limited number of doses in any single prescription or limitations on
    refills of the product.

-   Specialized product packaging to enhance safe use of the product.

-   Specialized systems or records that are used to attest that safety
    measures have been satisfied (e.g., prescription stickers, physician
    attestation of capabilities).

### 3. Performance-Linked Access Systems

### 

Performance-linked access systems include systems that link product
access to laboratory testing results or other documentation. Tools in
this category, because they are very burdensome and can disrupt usual
patient care, should be considered 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.

Examples of tools in this category include:

-   the sponsor\'s use of compulsory reminder systems, as described in
    the previous section (e.g., the product is not made available unless
    there is an agreement or acknowledgment, documented qualifications,
    enrollment, and/or appropriate testing or laboratory records)

-   prescription only by specially certified healthcare practitioners

-   product dispensing limited to pharmacies or practitioners that elect
    to be specially certified

-   product dispensing only to patients with evidence or other
    documentation of safe-use conditions (e.g., lab test results)

Performance-linked access systems should seek to avoid unnecessary or
unintended restrictions or fragmentation of healthcare services that may
limit access by physicians, pharmacists, or patients, or that may lead
to discontinuities in medical or pharmacy care.

## Description of RiskMAP Tools 

FDA plans to develop a RiskMAP Web site that will include (1)
descriptions of tools that are currently used in RiskMAPs and (2) other
information relevant to RiskMAP development (see section IV.D below).
The information will be made available consistent with federal law and
regulations governing disclosure of information by FDA to the public.
The list of tools will be intended to assist sponsors in designing a
RiskMAP but will not suggest that the listed tools are FDA-approved or
-validated. On the contrary, FDA does not suggest that the tools listed
on the Web site are the only tools that could be useful and encourages
sponsors to develop tools that may be optimal for their particular
products. See also Section V.D on making information from RiskMAP
evaluations available to the public.

## Selecting and Developing the Best Tools 

Given the variety of available tools, FDA recommends that a sponsor
carefully consider which tool or tools are most appropriate, given the
goals and objectives of its product's RiskMAP. A tool could be developed
or selected based on its individual impact and/or because of its impact
when used in coordination with other tools. Generally, the best tools
would be those that have a high likelihood of achieving their objective
based on positive performance in other RiskMAPs or in similar settings
and populations. Relevant non-RiskMAP evidence and experience can be
found in healthcare quality initiatives, public health education and
outreach, marketing, and other outcomes-based research (see section V
for a more detailed discussion of evaluating tools' effectiveness).

Although FDA suggests that the best tool or tools be selected on a
case-by-case basis, the following are generally applicable
considerations in designing a RiskMAP. In choosing tools for a RiskMAP,
FDA recommends that sponsors:

-   Maintain the widest possible access to the product with the least
    burden to the healthcare system that is compatible with adequate
    risk minimization (e.g., a reminder system tool should not be used
    if targeted education and outreach would likely be sufficient).

-   Identify the key stakeholders who have the capacity to minimize the
    product's risks (such as physicians, pharmacists, pharmacies,
    nurses, patients, and third-party payers) and define the anticipated
    role of each group.

-   Seek input from the key stakeholders on the feasibility of
    implementing and accepting the tool in usual healthcare practices,
    disease conditions, or lifestyles, if possible. Examples of
    considerations could include (but would not be limited to) patient
    and healthcare practitioner autonomy, time effectiveness, economic
    issues, and technological feasibility.

-   Acknowledge the importance of using tools with the least burdensome
    effect on healthcare practitioner-patient, pharmacist-patient,
    and/or other healthcare relationships.

-   Design the RiskMAP to be:

    1.  compatible with current technology

    2.  applicable to both outpatient and inpatient use

    3.  accessible to patients in diverse locales, including non-urban
        settings

    4.  consistent with existing tools and programs, or systems that
        have been shown to be effective with similar products,
        indications, or risks

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-   Select tools based on available evidence of effectiveness in
    achieving the specified objective (e.g., tools effectively used in
    pregnancy prevention).

-   Consider indirect evidence of tool effectiveness in a related area
    that supports the rationale, design, or method of use (e.g., tools
    applied in modifying patient or healthcare practitioner behaviors in
    medical care settings).

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-   Consider, and seek to avoid, unintended consequences of tool
    implementation that obstruct risk minimization and product benefit,
    such as obstructing patient access or driving patients to seek
    alternative product sources (e.g., Internet sales, counterfeit
    products) or less appropriate products.

FDA recognizes that once it approves a product for marketing, healthcare
practitioners are the most important managers of product risks. FDA
believes that by including information in the FDA-approved professional
labeling on the conditions in which medical products can be used safely
and effectively by their intended population and for their intended use
or uses, the Agency and the sponsor encourage healthcare practitioners
to prescribe medical products in circumstances that yield a favorable
benefit-risk balance. However, as the Agency has long recognized, the
FDCA and FDA regulations establish requirements governing the safety and
effectiveness of medical products. FDA does not have authority under
these provisions to control decisions made by qualified healthcare
practitioners to prescribe products for conditions other than those
described in FDA-approved professional labeling, or to otherwise
regulate medical or surgical practice.

## Mechanisms Available to the FDA to Minimize Risks

This guidance focuses on the tools that industry can incorporate into
RiskMAPs. As noted, FDA has a variety of risk management measures at its
disposal under the FDCA and FDA regulations (see e.g., FDA requirements
for professional labeling and adverse event monitoring and reporting).

FDA must occasionally invoke other mechanisms to minimize the risks from
medical products that pose serious risks to the public health. These
tools include:

-   FDA-requested product recalls, warning and untitled letters, and
    import alerts

-   safety alerts, guidance documents, and regulations

-   judicial enforcement procedures such as seizures or injunctions

Further information on these mechanisms is available on the Internet at
http://www.fda.gov.

# V. RiskMAP Evaluation: Assessing the Effectiveness of Tools and the Plan

As FDA and sponsors seek additional knowledge about the design,
effectiveness, burdens, and potential unintended consequences of
RiskMAPs, it is important to collect as much information as possible on
plan performance. RiskMAPs and their component objectives and tools
should be monitored and evaluated in a timely manner to identify areas
for improvement.

## 

## Rationale for RiskMAP Evaluation

At least two studies have documented poor or limited implementation and
effectiveness of traditional risk minimization tools. In particular, the
studies examined situations in which labeling changes (with or without
Dear Healthcare Practitioner letters) were used to reduce safety
problems.[^9] The iterative process of risk assessment, risk
minimization, and reevaluation previously described is intended to avoid
repeating these experiences by identifying poorly performing or
ineffective RiskMAPs or RiskMAP components as soon as possible.
Ultimately, RiskMAP evaluation is intended to ensure that the energy and
resources expended on risk minimization are actually achieving the
desired goals of continued benefits with minimized risks. FDA considers
evaluation of the effectiveness of a RiskMAP to be important and
recommends that every RiskMAP contain a plan for periodically evaluating
its effectiveness after implementation (see section VII for a detailed
discussion of RiskMAP submissions to FDA).[^10]

The evaluation of RiskMAPs can take several forms. Most critical is
determining the performance of the overall RiskMAP in achieving its
targeted health outcomes or goals. Separate but related assessments can
be done for (1) individual tool performance, (2) acceptability of
RiskMAP tools by consumers and healthcare practitioners, and (3)
compliance with important RiskMAP processes or procedures.

Generally, FDA anticipates that RiskMAP evaluations would involve the
analysis of observational or descriptive data. The specific types of
data gathered in a RiskMAP evaluation will determine whether it would be
appropriate to include a statistical analysis of evaluation results.

## Considerations in Designing a RiskMAP Evaluation Plan

FDA recommends that RiskMAP evaluation plans be tailored to the specific
product and designed to assess whether the RiskMAP's goals have been
achieved through its objectives and tools. The following are generally
applicable guidelines for sponsors designing RiskMAP evaluation plans.

### Selecting Evidence-Based Performance Measures

The Agency recommends that sponsors select well-defined, evidence-based,
and objective performance measures tailored to the particular RiskMAP to
determine whether the RiskMAP's goals or objectives are being achieved.
An appropriate measure could be a number, percentage, or rate of an
outcome, event, process, knowledge, or behavior. Ideally, the chosen
measure would directly measure the RiskMAP's health outcome goal. For
example, for a RiskMAP with a goal of preventing a particular
complication outcome from product use, a sample performance measure
could be the complication rate. For evaluation purposes, a target for
that measure could be established to be no more than a specified number
or rate of that complication. In some cases, however, a health outcome
cannot be practically or accurately measured. In those cases, other
measures can be used that are closely related to the health outcome,
such as the following:

-   Surrogates for health outcome measures (e.g., emergency room visits
    for an adverse consequence, pregnancy test results for determining
    if pregnancy occurred). The sensitivity, specificity, and predictive
    value of surrogate markers should be established before their use as
    a performance measure.

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-   Process measures that reflect desirable safety behaviors (e.g.,
    performance of recommended laboratory monitoring, signatures
    attesting to knowledge or discussions of risk).

-   Assessments of comprehension, knowledge, attitudes, and/or desired
    safety behaviors about drug safety risks (e.g., provider,
    pharmacist, or patient surveys).

    FDA recommends that the validity of a measure be judged by how
    closely it is related to the desired health outcome goal of the
    RiskMAP. Simply stated, the more closely related a measure is to the
    RiskMAP goal, the greater its degree of validity. For example, if
    the RiskMAP goal is avoidance of liver failure, then ascertainment
    of the rate of liver failure in the user population would be a
    highly valid performance measure. Hospitalization for severe liver
    injury would be another, but less direct, assessment of the RiskMAP
    goal. The frequency of liver function monitoring in users could be
    used to see if RiskMAP processes to prevent liver failure were being
    followed, but since liver function monitoring may not be tightly
    linked to the occurrence of liver failure, such process monitoring
    would have limited validity as an indicator of successful prevention
    of liver failure.

### 2. Compensating for an Evaluation Method's Limitations

Most evaluation measures have limitations. FDA suggests that, in
choosing among evaluation methods and measures, sponsors consider their
strengths and limitations. The following are examples of some of the
limitations of evaluation methods:

-   Spontaneous adverse event data are a potentially biased outcome
    measure because reporting of adverse events varies due to many
    factors and represents an unknown and variable fraction of the
    adverse outcomes that are actually occurring. As a result,
    systematic data collection or active surveillance of adverse events
    in populations with well-defined exposure to the product would be
    preferred for purposes of evaluation.

-   Population-based evaluation methods can use administrative or
    claims-based data systems that capture service or payment claims to
    measure rates of events, although it is usually recommended that
    medical records be examined to validate the actual occurrence of
    coded diagnoses and procedures. Administrative data may come from
    various insurers, purchasing groups, or networks that are tied to
    employment or entitlement programs, so it is important to determine
    if an administrative data system is representative of the general
    population being treated with the product. Also, unless enrollment
    in an administrative claims system is large, the number of patients
    exposed to any single product is likely to be limited, as will be
    the power to detect uncommon adverse events.[^11] In addition, there
    may be data processing time lags of several months or longer before
    administrative data can be retrieved and analyzed.

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-   Active surveillance using sentinel reporting sites may be useful for
    evaluating adverse events, but it is costly and may not detect rare
    events. Surveys of healthcare practitioners or patients using
    various modes (in-person, mail, telephone, electronic) can be
    another useful form of active surveillance of knowledge, attitudes,
    policies, and practices of healthcare practitioners, institutions,
    and patients about recommended RiskMAP tools and their associated
    processes. However, issues relating to response rates,
    representativeness, and reporting biases may limit the accuracy of
    survey results.[^12]

    These examples illustrate how using only one evaluation method could
    skew assessment of the performance of a RiskMAP. Therefore, FDA
    recommends that, whenever feasible, sponsors design evaluation plans
    to include at least two different quantitative, representative, and
    minimally biased evaluation methods for each critical RiskMAP goal.
    By using two methods, one method can compensate for the limitations
    of the other. For example, surveys of healthcare practitioners may
    indicate high compliance with systems for preventing product
    complications. However, systematically collected or spontaneous
    reports might show that product complications are occurring, thus
    suggesting that prevention efforts in actual practice may be
    ineffective or incompletely applied. If it is not practical to use
    two complementary and representative methods, FDA suggests using
    other quantitative methods such as multiple site sampling or audits
    that aim for high coverage or response rates by the affected
    population. If RiskMAPs use multiple tools or interventions, it may
    be useful to consider using evaluation methods applicable to the
    program as a whole. For example, a systematic program evaluation
    model, such as Failure Modes and Effect Analysis (FMEA),[^13]^,^
    [^14] can provide a framework for evaluating the individual RiskMAP
    components and the relative importance of each in achieving the
    overall RiskMAP goal or goals.

### 3. Evaluating the Effectiveness of Tools in Addition to RiskMAP Goals

FDA recommends that sponsors periodically evaluate each RiskMAP tool to
ensure it is materially contributing to the achievement of RiskMAP
objectives or goals. Tools that do not perform well may compromise
attainment of RiskMAP goals, add unnecessary costs or burdens, or limit
access to product benefits without minimizing risks. Tools that are
implemented incompletely or in a substandard fashion could result in
additional tools being adopted unnecessarily. For all these reasons,
evaluating tools is important. Data from such evaluations may make it
possible to improve a tool's effectiveness or eliminate the use of a
tool that fails to contribute to achieving a RiskMAP goal. By
eliminating ineffective tools, resources can be concentrated on useful
tools.

Distinguishing between the evaluation of RiskMAP goals and tools is
important because the achievement of goals and the performance of tools
may not be linked. For example, the overall goal of a RiskMAP may be
achieved despite individual tools performing poorly. The reverse
situation may also occur, with component tools performing well but
without appropriate progress in achieving the RiskMAP goal. This
situation may occur if a surrogate objective correlates poorly to the
desired health outcome. The first example (i.e., the RiskMAP goal may be
achieved despite individual tools performing poorly) may afford an
opportunity to discontinue a tool, whereas its converse may trigger the
implementation of new or improved tools, or even a redesign of the
overall RiskMAP. Two important factors that contribute to tool
effectiveness are its acceptability and unintended consequences. Since
tool performance will often depend upon the understanding, cooperation,
efforts, and resources of healthcare providers, pharmacists, and
patients, evaluation of acceptability and unintended consequences for
individual tools may help to improve the use of tools and thus their
performance.

### 4. Evaluating RiskMAP Tools Prior to Implementation

FDA recommends that, to the extent possible, sponsors evaluate tools for
effectiveness before implementation. As discussed in section IV.D, FDA
suggests that in selecting tools to include in a RiskMAP, a sponsor
consider tools that are likely to be effective. For example, the success
of potential RiskMAP tools might be predicted to some extent by evidence
in the scientific literature or from their use in other RiskMAPs.
Application of computer modeling or simulation techniques may also
assist in projecting potential outcomes of implementation of various
combinations of RiskMAP tools.

Besides using literature evidence and past RiskMAP experience to
identify tools with a known track record of effectiveness, sponsors can
pretest or pilot test a tool before implementation. Such testing,
ideally with a comparison group or time period, can help to assess
comprehension, acceptance, feasibility, and other factors that influence
how readily RiskMAP tools will fit into patient lifestyles and the
everyday practices of healthcare practitioners. Pretesting can
potentially avoid wasted time, expense, and escalation of RiskMAP tools
by discriminating between high- and low-performing tools. For example,
if a preventable risk is identified in Phase 2 trials, Phase 3 trials
could provide an opportunity to pretest targeted education and outreach
tools.

FDA recommends that pretesting methods be chosen on a case-by-case
basis, depending on the product, tool, objective, and goal. For example,
in certain preapproval situations, large simple safety studies may be a
means of generating useful information about the effectiveness of
RiskMAP tools in conditions close to actual practice.[^15] On the other
hand, for certain tools such as targeted education and outreach,
published *best practices* could be used as guidelines for
implementation. If time is particularly limited, multiple interviews or
focus group testing can assist in determining acceptance or
comprehension of a RiskMAP tool by major stakeholder groups. This action
might be particularly useful in situations where risks and benefits are
closely matched, and RiskMAP goals may include the making of informed
therapeutic choices by patients and prescribers

FDA recognizes that, in some cases, tools cannot be pretested for
logistical reasons. Pretesting of tools may not be practical in
situations in which newly recognized adverse events dictate the
importance of rapid implementation of a RiskMAP after approval and
marketing. In such instances, sponsors should seek to employ tools with
a proven track record of effectiveness. In general, the greater the rate
or severity of risks to be minimized, the more critical it becomes to
have compelling evidence of effectiveness of the tool through some form
of testing or prior use.

## FDA Assessment of RiskMAP Evaluation Results

FDA recommends that if a sponsor makes a RiskMAP submission to the
Agency, the submission describe when the sponsor will send periodic
evaluation results to FDA. As discussed in section VII.B, the Agency
recommends that sponsors analyze evaluation results and requests that
sponsors provide FDA with (1) the data, (2) all analyses, (3)
conclusions regarding effectiveness, and (4) any proposed modifications
to the RiskMAP. FDA, in turn, generally would perform its own assessment
of RiskMAP effectiveness according to the principles of this and the
other risk management guidances. At a minimum, FDA and sponsors would
discuss their respective RiskMAP evaluations in a meeting or
teleconference. In cases where risks are frequent and/or severe, or
where results are ambiguous or uncertain, or where there is disagreement
between the sponsor and FDA in the interpretation of the RiskMAP or tool
effectiveness, public and expert input would be sought through the FDA
Advisory Committee process. This will also allow airing and discussion
of important information about effective and ineffective RiskMAPs and
tools.

## Making Information From RiskMAP Evaluations Available to the Public

As discussed in section IV.C, FDA plans to maintain a RiskMAP Web site
that will describe all publicly available information about implemented
RiskMAPs (and their tools). On the same Web site, FDA intends to make
available, in summary format, information that has been publicly
discussed or is otherwise publicly available (from sponsors or other
sources) about the effectiveness of particular RiskMAP tools in
achieving risk minimization objectives. The summaries may derive from
materials presented and discussed at FDA Advisory Committee meetings
where the effectiveness of a particular RiskMAP has been discussed and
potential modifications have been entertained.

# 

# VI. COMMUNICATING WITH FDA REGARDING RiskMAP DEVELOPMENT AND DESIGN ISSUES

As discussed in section III.D, because risk and benefit information
emerge continually throughout a product's lifecycle, a sponsor could
decide, or FDA could recommend, that a RiskMAP is appropriate at several
different times. These times include:

-   before approval, when a risk is identified from clinical studies,
    nonclinical studies, or in similar class of products, and risk
    minimization is appropriate as the product is introduced into the
    marketplace

-   after marketing, if pharmacovigilance efforts identify a new serious
    risk and minimization of the risk will contribute to a favorable
    benefit-risk balance

-   when marketing a generic product that references an innovator drug
    with a RiskMAP

If a sponsor would like to initiate a dialogue with FDA to benefit from
the Agency's experience in reviewing previously implemented plans, the
Agency recommends that the sponsor contact the product\'s review
division. The review division is the primary contact for a sponsor. The
review division may choose to consult with other Offices in assisting
the sponsor in developing a RiskMAP. These consulting offices could
include CDER's Office of Drug Safety (ODS), CBER's Office of Biostatics
and Epidemiology (OBE), or CDER's Office of Generic Drugs (OGD), as
appropriate. In any particular case, it is helpful if the sponsor and
FDA:

-   share information and analyses regarding the product's risks and
    benefits

-   discuss the choice of RiskMAP goals, objectives, and tools

-   discuss the evaluation plan, including (1) times for evaluation, (2)
    performance measures and their targets, and (3) analyses

Sponsors may wish to discuss RiskMAP issues with FDA at pre-defined
meeting times (e.g., end-of-phase-2 meetings), if appropriate, or
request meetings where RiskMAPs can be specifically considered. To
maximize the value of their discussions with FDA, we recommend that
sponsors who seek the Agency's guidance apprise reviewers of the
rationale for and data underlying RiskMAPs under consideration. FDA
requests that sponsors also share relevant background information and
questions for discussion before their meetings with FDA.

Both CDER and CBER will develop internal Manuals of Policies and
Procedures (MaPPs) (or standard operating procedures (SOPs)) regarding
the review of RiskMAPS. The procedures will define milestone points at
which RiskMAP discussion is logical and will promote consistency in
RiskMAP review and design. All RiskMAPs involving reminder tools or
performance-linked access systems will be considered at the Center level
as a secondary method of ensuring consistency across product classes and
across divisions.

If the sponsor decides to submit a RiskMAP before marketing approval of
the product, most times the RiskMAP will be submitted to the new drug
application (NDA) or biologics license application (BLA) for the product
in question. However, if a risk is identified early (e.g., the product
is a teratogen), and the sponsor wishes to institute formal risk
management activities during Phases 1 to 3 studies, the sponsor can
submit the RiskMAP to the investigational new drug application (IND). If
a RiskMAP is being considered in a product's postmarket phase, FDA
recommends that it be submitted as a supplement to the relevant NDA or
BLA. Additional user fees will only be applicable to a supplement if FDA
determines that new clinical data are required for its approval. This
would be unlikely for a RiskMAP supplement.

FDA encourages early and open discussion of safety concerns and whether
such concerns may merit a RiskMAP. Early discussion of RiskMAPs could
provide the opportunity to pretest risk minimization tools.

# VII. REcommended Elements of a RISKMAP SUBMISSION TO FDA

## Contents of a RiskMAP Submission to FDA

#####  {#section-11 .TOC-5}

FDA suggests that a RiskMAP submission to FDA include the following
sections, as well as a table of contents:

-   Background

-   Goals and Objectives

-   Strategy and Tools

-   Evaluation Plan

### 1. Background 

FDA suggests that the Background section explain why a RiskMAP is being
considered and created. We recommend that it describe the risks to be
minimized and the benefits that would be preserved by implementation of
a RiskMAP. Further, we suggest that this section describe, to the extent
possible, the type, severity, frequency, and duration of the product\'s
risks, with particular attention to the risk or risks addressed by the
RiskMAP.

The following are sample questions regarding risk characterization that
we recommend be addressed in the Background section:

-   What is the rationale for the RiskMAP?

-   What is the risk the RiskMAP addresses? Is there more than one risk
    to be minimized? If there is, how do they relate to each other with
    regard to the following bulleted items?

-   What is the magnitude and severity of the risk?

-   Who is at highest risk?

-   Are particular populations at risk (e.g., children, pregnant women,
    the elderly)?

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-   Is the risk predictable?

-   Is the risk preventable?

-   Is the risk reversible?

-   Is the risk time-limited, continuous, or cumulative?

These questions are similar in intent to what the ICH calls a Safety
Specification in its E2E guidance.[^16]

FDA recommends that this section include a discussion that considers the
product's risks in the context of its benefits. The following are sample
questions that address benefit characterization.

-   What is the overall nature or extent of benefit and what are the
    expected benefits over time (i.e., long-term benefits)?

-   How do the populations most likely to benefit from this product
    compare to those that may be at highest risk?

-   How would implementation of a RiskMAP affect individual and
    population benefits? Will it increase the likelihood that benefits
    will exceed risks in patients using the product? Will the RiskMAP
    affect access to the product by patients who benefit from it?

-   Could certain individuals and/or populations likely to benefit from
    the product potentially have less access to the product because of
    the tools in the RiskMAP?

We suggest that the Background section include a discussion, if
pertinent, about the successes and failures of other regulatory
authorities, systems of healthcare, or sponsor actions in minimizing the
risks of concern for this product. Information provided by the sponsor
regarding relevant past experiences, domestically or in other countries,
will assist in harmonizing plans as well as avoiding the cost of
implementing RiskMAP tools already deemed unsuccessful. We encourage
sponsors to provide applicable information or evaluations from past
experiences with products or programs that are similar to the proposed
RiskMAP.

### 2. Goals and Objectives 

FDA suggests that the Goals and Objectives section describe the goals
and objectives of the RiskMAP.[^17] In addition, we recommend that this
section describe how the stated objectives will individually and
collectively contribute to achieving the goal or goals.

### 3. Strategy and Tools 

FDA suggests that the Strategy and Tools section define the overall
strategy and tools to be used to minimize the risk or risks targeted by
the RiskMAP. We recommend that the sponsor provide a rationale for
choosing the overall strategy. We suggest that the sponsor describe how
each tool fits into the overall RiskMAP and its relationship to the
other tools. FDA suggests that the sponsor also provide the rationale
for choosing each tool (see section IV.D for a discussion of
considerations in choosing tools). In particular, we recommend that the
sponsor describe the available evidence regarding the tool's
effectiveness and, where applicable, provide results from pretesting. In
addition, we suggest that the sponsor state whether it sought input from
patient or healthcare interests, and if it did, we suggest that the
sponsor describe the feedback that was received regarding the
feasibility of its RiskMAP. FDA plans to maintain a Web site that will
describe publicly available summary information about effectiveness of
RiskMAP tools (see section V.D).

We recommend this section also include an implementation scheme that
describes how and when each RiskMAP tool would be implemented and
coordinated. FDA suggests that sponsors specify overall timelines and
milestones. For example, this section could address whether targeted
education and outreach tools would be implemented before, or
concurrently with, other tools.

### 4. Evaluation Plan 

FDA suggests that the Evaluation Plan section describe the evaluation
measurements or measures that will be used to periodically assess the
effectiveness of the RiskMAP's goals, objectives, and tools. For a
detailed discussion of RiskMAP evaluation, see section V.

We recommend that this section include:

-   The proposed evaluation methods for assessing RiskMAP effectiveness
    (e.g., claims-based data systems, surveys, registries) and the
    rationales for the sponsor's chosen measures.

-   Targeted values for each measure and the time frame for achieving
    them. FDA recommends the sponsor include interpretations of expected
    results under best- and worst-case scenarios. In addition, we
    suggest the sponsor specify what values of measures at specific time
    points will trigger consideration of RiskMAP modification.

-   The nature and timing of data collection, analyses, and audits or
    monitoring that will be used to assess the performance of each
    individual tool in achieving the RiskMAP's objectives and goals.
    Again, we suggest specifying target values for measures.

-   A schedule for submitting progress reports to FDA regarding the
    evaluation results for the RiskMAP's individual tools, objectives,
    and goals (see section VII.B for a discussion of progress reports).
    We recommend that the timing and frequency of progress reports be
    based primarily on the nature of the risk, tools used, and outcomes
    under consideration. FDA recommends that progress reports be
    included in periodic safety update reports or traditional periodic
    reports.

Where applicable and possible, we recommend that the Evaluation Plan
section discuss potential unintended and untoward consequences of the
RiskMAP. Such a discussion would be particularly valuable if there are
therapeutic alternatives with similar benefits and risks. We suggest
that sponsors discuss how unintended consequences would be assessed
after RiskMAP implementation. The goal of the assessment would be to
ensure that overall population risks are minimized and specific product
benefits, including access, are preserved.

# 

## Contents of a RiskMAP Progress Report 

FDA recommends that a RiskMAP progress report contain the following
sections, accompanied by a table of contents:

-   Summary of the RiskMAP

-   Methodology

-   Data

-   Results

-   Discussion and Conclusions

### 1. Summary 

We suggest that the Summary section briefly provide background on and an
overview of the RiskMAP, and describe the overall RiskMAP goals and
objectives, as well as its strategy and tools. We recommend that this
section also summarize (1) the evaluation methods used and (2) the
relevant measures and time frames for achieving targeted values.

### 2. Methodology 

We recommend that the Methodology section provide a brief overview of
the evaluation methods used (e.g., ascertainment of outcomes,
comprehension testing, patient surveys, process audits). FDA suggests
that it describe the evaluation plan, sources of potential measurement
error or bias for the outcome of interest, and any analytical methods
used to account for them. Since RiskMAP evaluations will often rely upon
observational data, we recommend that the analytical plan address issues
such as measurement errors, sensitivity, and specificity of the
measures, as well as power for detecting differences where appropriate.

### 3. Data 

To the extent possible, we recommend that the Data section of a RiskMAP
progress report contain data that would allow FDA to analyze the
information and make conclusions independently.

### 4. Results 

To the extent possible, we recommend that the Results section of a
RiskMAP progress report contain the primary data from each evaluation
method and analyses of the evaluation data, statistical estimation if
appropriate, and the sponsor\'s comparison of tool, objective, and/or
goal achievement relative to targeted performance measures.

### 5. Discussion and Conclusions 

FDA recommends that this section describe whether the RiskMAP has met or
is making progress in meeting the stated measures for each tool,
objective, and goal. We suggest that this discussion take all available
data, evaluations, and analyses into consideration.

Progress towards achieving RiskMAP goals or performance measures should
be reported. Where appropriate, sponsors are encouraged to propose
modifications to the RiskMAP and discuss them with FDA.

[^1]: This guidance has been prepared by the PDUFA III Risk Management
    Working Group, which includes members from the Center for Drug
    Evaluation and Research (CDER) and the Center for Biologics
    Evaluation and Research (CBER) at the Food and Drug Administration
    (FDA).

[^2]: For ease of reference, this guidance uses the term *product* or
    *drug* to refer to all drug products (excluding blood and blood
    components) regulated by CDER or CBER. Similarly, for ease of
    reference, this guidance uses the term *approval* to refer to both
    drug approval and biologic licensure.

    **Paperwork Reduction Act Public Burden Statement**: This guidance
    contains information collection provisions that are subject to
    review by the Office of Management and Budget (OMB) under the
    Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3520). The
    collection(s) of information in this guidance were approved under
    OMB Control No. 0910-0001 (until March 31, 2005) and 0910-0338
    (until August 31, 2005).

[^3]: See 45 CFR part 46 and 21 CFR parts 50 and 56. See also the Health
    Insurance Portability and Accountability Act of 1996 (HIPAA) (Public
    Law 104-191) and the Standards for Privacy of Individually
    Identifiable Health Information (the Privacy Rule) (45 CFR part 160
    and subparts A and E of part 164). The Privacy Rule specifically
    permits covered entities to report adverse events and other
    information related to the quality, effectiveness, and safety of
    FDA-regulated products both to manufacturers and directly to FDA (45
    CFR 164.512(b)(1)(i) and (iii) and 45 CFR 164.512(a)(1)). For
    additional guidance on patient privacy protection, see
    http://www.hhs.gov/ocr/hipaa.

[^4]: For example, see the Proposed Rule on Requirements on Content and
    Format of Labeling for Human Prescription Drugs and Biologics;
    Requirements for Prescription Drug Product Labels that published in
    the *Federal Register* on December 22, 2000 (65 FR 81081).

[^5]: Although all products with RiskMAPs would also have FDA-approved
    professional labeling, the term *tool* as used in this document
    means a risk minimization action in addition to routine risk
    minimization measures. Some tools may be incorporated into a
    product's FDA-approved labeling, such as Medication Guides or
    patient package inserts. As used in this document, the FDA-approved
    professional labeling refers to that portion of approved labeling
    that is directed to the healthcare practitioner audience. See
    section IV for a more detailed discussion of other non-routine risk
    minimization tools that focus on targeted education and outreach.

[^6]: This ICH guidance is available on the Internet at
    <http://www.fda.gov/cder/guidance/index.htm> under the topic ICH
    Efficacy. The draft E2E guidance was made available on March 30,
    2004 (69 FR 16579). ICH agreed on the final version of the E2E
    guidance in November 2004.

[^7]: This guidance is directed primarily toward sponsors of innovator
    products. However, a generic product may have the same benefit-risk
    balance as an innovator product and so may be considered for a
    similar RiskMAP.

[^8]: See section VII for a detailed discussion of RiskMAP submissions.

[^9]: Smalley W, D Shatin, D Wysowski, J Gurwitz, S Andrade et al.,
    2000, *Contraindicated Use of Cisapride: Impact of Food and Drug
    Administration Regulatory Action.* JAMA 284(23):3036-3039; Weatherby
    LB, BL Nordstrom, D Fife, and AM Walker, 2002, *The Impact Of
    Wording in "Dear Doctor" Letters and In Black Box Labels*. Clin
    Pharmacol Ther 72:735-742.

[^10]: ^?^ As noted in section III.B, sponsors should not develop a
    RiskMAP for a product for which routine risk minimization measures
    are sufficient. Similarly, formal evaluation plans and performance
    measures should not be developed for these products. Instead,
    evaluation by routine postmarketing surveillance should be
    sufficient, although some products may also have a Pharmacovigilance
    Plan as described in the *Pharmacovigilance Guidance*. If a RiskMAP
    is later developed for this type of product based on new risk
    information, then a sponsor should consider submitting a formal
    evaluation plan.

[^11]: For further discussion of administrative claims systems, please
    consult the pharmacovigilance guidance.

[^12]: ^?^ For a more detailed discussion of survey development and
    implementation, please consult the pharmacovigilance guidance.

[^13]: Stamatis DH, *Failure Mode and Effects Analysis: FMEA From Theory
    to Execution,* Milwaukee: American Society for Quality, Quality
    Press, 2003.

[^14]: Cohen Michael R ed, *Medication Errors: Causes, Prevention, and
    Risk Management,* Washington, DC: American Pharmaceutical
    Association, 1999.

[^15]: For a detailed discussion of large simple safety studies, please
    consult the premarketing guidance.

[^16]: Available on the Internet at
    <http://www.fda.gov/cder/guidance/index.htm> under the topic ICH
    Efficacy.

[^17]: See section IV for a discussion of goals and objectives.