**Guidance for Industry**

**Premarketing Risk Assessment**

***DRAFT GUIDANCE***

**This guidance document is being distributed for comment purposes
only.**

Comments and suggestions regarding this draft document should be
submitted within 60 days of publication in the *Federal Register* of the
notice announcing the availability of the draft guidance. Submit
comments to the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All
comments should be identified with the docket number listed in the
notice of availability that publishes in the *Federal Register*.

For questions regarding this draft document contact (CDER) Barbara Gould
at 301-827-2506, or (CBER) Patricia Rohan 301-827-3070.

**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)**

**May 2004**

**Clinical Medical**

**Guidance for Industry**

**Premarketing Risk Assessment**

*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*

*/or*

*Office of Communication, Training and*

*Manufacturers Assistance, HFM-40*

*Center for Biologics Evaluation and Research*

*Food and Drug Administration*

*1401 Rockville Pike, Rockville, MD 20852-1448*

*http://www.fda.gov/cber/guidelines.htm.*

*(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)**

**May 2004**

**Clinical Medical**

##  {#section .TOC-2}

**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 Guidance Performance Goal [2](#a.-pdufa-iiis-risk-management-guidance-goal) {#a.-pdufa-iii-guidance-performance-goal-2 .TOC-2}

## B. Overview of the Risk Management Guidances [2](#b.-overview-of-the-risk-management-guidances) {#b.-overview-of-the-risk-management-guidances-2 .TOC-2}

# III. THE ROLE OF RISK ASSESSMENT IN RISK MANAGEMENT [3](#iii.-the-role-of-risk-assessment-in-risk-management) {#iii.-the-role-of-risk-assessment-in-risk-management-3 .TOC-1}

# IV. GENERATING RISK INFORMATION DURING CLINICAL TRIALS [4](#iv.-generating-risk-information-during-clinical-trials) {#iv.-generating-risk-information-during-clinical-trials-4 .TOC-1}

## A. Size of the Premarketing Safety Database [5](#a.-size-of-the-premarketing-safety-database) {#a.-size-of-the-premarketing-safety-database-5 .TOC-2}

## B. Considerations for Developing a Premarketing Safety Database [7](#b.-considerations-for-developing-a-premarketing-safety-database) {#b.-considerations-for-developing-a-premarketing-safety-database-7 .TOC-2}

### 1. Long-Term Controlled Safety Studies [7](#long-term-controlled-safety-studies) {#long-term-controlled-safety-studies-7 .TOC-3}

### 2. A Diverse Safety Database [8](#a-diverse-safety-database) {#a-diverse-safety-database-8 .TOC-3}

### 3. Exploring Dose Effects Throughout the Clinical Program [8](#exploring-dose-effects-throughout-the-clinical-program) {#exploring-dose-effects-throughout-the-clinical-program-8 .TOC-3}

## C. Detecting Unanticipated Interactions as Part of a Safety Assessment [9](#c.-detecting-unanticipated-interactions-as-part-of-a-safety-assessment) {#c.-detecting-unanticipated-interactions-as-part-of-a-safety-assessment-9 .TOC-2}

## D. Developing Comparative Safety Data [10](#d.-developing-comparative-safety-data) {#d.-developing-comparative-safety-data-10 .TOC-2}

# V. SPECIAL CONSIDERATIONS FOR RISK ASSESSMENT [11](#v.-special-considerations-for-risk-assessment) {#v.-special-considerations-for-risk-assessment-11 .TOC-1}

## A. Risk Assessment During Product Development [11](#a.-risk-assessment-during-product-development) {#a.-risk-assessment-during-product-development-11 .TOC-2}

## B. Risk Assessment and Minimizing the Potential for Medication Errors [13](#b.-risk-assessment-and-minimizing-the-potential-for-medication-errors) {#b.-risk-assessment-and-minimizing-the-potential-for-medication-errors-13 .TOC-2}

## C. Safety Aspects that Should Be Addressed During Product Development [14](#c.-safety-aspects-that-should-be-addressed-during-product-development) {#c.-safety-aspects-that-should-be-addressed-during-product-development-14 .TOC-2}

# VI. DATA ANALYSIS AND PRESENTATION [15](#vi.-data-analysis-and-presentation) {#vi.-data-analysis-and-presentation-15 .TOC-1}

## A. Describing Adverse Events to Identify Safety Signals [15](#a.-describing-adverse-events-to-identify-safety-signals) {#a.-describing-adverse-events-to-identify-safety-signals-15 .TOC-2}

### 1. Accuracy of Coding [15](#accuracy-of-coding) {#accuracy-of-coding-15 .TOC-3}

### 2. Coding Considerations During Adverse Event Analysis [16](#coding-considerations-during-adverse-event-analysis) {#coding-considerations-during-adverse-event-analysis-16 .TOC-3}

## B. Analyzing Temporal or Other Associations [17](#b.-analyzing-temporal-or-other-associations) {#b.-analyzing-temporal-or-other-associations-17 .TOC-2}

## C. Analyzing Dose Effect as a Contribution to Risk Assessment [18](#c.-analyzing-dose-effect-as-a-contribution-to-risk-assessment) {#c.-analyzing-dose-effect-as-a-contribution-to-risk-assessment-18 .TOC-2}

## D. Role of Data Pooling in Risk Assessment [19](#d.-role-of-data-pooling-in-risk-assessment) {#d.-role-of-data-pooling-in-risk-assessment-19 .TOC-2}

## E. Using Pooled Data During Risk Assessment [20](#e.-using-pooled-data-during-risk-assessment) {#e.-using-pooled-data-during-risk-assessment-20 .TOC-2}

## F. Rigorous Ascertainment of Reasons for Withdrawals from Studies [21](#f.-rigorous-ascertainment-of-reasons-for-withdrawals-from-studies) {#f.-rigorous-ascertainment-of-reasons-for-withdrawals-from-studies-21 .TOC-2}

## G. Long-term Follow-up [21](#g.-long-term-follow-up) {#g.-long-term-follow-up-21 .TOC-2}

## H. Important Aspects of Data Presentation [22](#h.-important-aspects-of-data-presentation) {#h.-important-aspects-of-data-presentation-22 .TOC-2}

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

**Guidance for Industry**[^1]

**Premarketing Risk Assessment**

This draft guidance, when finalized, will represent 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 good risk assessment
practices during the development of prescription drug products,
including biological drug products.[^2] This is one of three guidances
that are being developed on risk management activities. Specifically,
this document discusses the generation, acquisition, analysis, and
presentation of premarketing safety data.

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

## A. 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 producing three draft guidance documents on risk management
activities:

-   *Premarketing Risk Assessment* *(Premarketing Guidance)*

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

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

## B. Overview of the Risk Management Guidances 

Like the concept papers that preceded them, each of the three draft
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 (e.g., FDCA sec. 503(b) (21 U.S.C. 353(b)), which
> provides for limiting drugs to prescription status, FDA regulations
> regarding spontaneous adverse event reporting and FDA-approved
> professional labeling). As a result, many of the recommendations
> presented here focus on situations when a product may pose an unusual
> type or level of risk. To the extent possible, we have specified in
> the text whether a recommendation is intended to apply to 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] Sponsors should comply with
> ethical principles for patient protection.

-   To the extent possible, this guidance conforms with FDA's commitment
    to harmonize international definitions and standards as appropriate.

> The topics covered in this guidance are being discussed in a variety
> of international forums. We are participating in these discussions and
> believe that, to the extent possible, the recommendations in this
> guidance reflect current thinking on related issues.

-   When planning risk assessment and risk minimization activities,
    sponsors should consider stakeholder input (e.g., from consumers,
    pharmacists, physicians, 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 ASSESSMENT IN RISK MANAGEMENT

Risk management is an iterative process designed to optimize the
benefit-risk balance for regulated products. Risk assessment consists of
identifying and characterizing the nature, frequency, and severity of
the risks associated with the use of a product. Risk assessment occurs
throughout a product's lifecycle, from the early identification of a
product as a candidate, through the premarketing development process,
and after marketing. Premarketing risk assessment represents the first
step in this process, and this guidance focuses on risk assessment prior
to marketing.

It is critical to FDA's decision on product approval that a product's
underlying risks and benefits be adequately assessed during the
premarketing period. For the underlying risks, sponsors should provide a
body of evidence from the clinical trials that adequately characterizes
the product\'s safety profile.[^4]

This guidance provides general recommendations for assessing risk. The
adequacy of this assessment is a matter of both quantity (ensuring that
enough patients are studied) and quality (the appropriateness of the
assessments performed and how results are analyzed). Quantity is, in
part, considered in other Agency guidances,[^5] but it is discussed
further here. This guidance also addresses the qualitative aspects of
risk assessment.

Although risk assessment continues through all stages of product
development, this guidance focuses on risk assessment during the later
stages of clinical development, particularly during phase 3 studies. The
guidance is not intended to cover basic aspects of preclinical safety
assessments (i.e., animal toxicity testing) or routine clinical
pharmacology programs. Good clinical risk assessment in the later stages
of drug development should be guided by the results of comprehensive
preclinical safety assessments and a rigorous, thoughtful clinical
pharmacology program (including elucidation of metabolic pathways,
identification of possible drug-drug interactions, and determination of
any effects from hepatic and/or renal impairment). These issues are
addressed in other FDA guidances and guidances developed under the
auspices of the International Conference for Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH).

# IV. GENERATING RISK INFORMATION DURING CLINICAL TRIALS

Providing detailed guidance on what constitutes an adequate safety
database for all products is impossible. The nature and extent of safety
data that would provide sufficient information about risk for purposes
of approving a product are individualized decisions based on a number of
factors (several of which are discussed below). In reaching a final
decision on approvability, both existing risk information and any
outstanding questions regarding safety are considered in a product's
risk assessment and weighed against the product's demonstrated benefits.
The fewer a product's demonstrated benefits, the less acceptable may be
higher levels of demonstrated risks. Likewise, the fewer the benefits,
generally, the less uncertainty may be accepted about a product's risks.

To maximize the information gained from clinical trials, FDA recommends
that sponsors pay careful attention from the outset of development to
the overall design of the safety evaluation. Potential problems that may
be suspected because of preclinical data or because of effects of
related drugs should be targeted for evaluation. And, because it is
impossible to predict every important risk, as experience accrues,
sponsors should refine or modify their safety evaluations.

## A. Size of the Premarketing Safety Database

Even large clinical development programs cannot reasonably be expected
to identify all risks associated with a product. Some risks become
apparent only when a product is used in tens of thousands or even
millions of patients in the general population. However, the larger and
more comprehensive a preapproval database, the more likely it is that
serious adverse events will be detected.

The appropriate size of a safety database supporting a new product will
depend on a number of factors specific to that product, including:

-   Its novelty (i.e., whether it represents a new treatment or is
    similar to available treatment)

-   The potential advantages of the product over existing therapy

-   The intended population

-   The intended duration of use

Safety databases for products intended to treat life-threatening
diseases are usually smaller than for products supporting symptomatic
treatment of nonserious disease. A larger safety database may be
appropriate if a product's preclinical assessment or human clinical
pharmacology studies identify signals of risk that warrant additional
clinical data to properly define the risk.

For products intended for short-term or acute use, FDA believes it is
difficult to offer general guidance on the appropriate target size of
clinical safety databases. This is because of the wide range of
indications and diseases (e.g., acute strokes to mild headaches) that
may be targeted by such therapies. Sponsors are therefore encouraged to
discuss with the relevant review division the appropriate size of the
safety database for such products. Products intended for
life-threatening and severely debilitating diseases are often approved
with relatively small safety databases and, thus, relatively greater
uncertainty regarding their adverse effects. Section 312.82(b) (21 CFR
312.82(b)) provides that end-of-phase 1 meetings will be used to agree
on the design of phase 2 trials "with the goal that such testing will be
adequate to provide sufficient data on the drug's safety and
effectiveness to support a decision on its approvability for
marketing."[^6]

For products intended for long-term treatment (e.g., chronic or
recurrent intermittent) of non-life-threatening conditions, the ICH and
FDA have generally recommended that 1500 subjects be exposed to the
investigational product (with 300 to 600 exposed for 6 months, and 100
exposed for 1 year).[^7] For those products characterized as chronic use
products in the ICH guidance E1A, FDA recommends that the 1500 subjects
include only those who have been exposed to the product in multiple dose
studies, because many adverse events of concern (e.g., hepatotoxicity,
hematologic events) do not appear with single doses or very short-term
exposure. Also, the 300 to 600 subjects exposed for 6 months and 100
patients exposed for 1 year should have been exposed to relevant doses,
with a reasonable representation of subjects exposed at the highest
proposed dose.

We note that it is common for well-conducted clinical development
programs to explore doses higher than those ultimately proposed for
marketing. In such cases, data from patients exposed to doses in excess
of those ultimately proposed are informative and should be counted as
contributing to the relevant safety database.

The E1A guidance describes a number of circumstances in which a safety
database larger than 1500 patients may be appropriate, including the
following:

1\. There is concern that the drug would cause late developing adverse
events, or cause adverse events that increase in severity or frequency
over time. The concern could arise from:

-   Data from animal studies

-   Clinical information from other agents with related chemical
    structures or from a related pharmacologic class

-   Pharmacokinetic or pharmacodynamic properties known to be associated
    with such adverse events

2\. There is a need to quantitate the occurrence rate of an expected
specific low-frequency adverse event. Examples would include situations
where a specific serious adverse event has been identified in similar
products or where a serious event that could represent an alert event is
observed in early clinical trials.

3\. A larger database would help make risk-benefit decisions in
situations when the benefit from the product:

-   Is small (e.g., symptomatic improvement in less serious medical
    conditions)

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-   Will be experienced by only a fraction of the treated patients
    (e.g., certain preventive therapies administered to healthy
    populations)

-   Is of uncertain magnitude (e.g., efficacy determination on a
    surrogate endpoint)

4\. Concern exists that a product may add to an already significant
background rate of morbidity or mortality, and clinical trials should be
designed with a sufficient number of patients to provide adequate
statistical power to detect prespecified increases over the baseline
morbidity or mortality.

In addition to the considerations provided in E1A, there are other
circumstances in which a larger database may be appropriate.

1\. The proposed treatment is for a healthy population (e.g., the
product under development is for chemoprevention or is a preventive
vaccine).

2\. A safe and effective alternative to the investigational product is
already available.

The FDA is not suggesting that development of a database larger than
that described in E1A is required or should be the norm. Rather, the
appropriate database size would depend on the circumstances affecting a
particular product, including the considerations outlined above.
Therefore, FDA recommends that sponsors communicate with the review
division responsible for their product early in the development program
on the appropriate size of the safety database. FDA also recommends that
sponsors revisit the issue at appropriate regulatory milestones (e.g.,
end-of-phase 2 and pre-NDA meetings).

## B. Considerations for Developing a Premarketing Safety Database

Although the characteristics of an appropriate safety database are
product-specific, some general principles can be applied. In general,
efforts to ensure the quality and completeness of a safety database
should be comparable to those made to support efficacy. Because data
from multiple trials are often examined when assessing safety, it is
particularly critical to examine terminology, assessment methods, and
use of standard terms to be sure that information is not obscured or
distorted. Ascertainment and evaluation of the reasons for leaving
assigned therapy during study (deaths and dropouts for any reason) are
particularly important for a full understanding of a product's safety
profile.

The following elements should be considered by sponsors when developing
proposals for their clinical programs as these programs pertain to risk
assessment.

### 1. Long-Term Controlled Safety Studies

It is common in many clinical programs for much of patient exposure data
and almost all of long-term exposure data to come from single-arm or
uncontrolled studies. Although these data can be informative, it may be
preferable in some circumstances to develop controlled, long-term safety
data. Such data allow for comparisons of event rates and facilitate
accurate attribution of adverse events. Control groups may be given an
active comparator or a placebo, depending on the disease being treated.

The usefulness of active comparators in long-term safety studies depends
on the adverse events of interest.

-   Generally, serious events that rarely occur spontaneously (e.g.,
    severe hepatocellular injury or aplastic anemia) are of significance
    and interpretable whenever they occur since the expected rate is
    essentially zero in populations of any feasible size. They thus can
    usually be appropriately interpreted without a control group.

-   On the other hand, control groups are needed to detect increases in
    rates of events that are relatively common in the treated population
    (e.g., sudden death in patients with ischemic cardiac disease).
    Control groups are particularly important when an adverse event
    could be considered part of the disease being treated (e.g., asthma
    exacerbations occurring with inhalation treatments for asthma).

Therefore, FDA decisions as to when long-term comparative safety studies
are conducted should be based on the intended use of the product, the
nature of the labeled patient population (e.g., more useful if there is
a high rate of serious adverse events), and its earlier clinical and
preclinical safety assessments. (See section D below for further
discussion of comparative trials.)

### 2. A Diverse Safety Database

Premarketing safety databases should include, to the extent possible, a
diverse population in phase 3 studies. FDA has previously addressed this
issue in a memorandum,[^8] and the recommendations provided here are
intended to supplement that document. We recommend that, to the extent
feasible, only patients with obvious contraindications be excluded from
study entry in phase 3 trials. Inclusion of a diverse population allows
for the development of safety data in a broader population that includes
patients previously excluded from clinical trials, such as the elderly
(particularly the very old), patients with concomitant diseases, and
patients taking usual concomitant medications. Broadening inclusion
criteria in phase 3 studies enhances the generalizability of study
findings and may, therefore, allow the product to be labeled for broader
use. Although some phase 3 efficacy studies may target certain
demographic or disease characteristics (and hence have narrower
inclusion and exclusion criteria), it may be useful to conduct
controlled safety and/or efficacy studies in less restricted
populations.

### 3. Exploring Dose Effects Throughout the Clinical Program

### 

Currently, it is common for only one dose, or perhaps a few doses, to be
studied beyond phase 2. Yet, a number of characteristics common to many
phase 2 studies limit the ability of these trials to provide definitive
data on exposure-response, or adequate data for definitive phase 3 dose
selection. These characteristics of phase 2 studies (in comparison to
phase 3 studies) include the following:

-   Shorter durations of exposure

-   Common use of pharmacodynamic (PD) endpoints, rather than clinical
    outcomes

-   Smaller numbers of patients exposed

-   Narrowly restrictive entry criteria

In circumstances when phase 2 studies cannot reasonably be considered to
have established a single most appropriate dose, more than one dose
level should usually be used in phase 3 trials to better characterize
the relationship between product exposure and resulting clinical benefit
and risk. In such cases, dose-response data from phase 3 trials with
multiple dose levels help to better define the relationship of exposure
to dose for both safety and effectiveness. Inadequate exploration of a
product's dose-response relationship in clinical trials raises safety
concerns, since recommending doses in labeling that exceed the amount
needed for effectiveness may increase risk to patients with no potential
for gain. Exposure-response data from phase 3 trials can also provide
critical information on whether dose adjustments should be made for
special populations. Finally, demonstrating a dose-response relationship
in late phase clinical trials with meaningful clinical endpoints may aid
the assessment of efficacy, since showing a dose ordering to efficacy
can be compelling evidence of effectiveness.[^9]

## C. Detecting Unanticipated Interactions as Part of a Safety Assessment

Even a well-conducted and reasonably complete general clinical
pharmacology program does not guarantee a full understanding of all
possible risks related to product interactions. Therefore, risk
assessment programs should address a number of potential interactions
during controlled safety and effectiveness trials and, where
appropriate, in specific, targeted safety trials. This examination for
unanticipated interactions should include the potential for the
following:

-   Drug-drug interactions in addition to those resulting from known
    metabolic pathways (e.g., the effect of azole antibiotics on a CYP
    3A4 dependent drug)

> We recommend that these examinations target a limited number of
> specific drugs, such as likely concomitant medications (e.g., for a
> new cholesterol lowering treatment, examining the consequences of
> concomitant use of HMG CoA reductase inhibitors and/or binding
> resins). The interactions of interest could be based, for example, on
> known or expected patterns of use, indications sought, or populations
> that are likely users of the drug.

-   Product-demographic relationships --- by ensuring sufficient
    diversity of the population (including gender, age, and race) to
    permit some assessments of safety concerns in demographic population
    subsets of the intended population

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-   Product-disease interactions --- by ensuring sufficient variability
    in disease state and concomitant diseases

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-   Product-dietary supplement interactions for commonly used
    supplements that are likely to be co-administered or for which
    reasonable concerns exist

Again, FDA recommends that any such examinations target likely
concomitant use based, for example, on indications sought, intended
patterns of use, or the population of intended users of the drug and
based on a history of drug and dietary supplement use elicited from
subjects.

Generally, a sponsor determines its product\'s intended use and intended
population(s) during product development. Decisions as to which
interactions to either explore or specifically test in clinical trials
could be based on these determinations and/or surveys and epidemiologic
analyses.

One important way to detect unexpected relationships is by incorporating
pharmacokinetic (PK) assessments (e.g., population PK studies) into a
subset of clinical trials, including safety trials. PK assessments could
aid in the detection of unexpected PK interactions and, in some cases,
with careful analysis, could suggest exposure-response relationships for
both safety and efficacy. Such data would allow for better assessment of
whether PKs contribute to any adverse events seen in the clinical
trials, particularly rare, serious, and unanticipated events.

When a product has one or more biomarkers pertinent to a known safety
concern, the marker should be studied during the PK studies and clinical
development (e.g., creatine phosphokinase assessments used in the
evaluation of new HMG CoA reductase inhibitors as a marker for
rhabdomyolysis, or assessments of QT/QTc effects for new
antihistamines).

## D. Developing Comparative Safety Data 

Depending on the drug and its indication, much of the safety data in an
application may be derived from placebo-controlled trials and single-arm
safety studies, with little or no comparative safety data. Although
comparative safety data from controlled trials comparing the drug to an
active control (these could also include placebo group) generally are
not necessary, situations in which such data would be desirable include
the following:

-   The background rate of adverse events is high.

> The new drug may seem to have a high rate of adverse events in a
> single-arm study when, in fact, the rate is typical of that for other
> drugs. Use of a placebo would also help to show whether either drug
> actually caused the adverse events.

-   There is a well-established related therapy.

> A comparative study could show whether the toxicity profile for the
> established therapy is generally similar to that for the novel
> therapy, or whether important differences exist.

-   There is a well-established treatment with an effect on survival or
    irreversible morbidity.

> In such cases, not only are comparative data important scientifically,
> but the use of the comparator would likely be required ethically, as a
> placebo control could not be used and a single-arm trial would
> generally be uninformative.

-   The sponsor hopes to claim superiority for safety or
    effectiveness*.*

> If a comparative effectiveness claim were sought, it would be expected
> that the studies would also address comparative safety, since a gain
> in effectiveness could be outweighed by or negated by an accompanying
> safety disadvantage.

# V. SPECIAL CONSIDERATIONS FOR RISK ASSESSMENT

Although many of the previous comments and recommendations are intended
to apply to new product development programs generally, some risk
assessment issues would apply only in certain circumstances or to
certain types of products. [^10]

## A. Risk Assessment During Product Development

The following are examples of how risk assessment strategies could be
tailored to suit special situations.

-   If a product is intended to be chronically used (particularly when
    it has a very long half-life) and/or has dose-related toxicities, it
    can be useful to examine whether a lower or less frequent
    maintenance dose would be appropriate.

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-   If a product's proposed dosing includes a proposed titration scheme,
    the scheme could be based on specific studies to define how
    titration is best performed and the effects of titration on safety
    (and efficacy).

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-   Certain kinds of adverse effects are not likely to be detected or
    readily reported by patients without special attention. When a drug
    has the potential for such effects, additional testing may be
    appropriate.

> For example, for drugs with likely CNS effects, sponsors should
> conduct an assessment of cognitive function, motor skills, sexual
> function, and mood. The use of targeted safety questionnaires or
> specific psychometric or other validated instruments is often
> important for such assessments, since routine adverse event monitoring
> and safety assessments tend to underestimate or even entirely miss
> such effects.

-   If a product is to be studied in pediatric patients, special safety
    issues should be considered (e.g., effects on growth and
    neurocognitive development if the drug is to be given to very young
    children/infants; safety of excipients for the very young; universal
    immunization recommendations and school entry requirements for
    immunization).

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-   Particularly in circumstances when earlier safety data signal an
    unusual or important concern, a sponsor should consider reserving
    blood samples (or any other bodily fluids/tissues that may be
    collected during clinical trials) from some or all patients in phase
    3 studies for possible assessments at a later time. Such later
    assessments could include pharmacogenomic markers, immunogenicity,
    or measurements of other biomarkers that might prove helpful
    clinically. Having samples available for retrospective analysis of
    pharmacogenomic markers could help to link the occurrence of serious
    adverse events to particular genetic markers (e.g., haplotypes).

In some circumstances, a large, simple, safety study (LSSS) may be
appropriate. An LSSS is usually a randomized clinical study designed to
assess limited, specific outcomes in a large number of patients. These
outcomes --- generally important safety endpoints or safety concerns
suggested by earlier studies --- should be defined a priori with the
study specifically designed to assess them. Although the large simple
study model arose in the context of effectiveness assessment, and thus
always involved randomized, controlled trials, an LSSS could in some
cases be useful even without a control group, e.g., to assess the rate
of rare events. An LSSS is most commonly performed postapproval either
as a phase 4 commitment or outside of a formal phase 4 commitment in
response to a new safety concern. Circumstances in which an LSSS may be
appropriate prior to approval include the following.

-   When there is a significant safety signal of concern (e.g.,
    hepatotoxicity, myotoxicity) arising out of the developing clinical
    trial database that is not sufficiently resolved by the available
    data or is unlikely to be sufficiently addressed by the remaining
    ongoing studies. In these circumstances, an LSSS may be needed if
    the safety signal cannot otherwise be better delineated or refuted.

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-   When there are early signals (i.e., preclinical or clinical) of
    serious toxicities or other unique or special considerations (e.g.,
    regarding the safety of the use of the product with a concomitant
    medication where the previous clinical data have not addressed the
    issue sufficiently). In such cases, LSSS data could help better
    characterize the risk.[^11]

In addition, a sponsor seeking to develop a product for preventive use
in at-risk, but otherwise healthy, individuals could conduct a large
trial to investigate the product's safety. The use of a large trial may
increase the chance of showing the product to have an acceptable
benefit-risk profile in such cases because the potential for benefit in
the exposed population would generally be small. Such large trials,
though not always LSSSs in a strict sense, may in some cases
appropriately employ limited, targeted evaluations of both efficacy and
safety endpoints, similar to an LSSS.

## B. Risk Assessment and Minimizing the Potential for Medication Errors 

Sponsors can help minimize the risk of medication errors involving their
products by conducting a premarketing risk assessment to document that a
product\'s proprietary name, established name, container label, carton
labeling, patient/consumer labeling, professional package insert
labeling, and packaging do not inadvertently contribute to medication
errors. For purposes of this guidance, this premarketing risk assessment
is referred to as a medication error prevention analysis (MEPA). A
well-planned and conducted MEPA would do the following:

-   Identify known and potential medication errors

-   Identify reasons or potential causes for each identified error
    (e.g., dosage form, packaging, labeling, or confusion due to trade
    names when written or spoken)

-   Place each identified error into the context of its resultant risk,
    according to expected or potential outcomes

-   Minimize the potential for medication errors through premarketing
    risk minimization actions, including proper naming, labeling,
    design, and packaging

FDA currently undertakes some of the activities discussed in this
section. However, sponsors may be able to help reduce medication errors
if they engage in premarketing risk assessments to support their
proposed names, labeling, and packaging.

MEPAs can employ a number of techniques to assess for potential
medication errors, including Failure Mode and Effects Analysis (FMEA),
expert panels, computer assisted analysis, direct observation, clinical
trials, directed interviews of consumers, medical and pharmacy
personnel, focus groups, and simulated prescription and over the counter
(OTC) use studies. Sponsors should use multiple techniques when
performing MEPA assessments. The most appropriate mix of techniques for
any particular product will depend on the issues being assessed.

FDA recognizes the skill and experience of the U.S. Adopted Names
Council (USAN), on which the Agency has representation, in deriving
established names for drug products (see 21 CFR 299.4). USAN negotiates
with manufacturing firms in the selection of names for drugs. The FDA is
authorized, however, under section 508 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 358) to designate an official name for any drug
if it determines that such action is necessary or desirable in the
interest of usefulness or simplicity (see 21 CFR 299.4(a)). To
facilitate such determinations and due to the documented number of
errors associated with established names that have led to patient
injury, we recommend that sponsors perform MEPAs on established names
they propose for products. We recommend that sponsors use the risk
assessment techniques described above, as appropriate, before submitting
such names to the USAN Council and FDA.

The Agency cannot fully address MEPAs in this guidance. A specific and
expanded guidance on medication error prevention analysis is being
developed. Currently, sponsors planning to initiate a MEPA may seek
guidance on study design from the Division of Medication Errors and
Technical Support in the Office of Drug Safety when submitting a drug
application to a new drug review division, or from the Office of
Compliance and Biologics Quality when submitting an application to a
CBER product office.

## C. Safety Aspects that Should Be Addressed During Product Development 

The potential for the following serious adverse effects should be
addressed as a part of all new small molecule drug development programs.

-   Drug-related QTc prolongation

-   Drug-related liver toxicity

-   Drug-related nephrotoxicity

-   Drug-related bone marrow toxicity

-   Drug-drug interactions

-   Polymorphic metabolism

Prior experience has shown that when these effects occur, they are often
definable in clinical development programs (when properly assessed) and
have important safety ramifications for products. Although FDA believes
these potential effects should be addressed in all drug programs,
addressing them would not always involve the generation of data. For
example, a drug that is intended to be topically applied may be shown to
have no systemic bioavailability; therefore, systemic toxicities would
be of no practical concern.

Many of these potential effects are relevant to biological products;
some are not. In addition, for biological products such as cytokines,
antibodies, other recombinant proteins, and cell-, gene-, and
tissue-based therapeutics, it may be appropriate to assess other issues.
The issues listed here are dependent on the specific nature of the
biological product under development.

-   Potentially important issues for biological products include
    assessments of immunogenicity, both the incidence and consequences
    of neutralizing antibody formation and the potential for adverse
    events related to binding antibody formation.

-   For gene-based biological products, transfection of nontarget cells
    and transmissibility of infection to close contacts, and the genetic
    stability of products intended for long-persistence transfections
    constitute important safety issues.

-   For cell-based products, assessments of adverse events related to
    distribution, migration, and growth beyond the initial intended
    administration are important, as are adverse events related to cell
    survival and demise. Such events may not appear for a long time
    after product administration.

A complete discussion of assessment of safety issues unique to
biological products is beyond the scope of this guidance. We recommend
that sponsors address the unique safety concerns pertaining to the
development of any particular biological product with the relevant
product office.

# VI. DATA ANALYSIS AND PRESENTATION 

Many aspects of data analysis and presentation have been previously
addressed in guidance, most notably in FDA's *Guideline for the Format
and Content of the Clinical and Statistical Sections of an Application*
and the ICH guidance *E3 Structure and Content of Clinical Study
Reports*. We do not repeat that guidance here, but offer new guidance on
selected issues.

## A. Describing Adverse Events to Identify Safety Signals

Because individual investigators may use different terms to describe a
particular adverse event, sponsors should ensure that each
investigator's verbatim terms are coded to standardized, preferred terms
specified in a coding convention or dictionary. Proper coding allows
similar events that were reported using different verbatim language to
be appropriately grouped. Consistent and accurate coding of adverse
events allows large amounts of data regarding these events to be
analyzed and summarized and maximizes the likelihood that safety signals
will be detected. Inaccurate coding, inconsistent coding of similar
verbatim terms, and inappropriate lumping of unrelated verbatim terms or
splitting of related verbatim terms can obscure safety signals.

In general, FDA suggests that sponsors use one coding convention or
dictionary throughout a clinical program. Use of more than one coding
convention or dictionary can result in coding differences that prevent
adverse event data from being appropriately grouped and analyzed.

### 1. Accuracy of Coding

Sponsors should explore the accuracy of the coding process with respect
to both investigators and the persons who code adverse events.

-   Investigators may sometimes choose verbatim terms that do not
    accurately communicate the adverse event that occurred.

> -- The severity or magnitude of an event may be inappropriately
> exaggerated (e.g., if an investigator terms a case of isolated
> elevated transaminases *acute liver failure* despite the absence of
> evidence of associated hyperbilirubinemia, coagulopathy, or
> encephalopathy, which are components of the standard definition of
> acute liver failure).
>
> -- Conversely, the significance or existence of an event may be masked
> (e.g., if an investigator uses a term that is nonspecific and possibly
> unimportant to describe a subject's discontinuation from a study when
> the discontinuation is due to a serious adverse event).
>
> If adverse events are mischaracterized, sponsors could consider, in
> consultation with FDA, recharacterizing the event to make it
> consistent with accepted case definitions. We recommend that
> recharacterization be the exception rather than the rule and, when
> done, should be well documented with an audit trail.

-   In addition to ensuring that investigators have accurately
    characterized adverse events, we recommend that sponsors confirm
    that verbatim terms used by investigators have been appropriately
    coded.

> Sponsors should strive to identify obvious coding mistakes as well as
> any instances when a potentially serious verbatim term may have been
> inappropriately mapped to a more benign preferred term, thus
> minimizing the potential severity of an adverse event. One example is
> coding the verbatim term *facial edema* (suggesting an allergic
> reaction) as the nonspecific term *edema*; another is coding the
> verbatim term *suicidal ideation* as the more benign term *emotional
> liability*.

-   Prior to analyzing a product's safety database, sponsors should
    ensure that adverse events were coded with minimal variability
    across studies and individual coders.

> Consistency is important because adverse event coding may be performed
> over time, as studies are completed, and by many different
> individuals. Both of these factors are potential sources of
> variability in the coding process. To examine the extent of
> variability in the coding process, FDA recommends that sponsors focus
> on a subset of preferred terms, particularly terms that are vague and
> commonly coded differently by different people. For example, a sponsor
> might evaluate the consistency of coding verbatim terms such as
> *weakness* and *asthenia* or *dizziness* and *vertigo*. NOS (not
> otherwise specified)-type codes, such *as ECG abnormality NOS*, are
> also preferred terms to which a variety of verbatim terms may often be
> mapped. These should be examined for consistency as well. Sponsors
> should pay special attention to terms that could represent serious or
> otherwise important adverse reactions.

In addition to considering an adverse event independently and as it is
initially coded, sponsors should also consider a coded event in
conjunction with other coded events in some cases. Certain adverse
events or toxicities (particularly those with a constellation of
symptoms, signs or laboratory findings) may be defined as an
amalgamation of multiple preferred coding terms. Sponsors should
identify these events (e.g., acute liver failure) based on recognized
definitions.

### 

### 2. Coding Considerations During Adverse Event Analysis

When analyzing an adverse event, sponsors should consider the following:

-   Combining related coding terms can either amplify weak safety
    signals or obscure important toxicities.

> For example, the combination of dyspnea, cough, wheezing, or pleuritis
> might provide a more sensitive, although less specific, appraisal of
> pulmonary toxicity than any single term. Conversely, by combining
> terms for serious, unusual events with terms for more common, less
> serious events (e.g., constipation might include cases of toxic
> megacolon), the more important events could be obscured.

-   Coding methods can divide the same event into many terms. Dividing
    adverse event terms can decrease the apparent incidence of an
    adverse event (e.g., including pedal edema, generalized edema, and
    peripheral edema as separate terms could obscure the overall finding
    of fluid retention).

Although potentially important safety events cannot always be
anticipated in a clinical development program, sponsors, in consultation
with the Agency, should prospectively group adverse event terms and
develop case definitions whenever possible*.*

-   A prospective grouping approach is particularly important for
    syndromes such as serotonin syndrome, Parkinsonism, and drug
    withdrawal, which are not well characterized by a single term.

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-   Some groupings can be constructed only after safety data are
    obtained, at which time consultation with FDA might be considered.

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-   Sponsors should explain such groupings explicitly in their
    applications so that FDA reviewers have a clear understanding of
    what terms were grouped and the rationale for the groupings.

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-   For safety signals that are identified toward the end of a
    development program, the pre-NDA meeting would be a reasonable time
    to confer with FDA regarding such groupings or case definitions.

## B. Analyzing Temporal or Other Associations 

For individual safety reports, the temporal relationship between product
exposure and adverse event is a critical consideration in the assessment
of causality. However, temporal factors, including the duration of the
event itself, are often overlooked during the assessment of aggregate
safety data. Simple comparisons of adverse event frequencies between (or
among) treatment groups, which are commonly included in product
applications and reproduced in tabular format in labeling, generally do
not take into account the time dependency of adverse events. Temporal
associations can help further understand causality, adaptation, and
tolerance, but are not detected when only frequencies of adverse events
are compared.

Temporal analyses may be warranted for important adverse events whether
they arise from controlled clinical trial data or treatment cohorts. In
both cases, analyzing changes over time may be important for assessing
risk and causality (e.g., an increasing rate of events over time could
suggest causality). In addition, in the context of controlled clinical
trials, temporal analyses may provide insight into the relative
importance of differences in adverse event frequencies between study
groups.

Descriptions of risk as a function of subjects' duration of exposure to
a product, or as a function of time since initial exposure, can
contribute to the understanding of the product's safety profile.
Assessments of risk within discrete time intervals over the observation
period (i.e., a hazard rate curve) can be used to illustrate changes in
risk over time (e.g., flu-like symptoms with interferons that tend to
occur at the initiation of treatment but diminish in frequency over
time). It may be useful for sponsors to consider event rates (events per
unit of time) in reconciling apparent differences in the frequencies of
events between studies when there are disparities in subjects' time of
exposure or time at risk.

For important events that do not occur at a constant rate with respect
to time and for events in studies where the size of the population at
risk (denominator) changes over time, a life-table (e.g., Kaplan-Meier)
approach may be of value for evaluating risks of adverse events.
Clinically important events (e.g., those events for which the occurrence
of even a few cases in a database may be significant) are of particular
interest. Examples of such events include the development of restenosis
following coronary angioplasty, cardiac toxicity, and seizures.

Temporal associations identified in previous experience with related
products can help focus sponsor analyses of potential temporal
associations for a product under study, but sponsors should balance this
approach with an attempt to detect unanticipated events and associations
as well. Knowledge of a product's pharmacokinetic and pharmacodynamic
profiles, as well as an appreciation of physiologic, metabolic, and host
immune responses, may be important in understanding the possible timing
of treatment-related adverse events.

It is important to consider study and concomitant treatment regimens
(i.e., single treatment; short course of treatment; continuous,
intermittent, titrated, or symptom-based treatment) in temporal
analyses. Other important factors to consider in planning and
interpreting temporal analyses are (1) the initiation or withdrawal of
therapies and (2) changes in the severity or frequency of subjects'
preexisting conditions over time.

For events that decrease in frequency over time and are found to be
associated with the initiation of treatment, supplemental analyses may
be of value to discriminate the relative contributions of adaptation,
tolerance, dose reduction, symptomatic treatment, decreases in
reporting, and subject dropout.

## C. Analyzing Dose Effect as a Contribution to Risk Assessment

Sponsors should analyze event rates by dose for clinically important
adverse events that may be product related and events that might be
expected based on a product's pharmacologic class or preclinical data.

For studies involving the evaluation of a range of doses, dose response
is most commonly assessed by analyzing adverse event frequencies by
administered dose. In such studies, it may also be useful to consider
event frequencies by weight-adjusted or body surface area-adjusted dose,
especially if most patients are given the same dose regardless of body
weight or size. It should be recognized, however, that when doses are
adjusted by a subject's weight or body surface area, women are commonly
overrepresented on the upper end of the range of adjusted doses, and men
are commonly overrepresented on the lower end of this range. For
products administered over prolonged periods, it may be useful to
analyze event rates based on cumulative dose. In addition, when specific
demographic or baseline disease-related subgroups may be at particular
risk of incurring adverse events, exploration of dose response
relationships by subgroup is important.

Although the most reliable information on dose response comes from
randomized fixed dose studies, potentially useful information may emerge
from titration studies and from associations between adverse events and
plasma drug concentrations.

For dose titration or flexible dose studies, it would generally be
useful to assess the relationship between adverse event frequencies and
the actual doses subjects received preceding the adverse events or the
cumulative dose they received at the onset of the events. The choice is
a function of the mode of action, pharmacokinetics, and pharmacodynamics
of the product.

For products with a stepped dosing algorithm (i.e., incremental dosing
based on age or weight), the actual cut points of the paradigm are often
arbitrary in nature. It may be useful in such cases to make a specific
effort to examine safety (and efficacy) just above and below the cut
points. For example, if the dose of a product is to be 100 mg for
patients weighing less than 80 kg and 150 mg for patients weighing 80 kg
or more, an assessment of the comparative safety profiles of patients
weighing from 75 to 79.9 kg versus patients weighing from 80 to 84.9 kg
would be valuable.

As is typical of most safety evaluations, the likelihood of observing
false positive signals increases with the number of analyses conducted.
Positive associations between adverse events and dose, distinguished in
post hoc explorations of the data, should be considered with this in
mind. Such associations should be examined for consistency across
studies, if possible.

## D. Role of Data Pooling in Risk Assessment

Data pooling is the integration of patient-level outcome data from
several clinical studies to assess a safety outcome of interest.
Generally, data pooling is performed to achieve larger sample sizes and
data sets because individual clinical studies are not designed with
sufficient sample size to estimate the frequency of low incidence events
or to compare differences in rates or relative rates between the test
drug (exposed group) and the control (unexposed group). Use of pooled
data does not imply that individual study results should not be examined
and considered. When pooling data, sponsors should consider the
possibility that various sources of systematic differences can interfere
with interpretation of a pooled result. To ensure that pooling is
appropriate, sponsors should confirm that study designs as well as
ascertainment and measurement strategies employed in the studies that
are pooled are reasonably similar. Data pooling can be used for
comparative studies or for single-arm studies. Used appropriately,
pooled analyses can enhance the power to detect an association between
product use and an event and provide more reliable estimates of the
magnitude of risk over time. Pooled analyses can also provide insight
into a positive signal observed in a single study by allowing a broader
comparison. This can protect against chance findings in individual
studies. However, a finding should not be automatically dismissed,
especially if it is detected in a study of superior design or in a
different population.

Although false positive signals resulting from data pooling are
concerning, a false negative signal may have larger public health
implications. False negative signals may result from inappropriate
pooling. Therefore, any pooled analyses resulting in a reduced
statistical association between a product and an observed risk or
magnitude of risk, as compared to the original safety signal obtained
from one or more of the contributing studies, should be carefully
examined. Some issues for consideration include, but are not limited to,
differences in the duration of studies, heterogeneous patient
populations, and case ascertainment differences across studies (i.e.,
different methods for detecting the safety outcomes of interest, such as
differences in the intensities of patient follow-up).

A pooled analysis may be less informative when there is clinical
heterogeneity with regard to the safety outcome of interest (e.g., major
differences between trials). In these cases, sponsors should present
risk information on the range of results in individual studies
separately, rather than use a summary value from a pooled analysis.

## E. Using Pooled Data During Risk Assessment

All placebo-controlled studies in a clinical development program should
be considered and evaluated for appropriateness for inclusion in a
pooled analysis. Decisions to exclude certain placebo-controlled studies
from, or to add other types of studies (such as active-controlled
studies or open-label studies) to, a pooled analysis would depend on the
objectives of the analysis. Such analyses should be conducted in a
manner that is consistent with the following guiding principles:

-   Generally, phase 1 pharmacokinetic and pharmacodynamic studies
    should be excluded.

> These are usually single- or multiple-dose trials of a short duration
> conducted in healthy subjects or in patients with refractory or
> incurable end-stage disease who have confounding symptoms. Unless a
> risk were limited to a short period immediately after the first dose,
> inclusion of these studies in a pooled analysis would not increase the
> statistical power or contribute to the precision of the risk
> estimates. However, inclusion of these studies could (1) diminish the
> magnitude of apparent risk by including a population with little or no
> possibility of having had the adverse reaction or (2) increase the
> apparent magnitude of risk because of significant baseline symptoms
> unrelated to the drug;

-   The risk of the safety outcome of interest should be expressed in
    reference to total person-time (exposure time) or be evaluated using
    a time-to-event analysis.

> When the duration of drug exposure for the individual subjects
> included in a pooled analysis varies, sponsors should not express the
> risk merely in terms of *event frequency* (that is, using persons as
> the denominator). Use of the person-time approach relies on the
> assumption that the risk is constant over the period of the studies.
> Whenever there is concern regarding a non-constant nature of a risk, a
> time-to-event log-rank type analysis may be helpful, as it is a robust
> approach even when risk is not constant over time;

-   The patient population in the pooled analysis should be relatively
    homogeneous with respect to factors that may affect the safety
    outcome of interest (e.g., dose received, duration of therapy).

> The pooled analysis is most likely to be of a size sufficient to allow
> analyses of demographic subgroups (gender, age, race, geographic
> locations);

-   The studies included in a pooled analysis should have used similar
    methods of adverse event ascertainment, including ascertainment of
    the cause of drop outs.

> Study-specific incidence rate should be calculated and compared for
> any signs of case ascertainment differences. Since study-to-study
> variation is to be expected, it is a challenge to distinguish between
> possible case ascertainment differences and study-to-study variation.

There are some situations in which pooling may be relatively
straightforward. For example, a pooled analysis of similarly designed
phase 3 studies could readily be used to create a table of common
adverse events. This type of analysis is typically less subject to the
problems discussed above because (1) the studies are similar in study
design and patient population and (2) the intent of such an analysis is
often more descriptive than quantitative. However, if a specific safety
concern is raised during the clinical development program, the guiding
principles discussed above should be closely followed whenever a pooled
analysis is planned.

## F. Rigorous Ascertainment of Reasons for Withdrawals from Studies 

Subjects may dropout or withdraw from clinical trials for many reasons,
including perceived lack of efficacy, side effects, serious adverse
events, or an unwillingness to expend the effort necessary to continue.
The reasons for dropout are not always clear. This lack of information
may be largely irrelevant (e.g., discontinuation due to moving from the
area) or indicative of an important safety problem (e.g., stroke).
Therefore, regardless of the reason for withdrawal, sponsors should
account for all dropouts and try to ascertain what precipitated dropout
or withdrawal in all cases, particularly if a safety issue was a part of
the reason for withdrawal. It is not helpful to simply record vague
explanations such as "withdrew consent," "failed to return," or "lost to
follow-up." Participants who leave a study because of serious or
significant safety issues should be followed closely until they are
fully and permanently resolved, with follow-up data recorded in the case
report forms.

## G. Long-term Follow-up 

In some cases, it is recommended that all subjects be followed to the
end of the study or even after the formal end of the study (e.g., where
the drug has a very long half-life, is deposited in an organ such as
bone or brain, or has the potential for causing irreversible effects,
such as cancer). The concern over adequate follow-up for ascertaining
important safety events in such cases is particularly critical in
long-term treatment and clinical outcome studies. In such cases, FDA
recommends the follow-up for late safety events, even for subjects off
therapy, include those subjects who drop out of the trial or who finish
the study early due to meeting a primary outcome of interest.

## H. Important Aspects of Data Presentation

Once a product's safety data have been analyzed, we recommend that
comprehensive risk assessment information be presented succinctly. FDA
and ICH have provided extensive guidance regarding the presentation of
safety data,[^12]^,^[^13] and we offer these additional recommendations,
which have not been formerly addressed.

-   For selected adverse events, adverse event rates using a range of
    more restrictive to less restrictive definitions (e.g., myocardial
    infarction versus myocardial ischemia) should be summarized.

> The events chosen for such a summary might be limited to more serious
> events and events that are recognized to be associated with the
> relevant class of drugs;

-   For a drug that is a new member of an established class of drugs,
    the adverse events that are common to the class should be fully
    characterized in the NDA's integrated summary of safety.

> That characterization should include an analysis of the incidence of
> the pertinent adverse events, as well as any associated laboratory,
> vital sign, or ECG data. For example, the characterization of a drug
> joining a class that is associated with orthostatic hypotension would
> include analyses of orthostatic blood pressure changes as well as the
> incidence of syncope, dizziness, falls, or other events. When
> establishing case definitions for particular adverse events, we
> recommend that sponsors consider definitions previously used for the
> other drugs in the class.

-   The distribution of important variables across the pooled data, such
    as gender, age, extent of exposure, concomitant medical conditions,
    and concomitant medications (especially those that are used commonly
    to treat the indication being studied), should be included in the
    integrated summary of safety.

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-   The effect of differential discontinuation rates by treatment on
    adverse event occurrence should be characterized (e.g., when
    placebo-treated patients drop out of a trial earlier than patients
    being treated with an active drug)*.* This differential
    discontinuation can lead to misleading adverse event incidences
    unless patient exposure is used as the denominator for risk
    calculations.

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-   Case report forms (CRFs) submitted for patients who died or
    discontinued a study prematurely due to an adverse event should
    include hospital records, autopsy reports, biopsy reports, and
    radiological reports, where applicable.

> These source documents should become a formal part of the official CRF
> and be properly referenced.

-   Narrative summaries (as previously described in guidance[^14]) of
    important adverse events (e.g., deaths, events leading to
    discontinuation, other serious adverse events) should provide the
    detail necessary to permit an adequate understanding of the nature
    of the adverse event experienced by the study subject.

> Narrative summaries should not merely provide, in text format, the
> data that are already presented in the case report tabulation, as this
> adds little value. A valuable narrative summary would provide a
> complete synthesis of all available clinical data and an informed
> discussion of the case, allowing a better understanding of what the
> patient experienced. The following is a list of components that would
> be found in a useful narrative summary:
>
> -- Patient age and gender
>
> -- Signs and symptoms related to the adverse event being discussed
>
> -- An assessment of the relationship of exposure duration to the
> development of the adverse event
>
> -- Pertinent medical history
>
> -- Concomitant medications with start dates relative to the adverse
> event
>
> -- Pertinent physical exam findings
>
> -- Pertinent test results (e.g., lab data, ECG data, biopsy data)
>
> -- Discussion of the diagnosis as supported by available clinical data
>
> -- For events without a definitive diagnosis, a list of the
> differential diagnoses
>
> -- Treatment provided
>
> -- Re-challenge results
>
> -- Outcomes and follow-up information

[^1]: This guidance has been prepared by the Center for Drug Evaluation
    and Research (CDER) and the Center for Biologics Evaluation and
    Research (CBER) at the Food and Drug Administration.

[^2]: For ease of reference, this guidance uses the terms *product* and
    *drug* to refer to all products (excluding blood and blood
    components) regulated by CDER or CBER. Similarly, for ease of
    reference, this draft 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]: Section 505(d)(1) of the Federal Food, Drug, and Cosmetic Act (21
    U.S.C. 355(d)(1)) requires the conduct of \"adequate tests by all
    methods reasonably applicable to show whether or not . . . \[a\]
    drug is safe for use under the \[labeled\] conditions. . . ." See
    also 21 CFR 314.50(d)(5)(vi). Section 351 of the Public Health
    Service Act (42 U.S.C. 262) requires a demonstration that a biologic
    is \"safe, pure, and potent.\" See also 21 CFR 601.2.

[^5]: See the guidance for industry *E1A The Extent of Population
    Exposure to Assess Clinical Safety: For Drugs Intended for Long-Term
    Treatment of Non-Life-Threatening Conditions*, endorsed by the
    International Conference on Harmonisation of Technical Requirements
    for Registration of Pharmaceuticals for Human Use (ICH) and
    published in the *Federal Register* on March 1, 1995 (60 FR 11270).

[^6]: Subpart E of 21 CFR part 312 addresses investigational new drug
    (IND) applications for drugs intended to treat life-threatening and
    severely debilitating illnesses.

[^7]: See the guidance for industry *E1A The Extent of Population
    Exposure to Assess Clinical Safety: For Drugs Intended for Long-term
    Treatment of Non-Life-Threatening Conditions.*

[^8]: The memorandum from Janet Woodcock, M.D., to Michael Friedman,
    M.D., dated July 20, 1998, and titled *FDAMA -- Women and Minority
    Guidance Requirements* (with its attached report) discusses the
    regulations related to diversity. The memorandum can be found on the
    CDER guidance Web page under FDAMA guidances
    (<http://www.fda.gov/cder/guidance/women.pdf>).

[^9]: See FDA's guidance for industry *Exposure-Response Relationships
    --- Study Design, Data Analysis, and Regulatory Applications.*

[^10]: ^?^ The *Pharmacovigilance Guidance* discusses additional risk
    assessment strategies that may be initiated either pre- or
    postapproval. In particular, the *Pharmacovigilance Guidance*
    includes a detailed discussion of pharmacoepidemiologic safety
    studies. Although such studies should principally be initiated after
    marketing, the *Pharmacovigilance Guidance* discusses certain
    situations when they could be initiated preapproval.

[^11]: As mentioned in the *RiskMAP Guidance*, an LSSS could also be a
    method of evaluating the effectiveness of RiskMAP tools in actual
    practice prior to approval.

[^12]: See *Guideline for the Format and Content of the Clinical and
    Statistical Section of an Application*.

[^13]: See the guidance for industry *E3 Structure and Content of
    Clinical Study Reports*.

[^14]: See the guidance for industry *E3 Structure and Content of
    Clinical Study Reports*.