**Guidance for Industry**

**Premarketing Risk Assessment**

**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

**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*

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*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*

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*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)**

**March 2005**

**Clinical Medical**

##  {#section .TOC-2}

**TABLE OF CONTENTS**

# 

#  {#section-2 .TOC-1 .unnumbered}

# I. INTRODUCTION [2](#i.-introduction)II. BACKGROUND [3](#ii.-background) {#i.-introduction-2ii.-background-3 .TOC-1}

## A. PDUFA III's Risk Management Guidance Goal [3](#a.-pdufa-iiis-risk-management-guidance-goal) {#a.-pdufa-iiis-risk-management-guidance-goal-3 .TOC-2}

## B. Overview of the Risk Management Guidances [3](#b.-overview-of-the-risk-management-guidances) {#b.-overview-of-the-risk-management-guidances-3 .TOC-2}

# III. THE ROLE OF RISK ASSESSMENT IN RISK MANAGEMENT [4](#iii.-the-role-of-risk-assessment-in-risk-management) {#iii.-the-role-of-risk-assessment-in-risk-management-4 .TOC-1}

# IV. GENERATING RISK INFORMATION DURING CLINICAL TRIALS [5](#iv.-generating-risk-information-during-clinical-trials) {#iv.-generating-risk-information-during-clinical-trials-5 .TOC-1}

## A. Size of the Premarketing Safety Database [6](#a.-size-of-the-premarketing-safety-database) {#a.-size-of-the-premarketing-safety-database-6 .TOC-2}

## B. Considerations for Developing a Premarketing Safety Database [8](#b.-considerations-for-developing-a-premarketing-safety-database) {#b.-considerations-for-developing-a-premarketing-safety-database-8 .TOC-2}

### 1. Long-Term Controlled Safety Studies [9](#long-term-controlled-safety-studies) {#long-term-controlled-safety-studies-9 .TOC-3}

### 2. A Diverse Safety Database [9](#a-diverse-safety-database) {#a-diverse-safety-database-9 .TOC-3}

### 3. Exploring Dose Effects Throughout the Clinical Program [10](#exploring-dose-effects-throughout-the-clinical-program) {#exploring-dose-effects-throughout-the-clinical-program-10 .TOC-3}

## C. Detecting Unanticipated Interactions as Part of a Safety Assessment [11](#c.-detecting-unanticipated-interactions-as-part-of-a-safety-assessment) {#c.-detecting-unanticipated-interactions-as-part-of-a-safety-assessment-11 .TOC-2}

## D. Developing Comparative Safety Data [12](#d.-developing-comparative-safety-data) {#d.-developing-comparative-safety-data-12 .TOC-2}

# V. SPECIAL CONSIDERATIONS FOR RISK ASSESSMENT [12](#__RefHeading___Toc98731670) {#v.-special-considerations-for-risk-assessment-12 .TOC-1}

## A. Risk Assessment During Product Development [13](#a.-risk-assessment-during-product-development) {#a.-risk-assessment-during-product-development-13 .TOC-2}

## B. Assessing and Minimizing the Potential for Medication Errors [14](#b.-assessing-and-minimizing-the-potential-for-medication-errors) {#b.-assessing-and-minimizing-the-potential-for-medication-errors-14 .TOC-2}

## C. Addressing Safety Aspects During Product Development [16](#c.-addressing-safety-aspects-during-product-development) {#c.-addressing-safety-aspects-during-product-development-16 .TOC-2}

# VI. DATA ANALYSIS AND PRESENTATION [17](#vi.-data-analysis-and-presentation) {#vi.-data-analysis-and-presentation-17 .TOC-1}

## A. Describing Adverse Events to Identify Safety Signals [17](#a.-describing-adverse-events-to-identify-safety-signals) {#a.-describing-adverse-events-to-identify-safety-signals-17 .TOC-2}

### 1. Accuracy of Coding [17](#__RefHeading___Toc98731676) {#accuracy-of-coding-17 .TOC-3}

### 2. Coding Considerations During Adverse Event Analysis [19](#coding-considerations-during-adverse-event-analysis) {#coding-considerations-during-adverse-event-analysis-19 .TOC-3}

## B. Analyzing Temporal or Other Associations [20](#b.-analyzing-temporal-or-other-associations) {#b.-analyzing-temporal-or-other-associations-20 .TOC-2}

## C. Analyzing Dose Effect as a Contribution to Risk Assessment [21](#c.-analyzing-dose-effect-as-a-contribution-to-risk-assessment) {#c.-analyzing-dose-effect-as-a-contribution-to-risk-assessment-21 .TOC-2}

## D. Role of Data Pooling in Risk Assessment [22](#d.-role-of-data-pooling-in-risk-assessment) {#d.-role-of-data-pooling-in-risk-assessment-22 .TOC-2}

## E. Using Pooled Data for Risk Assessment [22](#e.-using-pooled-data-for-risk-assessment) {#e.-using-pooled-data-for-risk-assessment-22 .TOC-2}

## F. Rigorous Ascertainment of Reasons for Withdrawals from Studies [24](#f.-rigorous-ascertainment-of-reasons-for-withdrawals-from-studies) {#f.-rigorous-ascertainment-of-reasons-for-withdrawals-from-studies-24 .TOC-2}

## G. Long-term Follow-up [24](#g.-long-term-follow-up) {#g.-long-term-follow-up-24 .TOC-2}

## H. Important Aspects of Data Presentation [25](#h.-important-aspects-of-data-presentation) {#h.-important-aspects-of-data-presentation-25 .TOC-2}

#####  {#section-3 .TOC-5 .unnumbered}

**Guidance for Industry**[^1]

**Premarketing Risk Assessment**

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 good risk assessment
practices during the development of prescription drug products,
including biological drug products.[^2] This is one of three guidances
that were developed to address 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 developing 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.

-   *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 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 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
potential product, through the premarketing development process, and
after approval during 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. Sponsors seeking approval must provide from the
clinical trials a body of evidence that adequately characterizes the
product\'s safety profile.[^4]

This guidance provides general recommendations for assessing risk. The
adequacy of the assessment of risk is a matter of both quantity
(ensuring that enough patients are studied) and quality (the
appropriateness of the assessments performed, the appropriateness and
breadth of the patient populations studied, 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 from the outset of development, sponsors pay careful attention 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. Therefore, it is
expected that, even for a product that is rigorously tested preapproval,
some risks will become apparent only after approval, when the product is
used in tens of thousands or even millions of patients in the general
population. Although no preapproval database can possibly be sized to
detect all safety issues that might occur with the product once marketed
in the full population, the larger and more comprehensive the
preapproval database, the more likely it is that serious adverse events
will be detected during drug development.

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 availability of alternative therapies and the relative safety of
    those alternatives as compared to the new product

-   The intended population and condition being treated

-   The intended duration of use

Safety databases for products intended to treat life-threatening
diseases, especially in circumstances where there are no alternative
satisfactory treatments, are usually smaller than for products intended
to treat diseases that are neither life-threatening nor associated with
major, irreversible morbidity. 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. The appropriate size of the
preapproval safety database may warrant specific discussion with the
relevant review division. For instance, 21 CFR 312.82(b) (subpart E)
provides that for drugs intended to treat life-threatening and seriously
debilitating illnesses, end-of-phase 1 meetings can 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."

For products intended for short-term or acute use (e.g., treatments that
continue for, or are cumulatively administered for, less than 6 months),
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. Because
products intended for life-threatening and severely debilitating
diseases are often approved with relatively small safety databases,
relatively greater uncertainty remains regarding their adverse effects.
Similarly, when products offer a unique, clinically important benefit to
a population or patient group, less certainty in characterizing risk
prior to approval may be acceptable.

For products intended for long-term treatment of non-life-threatening
conditions, (e.g., continuous treatment for 6 months or more or
recurrent intermittent treatment where cumulative treatment equals or
exceeds 6 months), 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).[^6] 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 subjects exposed for 1 year
should have been exposed to relevant doses (i.e., doses generally in the
therapeutic range**)**

We note that it is common for well-conducted clinical development
programs to explore doses higher than those ultimately proposed for
marketing. For example, a dose tested in clinical trials may offer no
efficacy advantage and show some dose-related toxicities; therefore, the
sponsor does not propose the dose for marketing when the application is
submitted. In such cases, data from subjects exposed to doses in excess
of those ultimately proposed are highly informative for the safety
evaluation 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.

The determination of whether the above provisions of the ICH E1A
guidance are appropriate for a particular product development program
and how these considerations would best be addressed by that program
calls for evaluation on a case-by-case basis. Therefore, FDA recommends
that this issue be discussed with the relevant review division at the
end-of-phase 2 meeting, if not earlier.

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\. An effective alternative to the investigational product is already
available and has been shown to be safe.

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
(e.g., at the pre-IND meeting) 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 (e.g., use of the Medical Dictionary for
Regulatory Activities (MedDRA)) 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 subject 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
(i.e., the ethical and medical feasibility of using a placebo versus an
active comparator will depend 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) would be considered
    significant and interpretable whenever (1) they are clearly
    documented and (2) there is no likely alternative explanation, since
    the expected rate is essentially zero in populations of any feasible
    size. As a result, the events can usually be appropriately
    interpreted and regarded as a signal of concern whether or not there
    is 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
should be conducted for a product 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 earlier
clinical and preclinical safety assessments. Although it is clear that
long-term controlled studies will not usually be conducted, such studies
may be particularly useful when a safety issue is identified during
earlier development of the drug. In these cases, safety studies designed
to test specific safety hypotheses may be appropriate. This would be
especially true in situations where the safety issue of concern is more
common with cumulative exposure. (See section IV.D below for further
discussion of comparative trials.)

### 2. A Diverse Safety Database

Premarketing safety databases should include, to the extent possible, a
population sufficiently diverse to adequately represent the expected
target population, particularly in phase 3 studies. FDA has previously
addressed this issue in a memorandum,[^7] and the recommendations
provided here are intended to supplement that document. To the extent
feasible, only patients with obvious contraindications or other clinical
considerations that clearly dictate exclusion should be excluded from
study entry. Inclusion of a diverse population allows for the
development of safety data in a broad population that includes patients
sometimes excluded from clinical trials, such as the elderly
(particularly the very old), patients with concomitant diseases, and
patients taking concomitant medications. Broadening inclusion criteria
in phase 3 enhances the generalizability of the safety (and efficacy)
findings. Although some phase 3 efficacy studies may target certain
demographic or disease characteristics (and have narrower inclusion and
exclusion criteria), overall, the phase 3 studies should include a
substantial amount of data from 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 during drug development 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

Although phase 3 trials do not necessarily need to examine a range of
doses, such an examination is highly desirable, particularly when phase
2 studies cannot reasonably be considered to have established a single
most appropriate dose. When a dose is not established in phase 2, more
than one dose level should be examined in phase 3 trials of fixed dose
products to better characterize the relationship between product
exposure and resulting clinical benefit and risk. Dose-response data
from phase 3 trials with multiple dose levels will help to better define
the relationship of clinical response to dose for both safety and
effectiveness. Furthermore, inadequate exploration of a product's
dose-response relationship in clinical trials can raise safety concerns,
since recommending doses in labeling that exceed the amount needed for
effectiveness may increase risk to patients through dose-related
toxicities 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.[^8] When multiple dose levels are examined in phase 3
trials, the appropriate choice of doses to be included in these studies
would be based on prior efficacy and safety information, including prior
dose-ranging studies. In these circumstances, an end-of-phase 2 meeting
with the appropriate review division would be particularly useful.

## 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 examine a number of 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 (e.g., examination of the interactions
    between a new drug for the treatment of depression and St. John's
    Wort).

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 systematic
incorporation of pharmacokinetic (PK) assessments (e.g., universal
steady state sampling or population PK analyses) into some or all of the
later phase clinical trials, including any specific safety trials. PK
assessments can aid in the detection of unexpected PK interactions and,
in some cases, could suggest exposure-response relationships for both
safety and efficacy. Such data would allow for better assessment of
whether pharmacokinetics contribute to any adverse events seen in the
clinical trials, particularly rare, serious, and unanticipated events.

When a product has one or more well-established, valid 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. The additional use of a placebo would help to show whether
> either drug actually caused the adverse events.

-   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.
>
> In situations where there is a well-established related therapy, a
> comparative study of the new agent against that well-established
> therapy would be desirable (e.g., a new NSAID-like drug could be
> compared to a market-leading NSAID). Such a 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.

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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. [^9]

## A. Risk Assessment During Product Development

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

-   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 or specific
    assessments within existing trials may be appropriate.

> For example, for a new drug with recognized CNS effects (especially
> sedating effects), sponsors should conduct an assessment of cognitive
> function, motor skills, and mood. Similarly, since many
> antidepressants have significant effects on sexual function, new
> antidepressants should be assessed for these effects. 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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-   A sponsor may consider reserving blood samples (or any other bodily
    fluids/tissues collected during clinical trials) from some or all
    patients in phase 3 studies for possible assessments at a later
    time, particularly in circumstances when earlier safety data signal
    an unusual or important concern. Such later assessments could
    include pharmacogenomic markers, assessments for 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 unusual 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 --- for example, to assess
the rate of rare events (i.e., events so uncommon that usual safety
studies would not be expected to provide good estimates of risk).
Although an LSSS would most commonly be performed postapproval, either
as a phase 4 commitment to address a lingering safety issue that does
not preclude approval or outside of a formal phase 4 commitment in
response to a new safety concern that arises after marketing, there are
instances where an LSSS may be appropriate prior to approval. This would
be the case when, for instance, 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
appropriate if the safety signal cannot otherwise be better delineated
and the safety signal would have an impact on approvability.[^10]

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. Assessing and Minimizing the Potential for Medication Errors 

Sponsors can help minimize the occurrence of medication errors by
assessing, prior to marketing, common sources of medication errors. Such
errors may arise because of the product's inherent properties or because
of the inadvertent contribution of the proposed proprietary name, the
established name, the proposed labeling (e.g., container, carton,
patient/consumer labeling, or professional package insert), and the
proposed packaging.

Some medication errors, especially those involving parenteral products,
have been detected in clinical trials prior to marketing. When occurring
in clinical trials, events such as improper dilution or improper
administration techniques, which may result in non-optimal dosing,
should be carefully examined as warning signs that the product could be
subject to dosing errors that warrant changes in labeling, packaging, or
design. Even if errors are not observed in trials, careful consideration
should be given during development to the implications of the design of
the product, its packaging, and any device used to administer or deliver
the product. For example, when a concentrated product that requires
further dilution prior to intravenous administration is being developed,
packaging is important. Packaging such a product in a syringe would make
it possible to inject the product as a bolus without proper dilution,
increasing risks to patients. Similarly, when developing a product that
is administered or delivered by a device, the implications of mechanical
failure of the device should be examined. Any such occurrences seen or
considered during product development should be documented, reported,
and analyzed for potential remedial actions (e.g., redesign of the
device or modification of instructions for use).

Medication errors arising from confusion because of the similarity of
the drug name, when written and spoken, to the name of another drug are
less likely to be detected prior to marketing due to the controlled
environment of clinical trials. However, the many well-documented cases
of medication errors associated with similar proprietary names,
confusing labels and labeling, and product packaging suggest it is
important that sponsors carefully consider these issues before marketing
a product.

Premarketing assessments should focus on:

-   Identifying all medication errors that occur during product
    development

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

-   Assessing the resultant risk in the context of how and in whom the
    product will be used

-   Identifying the means to minimize, reduce or eliminate the
    medication errors by ensuring the proper naming, labeling, design,
    and packaging of the product

Depending on the nature of the product, the indication, how it is
administered, who will be receiving it, and the context in which it will
be used, one or more of the following techniques may be helpful in
assessing and preventing medication errors:

-   Conducting a Failure Mode and Effects Analysis[^11]^,^ [^12]

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-   Use of expert panels

-   Use of computer-assisted analysis

-   Use of direct observation during clinical trials

-   Directed interviews of consumers and medical and pharmacy personnel
    to better understand comprehension

-   Use of focus groups

-   Use of simulated prescription and over-the-counter (OTC) use studies

Additional information on the application of these assessment techniques
will be published in a future guidance document.

## C. Addressing Safety Aspects During Product Development 

FDA recommends addressing the potential for the following serious
adverse effects as a part of the new drug application (NDA) for all new
small molecule drugs:

-   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 these effects can often be identified
when properly assessed in clinical development programs. Although FDA
believes it is important to address these potential effects in all NDAs,
adequately addressing all of these considerations would not necessarily
involve the generation of additional data or the conduct of specific
trials. (For some issues, such as QTc, specifically conducted
preclinical and clinical studies are generally recommended.) 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.

Some of the above-listed 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 guidances *E3 Structure and Content of Clinical Study
Reports* and *M4* *Common Technical Document for the Registration of
Pharmaceuticals for Human Use*. We do not repeat that guidance here, but
offer new guidance on selected issues.

With regard to the guidance offered in this section of the document, it
is important to emphasize that the regulatory approach to the evaluation
of the safety of a product usually differs substantially from the
evaluation of effectiveness. Most studies in the later phases of drug or
biologic development are directed toward establishing effectiveness. In
such studies, critical efficacy endpoints are identified in advance, and
statistical planning is conducted based on being able to make definitive
statistical inferences about efficacy. In contrast, these later phase
trials are not generally designed to test specified hypotheses about
safety or to measure or identify adverse events with any prespecified
level of sensitivity. Therefore, the premarket safety evaluation is
often, by its nature, exploratory and is intended to identify common
adverse events related to the therapy, as well as to help identify
signals for serious and/or less common adverse events.

## A. Describing Adverse Events to Identify Safety Signals

Because individual investigators may use different terms to describe a
particular adverse event, FDA recommends that sponsors 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 (e.g., MedDRA) throughout a clinical program with the
understanding that, due to the duration of product development, the
coding convention used may undergo revisions. 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. To the extent possible, sponsors should use a single version
of the selected convention or dictionary without revisions. However, if
this is not possible, it is important to appropriately group and analyze
adverse events taking into account the revisions in subsequent versions.
It is not advisable to analyze adverse event data using one version and
then base proposed labeling on a different
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### 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 an adverse event is 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, be well documented with an audit trail.

-   We recommend that in addition to ensuring that investigators have
    accurately characterized adverse events, 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 coding 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 lability*.

-   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. FDA recommends that to examine the
> extent of variability in the coding process, 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 coding 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 circumstances. 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 or use accepted standardized 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 potential 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 may be obscured 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 potential causality. Analyses of temporal associations are
particularly worth conducting in situations where prior experience
(e.g., experience from similar products) has shown that a temporal
relationship between product exposure and ensuing adverse events is
likely to exist. 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 or 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, depletion of susceptibles, 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. Subgroup analyses have the
potential to provide a more reliable and relevant estimate of risk for
important subgroups of the target population. Alternatively,
multiplicity issues could result in an apparent signal that does not
represent a real finding (i.e., a false positive).

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
selected relatively early in product development. Although the cut
points may be based on the best knowledge available at the time, it is
useful in such cases to make a specific effort to explore safety (and
efficacy) just above and below these 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, as well as
signals that emerge from subgroup analysis, 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.

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 undue weight
being given to chance findings in individual studies. However, a finding
from a single study should not be automatically dismissed because of the
results of a pooled analysis, especially if it is detected in a study of
superior design or in a different population. Any pooled analysis
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 in deciding whether pooling is appropriate
include possible differences in the duration of studies, heterogeneity
of 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).
When there is clinical heterogeneity among trials with regard to the
safety outcome of interest (e.g., major disparity in findings for
particular safety endpoints), sponsors should present risk information
that details the range of results observed in the individual studies,
rather than producing a summary value from a pooled analysis.

## 

## E. Using Pooled Data for 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 should 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 dropouts.

> 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 when conducting a
prespecified pooled analysis.

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

Subjects may drop out 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
attempt to account for all dropouts.

-   Sponsors should 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," "administratively withdrawn,"
> or "lost to follow-up."

-   Participants who leave a study because of serious or significant
    safety issues should be followed closely until the adverse events
    are fully and permanently resolved or stabilized (if complete
    resolution is not anticipated), with follow-up data recorded in the
    case report forms.

-   Follow-up information should be pursued on patients withdrawn from
    the study (for reasons other than withdrawing consent in the absence
    of an adverse event).

> If this information is not obtainable, FDA recommends that the
> measures taken to obtain follow-up information be reflected on the
> case report forms and the resultant failure to obtain the information
> should be discussed in the clinical discussion of safety.

-   Patients considering withdrawing consent should be encouraged to
    provide the reason, and patients who withdraw should be encouraged
    to provide information as to whether the withdrawal of consent
    resulted from a serious or significant safety issue.

-   Some patients withdraw due to abnormal laboratory values, vital
    signs, or ECG findings that are not characterized as adverse events.
    Sponsors should include information on these types of
    discontinuations in addition to information on discontinuations due
    to adverse events.

## 

## 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. The
duration of follow-up, however, would be dependent on the circumstances
of the product development and therefore should be discussed with the
appropriate review division (e.g., during end-of-phase 2 meetings).

## H. Important Aspects of Data Presentation

We recommend that once a product's safety data have been analyzed,
comprehensive risk assessment information be presented succinctly. FDA
and ICH have provided extensive guidance regarding the presentation of
safety data,[^13]^,^[^14]^,^ [^15]and we offer these additional
recommendations, which have not been addressed previously.

-   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 important for the class of drug 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. We recommend
> that when sponsors are establishing case definitions for particular
> adverse events, they consider definitions previously used for the
> other drugs in the class or, if available, standard definitions.

-   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 copies of relevant hospital records, autopsy reports, biopsy
    reports, and radiological reports, when feasible. The possibility
    that such information may be reported to FDA should be stated in the
    informed consent document with a notation that the patient would not
    be identified in such reports.

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

-   Narrative summaries (as previously described in guidance[^16]) 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. (This level
    of detail may be unnecessary for events expected in the population
    (e.g., late deaths in a cancer trial). This issue should be
    discussed with the appropriate review division.)

> 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 (if performed)
>
> -- 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, including vaccines.
    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*, International
    Conference on Harmonisation (ICH).

[^6]: 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*, ICH*.*

[^7]: 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 page under Modernization Act guidance
    (http://www.fda.gov/cder/guidance/women.pdf).

[^8]: See FDA's guidance for industry *Exposure-Response Relationships
    --- Study Design, Data Analysis, and Regulatory Applications.*

[^9]: ^?^ 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 would principally be initiated after
    marketing, the *Pharmacovigilance Guidance* discusses certain
    situations when they could be initiated preapproval.

[^10]: 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.

[^11]: Stamatis, D.H., *Failure Mode and Effect Analysis: FMEA From
    Theory to Execution,.* Milwaukee: American Society for Quality,
    Quality Press, 2003.

[^12]: Cohen, Michael R. ed., *Medication Errors: Causes, Prevention,
    and Risk Management,* Washington D.C.: American Pharmaceutical
    Association, 1999.

[^13]: See *Guideline for the Format and Content of the Clinical and
    Statistical Section of an Application*.

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

[^15]: See the guidance for industry *M4 Common Technical Document for
    the Registration of Pharmaceuticals for Human Use*, ICH.

[^16]: See the guidance for industry *E3 Structure and Content of
    Clinical Study Reports*, ICH.