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

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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)

March 2005

Clinical Medical
Contains Nonbinding Recommendations

i

TABLE OF CONTENTS

I. INTRODUCTION............................................................................................................. 2

II. BACKGROUND ............................................................................................................... 3

A. PDUFA III’s Risk Management Guidance Goal ...................................................................3

B. Overview of the Risk Management Guidances......................................................................3

III. THE ROLE OF RISK ASSESSMENT IN RISK MANAGEMENT............................ 4

IV. GENERATING RISK INFORMATION DURING CLINICAL TRIALS.................. 5

A. Size of the Premarketing Safety Database .............................................................................6

B. Considerations for Developing a Premarketing Safety Database ..........................................8

1. Long-Term Controlled Safety Studies.......................................................................................9

2. A Diverse Safety Database ......................................................................................................9

3. Exploring Dose Effects Throughout the Clinical Program .......................................................10

C. Detecting Unanticipated Interactions as Part of a Safety Assessment..................................11

D. Developing Comparative Safety Data .................................................................................12

V. SPECIAL CONSIDERATIONS FOR RISK ASSESSMENT .................................... 12

A. Risk Assessment During Product Development...................................................................13

B. Assessing and Minimizing the Potential for Medication Errors ..........................................14

C. Addressing Safety Aspects During Product Development ...................................................16

VI. DATA ANALYSIS AND PRESENTATION................................................................ 17

A. Describing Adverse Events to Identify Safety Signals .........................................................17

1. Accuracy of Coding ..............................................................................................................17

2. Coding Considerations During Adverse Event Analysis...........................................................19

B. Analyzing Temporal or Other Associations ........................................................................20

C. Analyzing Dose Effect as a Contribution to Risk Assessment..............................................21

D. Role of Data Pooling in Risk Assessment ............................................................................22

E. Using Pooled Data for Risk Assessment ..............................................................................22

F. Rigorous Ascertainment of Reasons for Withdrawals from Studies....................................24

G. Long-term Follow-up ..........................................................................................................24

H. Important Aspects of Data Presentation .............................................................................25
Contains Nonbinding Recommendations

Guidance for Industry1

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. 

 

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). 
Contains Nonbinding Recommendations

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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)

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

• 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 fourpart 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) 
Contains Nonbinding Recommendations

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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. 

• 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). 

• 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. 

 

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. 
Contains Nonbinding Recommendations

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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. 

 

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). 
Contains Nonbinding Recommendations

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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 lifethreatening and severely debilitating diseases are often approved with relatively small safety 

databases, relatively greater uncertainty remains regarding their adverse effects. Similarly, when 
Contains Nonbinding Recommendations

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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)

 

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. 
Contains Nonbinding Recommendations

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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.
Contains Nonbinding Recommendations

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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 

 

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).
Contains Nonbinding Recommendations

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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. 

 

8

See FDA’s guidance for industry Exposure-Response Relationships — Study Design, Data Analysis, and 

Regulatory Applications.
Contains Nonbinding Recommendations

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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

• Product-disease interactions — by ensuring sufficient variability in disease state and 

concomitant diseases

• 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.
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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.

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

 

9

 The Pharmacovigilance Guidance discusses additional risk assessment strategies that may be initiated either preor postapproval. In particular, the Pharmacovigilance Guidance includes a detailed discussion of 
Contains Nonbinding Recommendations

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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 halflife) and/or has dose-related toxicities, it can be useful to examine whether a lower or less 

frequent maintenance dose would be appropriate.

• 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.

• 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).

• 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 

 

pharmacoepidemiologic safety studies. Although such studies would principally be initiated after marketing, the 

Pharmacovigilance Guidance discusses certain situations when they could be initiated preapproval. 
Contains Nonbinding Recommendations

14

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 

 

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.
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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 Analysis11, 12

• 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.

 

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.
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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 longpersistence 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.
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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 version.

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. 
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• 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 
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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. 

• Some groupings can be constructed only after safety data are obtained, at which time 

consultation with FDA might be considered. 

• 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. 

• For safety signals that are identified toward the end of a development program, the preNDA meeting would be a reasonable time to confer with FDA regarding such groupings 

or case definitions.
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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 
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21

(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.
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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:
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• 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-tostudy 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.
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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 
Contains Nonbinding Recommendations

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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, 15and 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. 

• 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. 

• 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, 

 

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.
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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 guidance16) 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

 

16 See the guidance for industry E3 Structure and Content of Clinical Study Reports, ICH.