Reviewer Guidance 

Conducting a Clinical Safety Review of 

a New Product Application and 

Preparing a Report on the Review 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

February 2005 

Good Review Practices 
Reviewer Guidance 

Conducting a Clinical Safety Review of 

a New Product Application and 

Preparing a Report on the Review 

Additional copies are available from: 

Office of Training and Communication 

Division of Drug Information, HFD-240 

Center for Drug Evaluation and Research 

Food and Drug Administration 

5600 Fishers Lane 

Rockville, MD 20857 

(Tel) 301-827-4573 

 http://www.fda.gov/cder/guidance/index.htm 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

February 2005 

Good Review Practices 
TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. GENERAL GUIDANCE ON THE CLINICAL SAFETY REVIEW .......................... 2

A. Introduction....................................................................................................................................2

B. Explanation of Terms....................................................................................................................3

C. Overview of the Safety Review .....................................................................................................4

D. Differences in Approach to Safety and Effectiveness Data ........................................................4

E. Identifying and Assembling Source Materials for the Safety Review.......................................6

F. Identifying Major Concerns at the Outset...................................................................................7

G. Auditing Source Materials............................................................................................................8

H. The Purpose of Individual Case Review/“Drug-relatedness”....................................................8

III. SPECIFIC GUIDANCE ON THE CONTENT OF THE SAFETY REVIEW............ 9

7.1 Methods and Findings..................................................................................................................11

7.1.1 Deaths.........................................................................................................................................11

7.1.2 Other Serious Adverse Events..................................................................................................15

7.1.3 Dropouts and Other Significant Adverse Events....................................................................16

7.1.3.1 Overall Profile of Dropouts ...................................................................................................16

7.1.3.2 Adverse Events Associated with Dropouts...........................................................................18

7.1.3.3 Other Significant Adverse Events.........................................................................................19

7.1.4 Other Search Strategies ............................................................................................................19

7.1.5 Common Adverse Events..........................................................................................................19

7.1.5.1 Applicant’s Approach to Eliciting Adverse Events in the Development Program...........20

7.1.5.2 Establishing Appropriate Adverse Event Categories and Preferred Terms.....................20

7.1.5.3 Incidence of Common Adverse Events — Assessment of Various Databases...................22

7.1.5.4 Common Adverse Event Tables............................................................................................23

7.1.5.5 Identifying Common and Drug-Related Adverse Events ...................................................23

7.1.5.6 Additional Analyses and Explorations ................................................................................. 24

7.1.6 Less Common Adverse Events .................................................................................................25

7.1.7 Laboratory Findings .................................................................................................................25

7.1.7.1 Overview of Laboratory Testing in the Development Program.........................................26

7.1.7.2 Selection of Studies/Analyses for Drug-Control Comparisons of Laboratory Values.....26
7.1.7.3 Standard Analyses and Explorations of Laboratory Data .................................................27

7.1.7.3.1 Analyses Focused on Measures of Central Tendency ......................................................27

7.1.7.3.2 Analyses Focused on Outliers or Shifts from Normal to Abnormal ...............................27

7.1.7.3.3 Marked Outliers and Dropouts for Laboratory Abnormalities......................................28

7.1.7.4 Additional Analyses and Explorations .................................................................................29

7.1.7.5 Special Assessments: Hepatotoxicity, QTc, Others ............................................................29

7.1.8 Vital Signs ..................................................................................................................................30

7.1.8.1 Extent of Vital Signs Testing in the Development Program ...............................................30

7.1.8.2 Selection of Studies and Analyses for Overall Drug-Control Comparisons......................30

7.1.8.3 Standard Analyses and Explorations of Vital Signs Data...................................................30

7.1.8.3.1 Analyses Focused on Measures of Central Tendency ......................................................30

7.1.8.3.2 Analyses Focused on Outliers or Shifts from Normal to Abnormal ...............................30

7.1.8.3.3 Marked Outliers and Dropouts for Vital Signs Abnormalities .......................................30

7.1.8.4 Additional Analyses and Explorations .................................................................................30

7.1.9 Electrocardiograms (ECGs) .....................................................................................................30

7.1.9.1 Extent of ECG Testing in the Development Program, Including Brief Review of 

Preclinical Results ................................................................................................................................30

7.1.9.2 Selection of Studies and Analyses for Overall Drug-Control Comparisons......................31

7.1.9.3 Standard Analyses and Explorations of ECG Data ............................................................31

7.1.9.3.1 Analyses Focused on Measures of Central Tendency ......................................................31

7.1.9.3.2 Analyses Focused on Outliers or Shifts from Normal to Abnormal ...............................31

7.1.9.3.3 Marked Outliers and Dropouts for ECG Abnormalities.................................................31

7.1.9.4 Additional Analyses and Explorations .................................................................................31

7.1.10 Immunogenicity .......................................................................................................................31

7.1.11 Human Carcinogenicity ..........................................................................................................31

7.1.12 Special Safety Studies..............................................................................................................32

7.1.13 Withdrawal Phenomena/Abuse Potential .............................................................................32

7.1.14 Human Reproduction and Pregnancy Data..........................................................................32

7.1.15 Assessment of Effect on Growth.............................................................................................32

7.1.16 Overdose Experience...............................................................................................................33

7.1.17 Postmarketing Experience......................................................................................................34

7.2 Adequacy of Patient Exposure and Safety Assessments ...........................................................34
7.2.1 Description of Primary Clinical Data Sources (Populations Exposed and Extent of 

Exposure) Used to Evaluate Safety .....................................................................................................34

7.2.1.1 Study Type and Design/Patient Enumeration......................................................................35

7.2.1.2 Demographics .........................................................................................................................36

7.2.1.3 Extent of Exposure (Dose/Duration).....................................................................................36

7.2.2 Description of Secondary Clinical Data Sources Used to Evaluate Safety...........................36

7.2.2.1 Other Studies ..........................................................................................................................37

7.2.2.2 Postmarketing Experience.....................................................................................................37

7.2.2.3 Literature ................................................................................................................................37

7.2.3 Adequacy of Overall Clinical Experience................................................................................37

7.2.4 Adequacy of Special Animal and/or In Vitro Testing ............................................................38

7.2.5 Adequacy of Routine Clinical Testing .....................................................................................38

7.2.6 Adequacy of Metabolic, Clearance, and Interaction Workup ..............................................39

7.2.7 Adequacy of Evaluation for Potential Adverse Reactions for Any New Drug and 

Particularly for Drugs in the Class Represented by New Drug; Recommendations for Further 

Study ......................................................................................................................................................39

7.2.8 Assessment of Quality and Completeness of Data ..................................................................41

7.2.9 Additional Submissions, Including Safety Update .................................................................42

7.3 Summary of Selected Adverse Reactions, Important Limitations of Data, and Conclusions42

7.4 General Methodology...................................................................................................................44

7.4.1 Pooling Data Across Studies to Estimate and Compare Incidence......................................44

7.4.1.1 Pooled Data vs. Individual Study Data.................................................................................44

7.4.1.2 Combining Data......................................................................................................................45

7.4.2 Explorations for Predictive Factors.........................................................................................45

7.4.2.1 Explorations for Dose Dependency for Adverse Findings ..................................................45

7.4.2.2 Explorations of Time-Dependency for Adverse Findings...................................................46

7.4.2.3 Explorations for Drug-Demographic Interactions ..............................................................47

7.4.2.4 Explorations for Drug-Disease Interactions.........................................................................48

7.4.2.5 Explorations for Drug-Drug Interactions ............................................................................48

7.4.3 Causality Determination ...........................................................................................................49

List of Tables.........................................................................................................................................51
Contains Nonbinding Recommendations

Reviewer Guidance1

Conducting a Clinical Safety Review of a New Product Application 

and Preparing a Report on the Review 

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 good review practice (GRP) guidance is intended to assist reviewers conducting the clinical 

safety reviews as part of the NDA and BLA review process, provide standardization and 

consistency in the format and content of safety reviews, and ensure that critical presentations and 

analyses will not be inadvertently omitted. The standardized structure also enables subsequent 

reviewers and other readers to readily locate specific safety information.

This guidance is an expansion of section 7 of the clinical review template and is entirely 

compatible with that template. The structure of this guidance, as an annotated outline, is meant to 

correlate exactly with the section headings of the review template, providing the pertinent 

guidance under each heading. The guidance also provides, as attachments, illustrations of 

displays and graphs that have been used successfully in the past. These are not requirements, but 

examples, and reviewers can substitute for, or modify, them, or simply find them unnecessary in 

particular cases. It is expected that new attachments will be added as examples become

available. 

The commentary and suggestions under each section of the guidance, together with appended 

examples, provide suggested analyses, methods of presentations, and discussion of special cases 

and potential difficulties. Some flexibility in implementing the guidance will be needed, as 

different types of applications and datasets may require modifications to the structure outlined in 

 

1

 This guidance has been prepared by the Integrated Summary of Safety group, a subcommittee of Good Review 

Practices Track 8. The Track 8 Committee has been charged with developing a guidance for the clinical review of a 

marketing application under the Good Review Practices (GRP) initiative. 

1
Contains Nonbinding Recommendations

this guidance. If sections are omitted, the review should briefly explain the reason for the 

omission. 

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. GENERAL GUIDANCE ON THE CLINICAL SAFETY REVIEW 

A. Introduction 

This Good Review Practice (GRP) Guidance provides an annotated outline of the safety 

component of a clinical review of an application (NDA, BLA) and guidance on how to conduct 

and organize the safety review. 2 It is usually most efficient and informative to include all the 

safety findings, whatever the source, in the safety section of the clinical review (i.e., apart from

the description of individual studies in the efficacy review). In some cases, however, it may be 

more appropriate to discuss some or all aspects of safety as part of the discussion of individual 

efficacy studies and reference them in this section (e.g., studies with mortality outcomes, 

development programs in which most of the safety data come from one or two large multi-center 

studies, and when evaluation and review of safety data may be more convenient or informative 

study by study). 

The safety review has two distinct components: (1) identification and assessment of the 

significance of the adverse events reported in clinical trials (controlled or uncontrolled) and (2) 

evaluation of the adequacy of the applicant’s safety evaluation. This guidance describes an 

approach that integrates safety findings across all studies and other clinical experience. 

Consideration of the safety findings in individual studies, without a thoughtful integration of the 

overall safety experience, is not adequate for a safety review.3 

Although much of the guidance in this document is directed primarily toward the clinical 

reviewer and toward the analysis of particular events, the evaluation of safety data also involves 

analyses of event rates, estimation of risk over time, exploration of possible subgroup 

differences, and identification of risk factors associated with serious events, all analyses that 

 

2 It is recognized that no drug is safe in the sense of being entirely free of adverse effects. Reference in the Food, 

Drug and Cosmetic Act to the “safety” of a drug for the uses recommended in labeling has been interpreted as 

meaning that the benefits of a drug outweigh its risks for those uses. The safety review, however, is not a risk 

benefit analysis, but rather, is the part of the NDA review that assesses and describes the risks of the drug. 

3

It is important to distinguish between the concept of performing an integrated safety review and the separate 

question of whether or not to pool data across studies in the conduct of that review. For the purpose of this 

document, an integrated safety review refers to the principle of bringing together in one place in the review all data 

and analyses pertinent to a particular safety issue (e.g., liver toxicity). Whether one looks primarily at data from

individual studies or at datasets resulting from pooling of certain studies to address a particular safety concern is not 

critical to the concept of an integrated review. Either approach, or both approaches, will usually be used by a 

reviewer in carrying out an integrated review. 

2
Contains Nonbinding Recommendations

involve substantial knowledge of methods of validly quantifying risk and providing measures of 

uncertainty. Clinical reviewers should therefore collaborate with their biostatistical colleagues 

when necessary in the preparation of reviews and consider when it may be appropriate to 

conduct a joint statistical and clinical review for particularly important safety issues. 

The conceptual framework of this guidance is similar to the framework used for advising 

manufacturers on submitting safety data in FDA's Guideline for the Format and Content of the 

Clinical and Statistical Section for New Drug Applications (Clinical/Statistical guidance)4

 as 

well as in the guidance M4: The Common Technical Document for the Conduct of Human 

Clinical Trials for Pharmaceuticals — Efficacy. 

B. Explanation of Terms 

Because several related terms are used in this guidance that could cause some confusion, the 

following explanations are intended as clarification. 

For purposes of this guidance, the term adverse reaction is used to refer to an undesirable effect, 

reasonably associated with the use of a drug, that may occur as part of the pharmacological 

action of the drug or may be unpredictable in its occurrence. This term does not include all 

adverse events observed during use of a drug, only those for which there is some basis to believe 

there is a causal relationship between the drug and the occurrence of the adverse event. The term

adverse event is used here to refer to any untoward medical event associated with the use of a 

drug in humans, whether or not it is considered drug-related. The phrases serious adverse drug 

experience and serious adverse event are used in this guidance to refer to any event occurring at 

any dose, whether or not considered drug-related, that results in any of the following outcomes: 

• Death 

• A life-threatening adverse experience 

• Inpatient hospitalization or prolongation of existing hospitalization 

• A persistent or significant disability/incapacity 

• A congenital anomaly or birth defect. 

Important medical events that may not result in death, be life-threatening, or require 

hospitalization may be considered serious adverse drug events when, based upon appropriate 

medical judgment, they may jeopardize the patient or subject and may require medical or 

surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 

medical events include allergic bronchospasm requiring intensive treatment in an emergency 

room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 

or the development of drug dependency or drug abuse. Documents developed by the 

International Conference on Harmonisation (e.g., E2) add to serious events those that prolong 

hospitalization but do not include cancer and overdose. 

 

4

 See http://www.fda.gov/cder/guidance/statnda.pdf. 

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Contains Nonbinding Recommendations

Finally, the term adverse dropout is used in this guidance to refer to subjects who did not 

complete the study because of an adverse event, whether or not considered drug-related; adverse 

dropouts include subjects who received the test drug, reference drugs, or placebo. 

C. Overview of the Safety Review

The safety review has four principal tasks: 

1) To identify and closely examine serious adverse events that suggest, or could suggest, 

important problems with a drug-- specifically, adverse reactions severe enough to prevent its 

use altogether, to limit its use, or require special risk management efforts 

2) To identify and estimate the frequency of the common (usually nonserious) adverse events 

that are, or may be, causally related to the use of the drug; 

3) To evaluate the adequacy of the data available to support the safety analysis and to identify 

the limitations of those data. At a minimum, this includes assessments of whether the extent 

of exposure at relevant doses is adequate 

4) To identify unresolved safety concerns that will need attention prior to approval or that 

should be assessed in the postmarketing period, including such concerns as the absence of 

data from high-risk populations or potential interactions 

In addition, the safety review should: 

• Identify factors that predict the occurrence of adverse reactions, including patient-related 

factors (e.g., age, gender, ethnicity, race, target illness, abnormalities of renal or hepatic 

function, co-morbid illnesses, genetic characteristics, such as metabolic status, environment) 

and drug-related factors (e.g., dose, plasma level, duration of exposure, concomitant 

medication) 

• Identify, where possible, ways to avoid adverse reactions (dosing, monitoring) and ways to 

manage them when they occur 

• For a drug that is to be approved, provide a comprehensive evaluation of risk information 

adequate to support a factual and sufficient summary of the risk information in labeling. 

D. Differences in Approach to Safety and Effectiveness Data 

Approaches to evaluation of the safety of a drug generally differ substantially from methods used 

to evaluate effectiveness. Most of the studies in phases 2-3 of a drug development program are 

directed toward establishing effectiveness. In designing these trials, critical efficacy endpoints 

are identified in advance, sample sizes are estimated to permit an adequate assessment of 

effectiveness, and serious efforts are made, in planning interim looks at data or in controlling 

multiplicity, to preserve the type 1 error (alpha error) for the main end point. It is also common 

to devote particular attention to examining critical endpoints by defining them with great care 

4
Contains Nonbinding Recommendations

and, in many cases, by using blinded committees to adjudicate them. In contrast, with few 

exceptions, phase 2-3 trials are not designed to test specified hypotheses about safety nor to 

measure or identify adverse reactions with any pre-specified level of sensitivity. The exceptions 

occur when a particular concern related to the drug or drug class has arisen and when there is a 

specific safety advantage being studied. In these cases, there will often be safety studies with 

primary safety endpoints that have all the features of hypothesis testing, including blinding, 

control groups, and pre-specified statistical plans. 

In the usual case, however, any apparent finding emerges from an assessment of dozens of 

potential endpoints (adverse events) of interest, making description of the statistical uncertainty 

of the finding using conventional significance levels very difficult. The approach taken is 

therefore best described as one of exploration and estimation of event rates, with particular 

attention to comparing results of individual studies and pooled data. It should be appreciated 

that exploratory analyses (e.g., subset analyses, to which a great caution is applied in a 

hypothesis testing setting) are a critical and essential part of a safety evaluation. These analyses 

can, of course, lead to false conclusions, but need to be carried out nonetheless, with attention to 

consistency across studies and prior knowledge. The approach typically followed is to screen 

broadly for adverse events and to expect that this will reveal the common adverse reaction 

profile of a new drug and will detect some of the less common and more serious adverse 

reactions associated with drug use. 

With respect to assessment of serious events, there are two distinct situations. First, there are the 

events readily recognized as consequences, or at least potential consequences, of the treatment 

(i.e., adverse reactions) because they would be unusual in the population under study. Second, 

and particularly critical, are serious events that are not so readily attributed to the drug because 

they can occur even without the drug, for example, because they are known to result from the 

underlying disease or are relatively common in the population being studied (e.g., heart attacks, 

strokes in an elderly population) and could therefore represent intercurrent illness. Adverse 

events that do not seem typical of what drugs do (that is, that are not hematologic, hepatic, renal, 

dermatologic or pro-arrhythmic) can be especially difficult to attribute to a drug. The history of 

the relatively late recognition of the practolol syndrome (sclerosing peritonitis, 

oculomucocutaneous syndrome), retroperitoneal fibrosis with methylsergide (Sansert), 

pulmonary hypertension with aminorex and other appetite suppressants, thromboembolic disease 

with oral contraceptives, endometrial cancer with post-menopausal estrogens, suicidal ideation 

with interferons, and more recently, cardiac valvular disorders with fenfluramine, illustrates this 

problem. Perhaps most difficult of all is the situation where the adverse event is, or could be, a 

consequence of the disease being treated. Thus, it was extremely difficult to discover that many 

drugs for heart failure (beta agonists, phosphodiesterase inhibitor inotropes, and a vasodilator, 

flosequinan) caused increased rates of the same kinds of death seen with the underlying disease 

(i.e., due to progressive heart failure or arrhythmias), that anti-arrhythmics could provoke new 

arrhythmias, and that interferon could cause depression in patients with cancer or multiple 

sclerosis, conditions that are themselves associated with mood alteration. Distinguishing the 

effects of a drug on the immune or other impaired systems in patients with cancer or HIV 

infection can also be difficult. Many years ago, a last resort drug for rheumatoid arthritis, 

azaribine (Triazure), was approved despite a number of arterial thrombi seen during 

development because those were thought to be more common in patients with RA (the drug was 

5
Contains Nonbinding Recommendations

removed from the market shortly after approval, however, when unusual thrombotic events (e.g., 

thrombosis of a digital artery) became apparent). Drugs for seizure disorders and schizophrenia 

can be difficult to assess with respect to causing sudden death because patients with the disorders 

they treat have a relatively high rate of this event. Usually, the only way to establish that these 

are adverse reactions is through controlled trials of significant size. Sometimes, the controlled 

trials to evaluate effectiveness will be large enough to address these issues, but sometimes, 

where there is a significant concern, special, large safety studies may be needed. 

There is no simple answer to these difficult assessments, but this guidance, similar to section H 

of the Clinical/Statistical guideline (Guideline for the Format and Content of the Clinical and 

Statistical Sections of New Drug Applications)5

and the guidance M4 The CTD — Efficacy,

suggest an approach, namely, close examination of all patients who die or who leave a study 

prematurely because of any adverse event (whether or not thought drug-related),6

 with explicit 

consideration of the possibility that the event was drug-related (the “prepared mind” approach). 

With respect to discovering that a drug causes a modestly increased rate of serious events that 

are relatively common in the population, only large controlled trials can provide a satisfactory 

answer and the reviewer needs to consider whether such trials are needed. In some cases, there 

are reasonably well-established surrogate markers that can predict severe injury. For example, 

an increased rate of transaminase elevations accompanied by a small number of cases in which 

bilirubin elevation accompanies the transaminase elevation can predict the occurrence of more 

severe liver injuries in some patients, and visual field defects may portend irreversible peripheral 

vision loss. Similarly, substantial QT interval prolongation on the electrocardiogram predicts the 

occurrence of Torsade de Pointes-type ventricular tachycardia. 

E. Identifying and Assembling Source Materials for the Safety Review 

Before beginning the safety review, the reviewer should identify and assemble (or locate 

electronically) all available materials for the review. These materials include: 

• The applicant’s Integrated Summary/Analysis of Safety (ISS) 

• Adverse event tables in the NDA/BLA submission7

• Case report forms (CRFs) for patients who experienced serious adverse events or who 

dropped out of a study because of an adverse event. The reviewer should request these CRFs 

 

5 See http://www.fda.gov/cder/guidance/statnda.pdf. 

6 21 CFR 314.50(f)(2) requires that CRFs be submitted for each patient who died during a clinical study or who did 

not complete the study because of an adverse event, whether believed to be drug related or not. It should be clear 

from the application that the ISS and other safety reports include all adverse events that were seen during 

development, not just those judged by investigators or the applicant to have been potentially drug-related. This is 

also a useful point to make at a pre-NDA/BLA meeting. 

7

If the reviewer determines that adverse event tables provided by the applicant are accurate and fairly represent the 

data they purport to display, the tables may be included in the safety review as appendices. If applicant-generated 

tables are used, the review should identify the applicant as the source. 

6
Contains Nonbinding Recommendations

if the applicant does not include them in the submission (although they are required under 21 

CFR 314.50). If the number of cases is very large (e.g., for dropouts) and many of the events 

are similar, it may be reasonable to request only a sample of CRFs.8 Note that, in some

cases, dropouts attributed to other reasons will upon review be associated with an adverse 

event. 

• Individual patient adverse reaction data listings, laboratory listings, and baseline listings, 

usually accessible electronically8

• The applicant’s narrative summaries of deaths, serious adverse events, and other events that 

resulted in dropouts 

• If available, displays of individual patient safety data over time for patients who experienced 

serious adverse events 

• The safety sections of the sponsor’s proposed labeling 

• Common Technical Document (CTD) safety-related sections (module 2, Sections 2.5.5, 

2.7.4), which give an overview of the applicant’s approach to the safety evaluation and a 

detailed summary of the safety data 

• Any other safety-related documents, such as discussions of related drugs, descriptions of use 

of adverse drug reactions (ADR) coding dictionaries to combine data across studies, specific 

studies of safety hypotheses

F. Identifying Major Concerns at the Outset 

Although the review will assess the data submitted, it may be useful to identify at the outset 

particular concerns that will be explored because they are suggested by the pharmacology of the 

drug or by safety concerns with pharmacologically related drugs. Thus, the clearance pathway 

of a drug will suggest certain potential drug-drug interactions or certain effects of decreased 

renal or hepatic function. Similarly, the pharmacologic class, and prior experience, could lead to 

focus on particular laboratory or clinical abnormalities (e.g., muscle or liver abnormalities with 

HMGCoA reductase inhibitors, QT prolongation with fluoroquinolone anti-infectives, 

gastrointestinal, renal, and cardiovascular effects of nonsteroidol anti-inflammatory drugs, liver 

abnormalities with endothelin receptor antagonists, cognitive impairment with sedating drugs, 

sexual dysfunction with selective serotonin reuptake inhibitors). These concerns are considered 

further in section 7.2.5. 

 

8

The reviewer should be able to easily access individual patient information. The reviewer may want to clarify 

formatting and accessibility concerns at the pre-NDA meeting. For hardcopy submissions, an index that directs the 

reviewer to the exact location (volume and page number) of the CRF, the narrative summary, and the individual 

patient safety data display is essential (for sample index see Table 8.0.1). For electronic submissions, the PDF files 

should have sufficiently detailed bookmarks to offer easy navigation by the reviewer. For example, narratives 

should be bookmarked by patient ID number, not just by study treatment or treatment assignment. 

7
Contains Nonbinding Recommendations

G. Auditing Source Materials 

Although there are no established standards for auditing safety data in a submission, the review 

should describe efforts to assess consistency of the data provided (e.g., comparing information 

included in case report forms, case report tabulations, and narrative summaries for individual 

patients). For important adverse events, for example, it is generally important to consider not 

only the applicant’s narrative description, but the associated CRF or hospital records and 

submitted laboratory, radiology, or pathology results. 

H. The Purpose of Individual Case Review/“Drug-relatedness” 

An important part of the safety review is reviewing individual cases of death, serious adverse 

events, adverse events leading to discontinuation (adverse drop-outs), and discontinued patients 

who are lost to follow-up. One reason to review the details of individual cases is to determine 

whether the event was coded to the correct preferred term. The assessment of causality for 

specific adverse events in NDAs/BLAs is heavily dependent on comparisons of event rates 

between treatment groups, and the numerator of these rate calculations includes events coded to 

the same preferred term. A case might be incorrectly included in the numerator of a rate 

calculation if the event is incorrectly coded to a specific preferred term. Events may be 

incorrectly coded to preferred term by the applicant when they summarize the data or because an 

investigator used a verbatim term incorrectly when recording the event in the case report form. 

An example of incorrect coding would be if an investigator used the verbatim term acute liver 

failure for a case of increased ALT and the applicant coded the event to acute liver failure. One 

would not want to include such a case in the numerator of a risk calculation for acute liver 

failure. Similarly, a case could be incorrectly excluded from a numerator. Inconsistent coding 

(e.g., peripheral edema coded as "heart failure" for one patient, but "metabolic abnormality" for 

another) could result in an inappropriately low numerator. 

A second reason to conduct individual case review of deaths, serious adverse events, and adverse 

events leading to discontinuation is to determine whether there is a likely explanation for the 

event other than the drug that is the subject of the application, such as another drug or 

concomitant illness (e.g., documented acetaminophen overdose in a case of acute liver failure 

would argue against attribution to the test drug; documented cholecystitis would argue against 

attribution of cholestasis to the test drug). If there is no likely alternative explanation for the 

event, the event must be considered at least possibly drug-related, and should be included in a 

rate calculation. 

A third reason for individual case review of deaths, serious adverse events, and adverse events 

leading to discontinuation is to look for other reasons that might exclude the drug as a cause of 

the event. One example would be when an adverse event occurred during a placebo washout 

period before exposure to study drug occurred. Events that occur prior to exposure would not be 

included in the numerator of risk calculations. Events that begin long after discontinuation of the 

drug might also be considered unlikely to be drug-related, but care must be taken in excluding 

them, as there are examples of such late drug-caused reactions (e.g., FIAU (fialuridine, a 

nucleoside analog) where liver failure was seen well after the drug was stopped, probably 

8
Contains Nonbinding Recommendations

because it induced mitochondrial DNA damage that became a problem only when mitochondria 

tried to replicate) and because some chronic reactions might not be detected immediately. 

A fourth reason for individual case review of deaths, serious adverse events, and adverse events 

leading to discontinuation is to look for results of rechallenge. A potentially important source of 

information about causality is when an individual is rechallenged with drug, accidentally or 

deliberately. Recurrence with rechallenge is a potentially strong indicator of causality, but 

interpretation of the results of rechallenge is highly dependent on the natural course of the event 

being considered. For noncyclical events that are exceedingly rare in the background (e.g., acute 

liver failure, aplastic anemia) recurrence of the event upon rechallenge (i.e., positive 

rechallenge) provides strong evidence of causality. Positive rechallenges are less definitive for 

diagnoses/events that can occur in cyclical or recurrent fashion (e.g., worsening glucose control 

in a subject with diabetes mellitus), but close observation of the patient’s whole course (i.e., both 

challenge periods and dechallenge periods) may be helpful. Rechallenges that do not result in 

recurrence of the event (i.e., negative rechallenge) suggest (but do not prove) that the drug did 

not cause the event. One must consider such factors as whether it was possible for the event to 

recur, the dose of drug and duration of exposure at which the subject was rechallenged, and 

whether the length of observation following rechallenge was sufficient to allow recurrence of the 

event of interest. 

It is important to distinguish the processes described above from the causality analyses of drugrelated events often provided by investigators and applicants in NDA/BLA submissions. The 

analyses of drug-related adverse events presented by applicants are usually based on assessments 

made by investigators at the time of an event, are highly dependent on information about the side 

effect profile of the drug available at the time of the study (e.g., what is in the investigator’s 

brochure), and are not informed by awareness of the entire safety database. These analyses are 

generally not expected to provide much useful information in assessing causality. 

Assessment of the drug-relatedness of an adverse event is fundamentally different for relatively 

frequent and relatively rare events. For the former, a reviewer would compare the incidence of 

adverse events occurring in the study drug group to that in the placebo (or other control) group 

(in RCT). For rare events, the expected rate in a clinical trial database would be zero. Thus, if 

even a few cases (sometimes even a single case) of a rare life-threatening event occurred when 

none was expected, that would represent a serious safety problem for a drug product that does 

not provide unique efficacy or some other advantage over available treatments. 

III. SPECIFIC GUIDANCE ON THE CONTENT OF THE SAFETY REVIEW 

The following sections bear the same names and numbers of the section of the clinical review 

template that contains the safety review (Section 7.0). 

This guidance organizes the safety review into three main sections: 

• Methods and Findings (Section 7.1) 

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Contains Nonbinding Recommendations

This section contains 17 subsections. Overall, this section should describe the relevant data 

sources, the safety assessments that were carried out, and the major findings of the detailed 

safety review. Section 7.1 should use a systematic approach to describing available data. It 

should focus first on the serious and potentially serious reactions, the kind that can affect the 

approval decision or severely limit the use of the drug (see Subsections 7.1.1 to 7.1.4). 

Focus should then move to the more common reactions that rarely influence approval but are 

often critical to patient and physician acceptance of the drug. Section 7.1 should then 

consider less common events, laboratory findings, vital signs, electrocardiograms (ECGs), 

immunogenicity, human carcinogenicity, human reproductive toxicity, withdrawal 

phenomena, abuse potential, and overdose (Subsections 7.1.5 to 7.1.17). 

 

• Adequacy of Patient Exposure and Safety Assessments (Section 7.2) 

This section should address the adequacy of exposure (e.g., overall patient numbers and 

numbers for specific demographic subsets, duration of exposure, the dose levels at which 

exposure took place,9

 the quality and completeness of safety evaluations, whether all 

necessary evaluations were conducted (e.g., animal tests, in vitro tests, long-term safety 

testing, specific assessments of ECG effects), and whether any additional safety assessments 

are needed (either pre- or postapproval). This section should also include a subsection on 

additional submissions of safety data, including safety update(s). 

• Summary of Selected Drug-Related Adverse Events, Important Limitations of the Data, and 

Conclusions (Section 7.3) 

This section should identify and briefly summarize the critical findings of the safety review, 

including the adverse events the reviewer considers to be important and drug-related and any 

important limitations of the safety database. 

This guidance also discusses general analytical methods that may be useful for multiple aspects 

of the safety assessment in section 7.4 (see page 45). This section discusses pooling of data, 

explorations for adverse reaction predictive factors, dose-dependency evaluations, time 

dependency evaluations, duration of adverse reactions, drug-demographic interactions, drugdisease interactions, and drug-drug interactions. 

The annotated outline of the review begins here: 

7.0 Integrated Review of Safety 

 

9 The proportion of patients exposed to the dose range that is effective should be considered. A total exposure 

consistent with ICH recommendations (1500 total with 300-600 for 6 months and 100 for one year), may, on 

examination, reveal far fewer who received an effective dose (i.e., the dose that would be used). ICH E-1 ([The 

Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-Term Treatment of Non-LifeThreatening Conditions, March 1995 (http://www.fda.gov/cder/guidance/iche1a.pdf)]) is clear in its expectation that 

the 6-month and one year exposures should be at dosage levels intended for clinical use. Although it is silent with 

respect to the 1500 figure, exposure at lower doses would not be expected to be informative about the safety of the 

clinically useful dose. 

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Contains Nonbinding Recommendations

7.1 Methods and Findings 

This section consists of 17 subsections (e.g., death, other serious adverse events, laboratory 

findings). Each of these subsections is organized somewhat differently, depending on the 

content. In presenting analyses in the safety review, it is important to clearly distinguish 

between the applicant’s analyses and conclusions and those of the reviewer. 

In discussing serious adverse events and dropouts (Sections 7.1.1, 7.1.2, and 7.1.3), it is critical 

that the reviewer identify individual patients in a way that enables subsequent readers to readily 

access data and supporting information if needed (e.g., study #, investigator #, patient ID#). 

7.1.1 Deaths 

Identifying Deaths Relevant to the Safety Review

Deaths occurring during the following time periods or under the following conditions should be 

assessed: 

• Deaths occurring during participation in any study, or during any other period of drug 

exposure 

• Deaths occurring after a patient leaves a study, or otherwise discontinues study drug, whether 

or not the patient completes the study to the nominal endpoint, if the death: 

– is the result of a process initiated during the study or other drug exposure, regardless of 

when it actually occurs; or 

– occurs within a time period that might reflect drug toxicity for a patient leaving a study 

or otherwise discontinuing drug. For drugs with prompt action and relatively short 

elimination half-lives, 4 weeks is a reasonable time period. For drugs with particularly 

long elimination half-lives or drug classes with recognized potential to cause late 

occurring effects (e.g., nucleoside analogs, gene therapies, or cell transplants), deaths 

occurring at longer times after drug discontinuation should be evaluated. 

The reviewer should consider all deaths that occurred in a drug’s development program and any 

other reports of deaths from secondary sources (e.g., postmarketing or literature reports), without 

regard to investigator or applicant judgment about causality. It is also important to consider 

deaths on control treatments for comparison, even though they are obviously not related to the 

drug in the application. Individual deaths should be listed in a table (see Table 7.1.1.1), unless 

they are an effectiveness study outcome. 

Applicants will provide line listings of all patients who died in studies, together with a brief

narrative. (See E3 Structure and Contents of Clinical Reports, Section 12.3.10 The narratives 

may also be placed in the Integrated Summary of Safety.) 

 

10 The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 

Human Use (ICH) E3 Structure and Contents of Clinical Study Reports. 

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Contains Nonbinding Recommendations

Distinguishing Expected from Unexpected Deaths

Certain causes of death are sufficiently unusual in the absence of drug therapy, even in large 

databases, that they would almost always be considered unexpected (e.g., aplastic anemia or 

acute hepatic necrosis) and deserve detailed individual discussion. Other fatal events occur at 

such frequency in the general population that they would be expected to occur in any large 

database absent drug therapy (e.g., fatal strokes and heart attacks), especially in the elderly.11 In 

most cases, these events need to be examined for frequency but discussion of individual cases is 

not helpful. Expected deaths would include: 

• Deaths in studies in which mortality is an endpoint and the cause of death is expected for the 

disease or condition 

• Deaths in studies in diseases where high mortality rates are expected and the cause of death 

is expected (e.g., cancers). Note, however, that early deaths in cancer studies are a concern 

as patients are usually selected for clinical trials because they were not expected to die soon. 

• Coincidental deaths resulting from progression of underlying disease present at enrollment in 

a study (e.g., a patient who dies from progression of cancer or Alzheimer’s Disease or an 

acute myocardial infarction attributed to underlying coronary artery disease present prior to 

study entry 

• Deaths from intercurrent long-term illness. These include the wide variety of fatal events 

that can be seen in any population, especially a relatively elderly population, such as sudden 

death (presumably representing an arrhythmia), fatal infections, surgical emergencies, or 

intracranial hemorrhage). 

Even though fatal events may be expected in a population, the reviewer should not without 

further consideration readily accept the conclusion that a fatal event is due to the underlying 

disease or an intercurrent illness and not the drug. For each fatal event, the reviewer should 

specifically consider the possibility that the event represents an as yet unsuspected adverse 

reaction. Even if there is nothing about these deaths to suggest a drug cause, it is critical to 

assess whether the rate of these events is increased. The best way to do this, of course, is by 

comparison with a control group (a single trial or pooled), but if no control group is available, it 

may be of value to look at databases of other drugs used in the same population. 

When distinguishing between unexpected and expected deaths, the reviewer should make clear 

the bases for the distinctions (e.g., early deaths in cancer patients are unexpected if the entered 

patients were chosen because they were not expected to die soon; hematologic deaths are 

unexpected in a postinfarction study). For unexpected deaths, the individual medical events 

associated with the death should be carefully evaluated and discussed in detail in the review. 

Expected deaths should be classified as to type of death, but it is usually not necessary to discuss 

in detail the individual medical events associated with those deaths. What is critical is to 

consider whether there is a suggestion that their rate is increased, the adequacy of the data to 

evaluate this, and the need to know more (e.g., because of experience with related drugs). 

 

11Note that unexpected is used differently from its use in 21 CFR 312.32, where it refers to adverse events not 

identified in the investigator’s brochure and therefore reportable in an IND Safety Report. 

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Contains Nonbinding Recommendations

Pooling of Relevant Data

Before conducting any mortality analyses, the reviewer must consider the poolability of the data 

pertinent to deaths. If data are not poolable, analyses should be conducted for separate 

databases, then examined together. See section 7.4.1. for discussion of pooling. 

Overall Mortality Analysis

The review should include an analysis of overall mortality for all phase 2 and 3 exposures across 

treatment groups as well as cause-specific mortality to the extent possible. The fineness of 

classification depends on the quality of data and the number of events (cardiovascular (broad) vs. 

AMI, sudden death, CHF (more specific)), recognizing that assessing cause-specific mortality is 

very difficult even in the best circumstances, such as a study in which there is an attempt to 

describe such endpoints prospectively.12 Death from an acute myocardial infarction can be 

indistinguishable from death resulting from an arrhythmia, for example. Analyses should be 

corrected for differences in drug exposure using person-time in the denominator to calculate 

mortality rates.13 If person-time exposure is not included in the submission (ideally, it should be 

requested at the pre-NDA/pre-BLA meeting), it should be requested as soon as the need is 

recognized. This correction can be done only for those deaths for which person-time data are 

available. It may be useful to present both crude mortality and mortality expressed in persontime in an appendix table (see Table 7.1.1.2 for sample display). Life table approaches may be 

helpful in cases when there are more than a few deaths, and when the direction of different 

studies varies significantly. Ideally, one would have mortality data from other databases for 

comparison (e.g., from other drugs in the same class). 

Discussion of Applicant’s Assessment of Deaths

The reviewer should describe and evaluate the applicant’s assessment of deaths, including the 

following: 

• The applicant’s criteria for including deaths in the NDA/BLA (e.g., whether the criteria were 

reasonable, whether the criteria were met)

• The methods used by the applicant to detect and classify deaths

• The applicant’s method of analyzing overall mortality and cause-specific mortality 

• The applicant’s judgments on the drug-relatedness of events associated with deaths

Reviewer’s Assessment of Deaths

 

12 Temple R, G Pledger, The FDA's Critique of the Anturane Reinfarction Trial, N Engl J Med 303:1488-1492, 

1980. 

13 Since placebo and active control patients can generally have had shorter durations of exposures than patients given 

the new drug, they may have had less opportunity for serious events to have occurred. 

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Contains Nonbinding Recommendations

The reviewer’s assessment of deaths, reflecting both the applicant’s and the reviewer’s analyses, 

should include the following: 

• Listing of information upon which reviewer assessment is based (e.g., CRFs, narrative 

summaries, consultant reports, autopsy reports) 

• Tabular Summary of Deaths. Deaths should be summarized in an appendix table, as 

illustrated in Table 7.1.1.1. It may be useful to distinguish between those deaths for which 

exposure data are available and those for which such data are unavailable (e.g., for 

postmarketing deaths, exposure data may never be available). In the table and subsequent 

discussion, there should be a clear identifier so that subsequent reviewers can identify the 

particular patient. 

• Analysis of overall mortality for Phase 2 and 3 drug exposures across treatment groups (see 

Table 7.1.1.2) 

• Analysis of cause-specific mortality across treatment groups (this could use a table similar to 

Table 7.1.1.2)

• The reviewer’s overall judgment about the drug-relatedness of medical events associated 

with death (i.e., which deaths were probably explained by factors other than the study drug 

(e.g., another drug, underlying illness, another illness common in the population) and which 

could not reasonably be explained by such factors). Differences from the applicant’s 

evaluation should be noted and discussed. 

• Further discussion of the individual events associated with death and believed to be 

potentially drug-related, either because they are increased in rate compared to control or 

because of the nature of the event (e.g., events typically drug-related, such as aplastic anemia 

or acute hepatic necrosis, or events that would not be expected in the population studied such 

as sclerosing abdominal or pulmonary conditions or rapidly progressive unexplained renal 

failure). Any uncertainty about drug-relatedness should lead to inclusion of the event. For 

each of these individual events, brief narratives should be included in the review or (if 

numerous) attached in an appendix. 

• Other relevant analyses, such as analysis of dose response (administered dose, body weight 

and surface area adjusted dose, cumulative dose, schedule (including duration of infusion for 

IV drugs) analysis of mortality within critical subgroups (e.g., demographic, disease severity, 

excretory function, concomitant therapy), drug-demographic, drug-disease, and drug-drug 

interactions (see section 7.4) 

• When deaths occur in uncontrolled studies, best available estimates of mortality in the 

population studied, in the absence of the treatment (see Section 7.4.3) 

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Contains Nonbinding Recommendations

• When deaths are relatively frequent, the reviewer should consider some of the approaches 

described for Common Adverse Events (see section 7.1.5) 

7.1.2 Other Serious Adverse Events 

Identification of Nonfatal, Serious Adverse Events

The reviewer should identify, without regard to the applicant’s causality judgment, all serious 

adverse events that occurred in the drug’s development program or were reported from

secondary sources (e.g., postmarketing or literature reports). Serious adverse events may, in 

addition to signs, symptoms, and diagnosable events, include changes in laboratory parameters, 

vital signs, ECG, or other parameters of sufficient magnitude to meet the regulatory definition of 

a serious adverse drug experience.14

Applicants generally provide a line listing of all patients in phase 2 and 3 of the development 

program who had an event meeting FDA's criteria for a serious adverse event. For each such 

event, the applicant should also provide a brief narrative (see ICH E3 Structure and Content of 

Clinical Study Reports, Section 12.3.2). Because the definition of serious is subject to some

interpretation, the reviewer should make clear how the applicant created the list. For example, 

applicants may include events considered serious by investigators, even if they do not technically 

meet the FDA or ICH definition for a serious event. If such events are included, the inclusion 

parameters should be noted. 

Discussion of Nonfatal Serious Adverse Events 

This section of the review should contain the following: 

• A brief description of data sources used in the review of individual cases (e.g., case report 

forms, applicant’s narrative summaries, hospital records). 

• The Tabular Summary of serious adverse events (see sample listing, Table 7.1.2.1) 

• An analysis of overall rate of serious events and rate of specific serious events, for each 

treatment group in critical subgroups (e.g., demographic, disease severity, excretory function, 

concomitant therapy), and by dose. The median duration of exposure should be examined 

across treatment groups. If there is a substantial difference in exposure across treatment 

groups, incidence rates should be calculated using person-time exposure in the denominator, 

rather than number of patients in the denominator, similar to the presentation for deaths in 

Table 7.1.1.2. 

• Reviewer’s overall assessment of which serious adverse events were probably explained by 

factors other than the study drug (e.g., another drug, underlying illness, another illness 

common in the population) and which could not reasonably be explained by such factors) 

 

14 See 21 CFR 312.32(a); 314.80(a); 600.80(a).

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Contains Nonbinding Recommendations

including any pertinent information from non-serious events (e.g., seizures not leading to 

hospitalization, all syncope) that may be related to the serious event. 

• Further discussion of each individual serious adverse event judged to be drug related (i.e., 

each adverse reaction), as needed, including any relationship of the reaction to death. For 

each of these reactions, brief narratives should be included in the review or (if numerous) 

attached in an Appendix. 

 

• A discussion or listing of serious events considered unlikely to be drug-related (may be 

identified in the Tabular Summary, illustrated in Table 7.1.1.1). 

If serious nonfatal adverse events are relatively frequent, the reviewer should consider some of 

the approaches described for Common Adverse Events (see section 7.1.5). 

7.1.3 Dropouts and Other Significant Adverse Events 

FDA regulations require that the CRFs from patients who discontinue treatment in association with 

an adverse event (adverse drop-out) be submitted with the application (21 CFR 314.50(f)(2)) and 

their analysis constitutes a critical part of the safety evaluation (see Section 7.1.3.2). 

ICH E3 (Guideline on Structure and Content of Clinical Study Reports) defines a new category 

of other significant adverse events. It includes: 

• Marked hematological or other lab abnormalities not meeting the definition of serious. This 

will need to be an individual judgment, probably depending on the drug (e.g., CPK elevation 

could have a different implication for a statin and a different drug) 

• Any events that led to an adverse dropout or any other intervention such as dose reduction or 

significant additional concomitant therapy (an expansion of the adverse dropout concept that 

appears in 21 CFR 314.50(f)(2), and in the Clinical/Statistical guideline, and M4: The CTD 

— Efficacy)

• Potentially important abnormalities not meeting the above definition of serious and not 

leading to death or modification of therapy (e.g., a single seizure, syncopal episode, 

orthostatic symptoms)

If the applicant has included listings for other significant adverse events these may be described 

here, under a subsection separate from the discussion of dropouts (see Section 7.1.3.3). 

Alternatively, marked laboratory changes may be described under Laboratory Findings (Section 

7.1.6). 

7.1.3.1 Overall Profile of Dropouts 

The review should contain an overall profile of dropouts from clinical trials. The profile should 

classify dropouts from the overall phase 2 and 3 study pool by reason for dropping out (e.g., 

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Contains Nonbinding Recommendations

adverse event, treatment failure, lost to follow-up). Where there are clinically relevant 

differences in dropout rates for certain subsets (e.g., dropouts in placebo-controlled trials vs. 

dropouts in other studies; dropouts in certain demographic or disease-related subgroups), the 

profile should also classify dropouts for those subsets. The reviewer should explain the basis for 

selecting identified subsets and provide mutually exclusive tabulations in which individual 

patients are counted only once.15 Ordinarily, the dropouts should be categorized in a table or 

tables appended to the safety review (see Table 7.1.3.1.1). It can be useful to display, 

graphically or in tables, the cumulative dropout rates for each treatment group within each study, 

especially for cause-specific reasons, when this information is available and to assess patient 

baseline risk factors that contribute to differential cumulative dropout patterns. When pooling 

data, consideration of dropout patterns over all studies may reveal information that is useful to 

the overall safety evaluation. 

When classifying dropouts, the reviewer should carefully examine the reasons identified by the 

applicant for subjects dropping out. Heightened scrutiny is warranted for: 

• Dropouts classified as administrative, lost to follow-up, or a similar term

• Dropouts for which the applicant changed the investigator’s determination of the reason for 

the drop out. 

Discontinuations attributed to adverse events require submission of the corresponding CRF but 

CRFs may not be submitted for dropouts classified as administrative or lost to follow-up. If 

such CRFs are not available, the reviewer may need to request at least a sample of them to 

determine whether these dropouts may have occurred in association with an adverse event. 

Where dropouts are reclassified by an applicant (i.e., assigned a reason for dropping out other 

than the one given in the CRF), the review should indicate how and by whom such 

reclassifications were made and comment on the appropriateness of decisions. 

Ordinarily, the reviewer should combine patients categorized as dropping out for intercurrent 

illness and patients categorized as dropping out for adverse drug reactions (if the applicant 

makes that distinction) under the general category of dropouts for adverse clinical events (CRFs 

should be provided for both of these categories). This categorization is neutral from the 

standpoint of causality judgment, recognizes the great difficulty in making distinctions between 

adverse drug reactions and intercurrent illness, and encourages the reviewer to consider the 

possibility that what seemed to be another illness or a consequence of the underlying illness was, 

in fact, an adverse drug reaction. 

The reviewer should examine the number and distribution of dropouts to identify potential 

problems with study conduct or analyses (e.g., a substantial number of dropouts due to lost to

follow-up and sites with disproportionately high dropout rates should be a sign of concern). For 

example, early dropouts generally, and differential (drug group vs placebo group) early dropouts 

 

15Mutually exclusive refers to the reason for dropping out. Patients should be identified with only one of the reasons. However, 

patients may be represented in more than one column (treatment group) of a table (e.g., patients in a crossover study may have 

survived several treatment arms and then dropped out). 

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Contains Nonbinding Recommendations

in particular, often present difficulties in conducting and interpreting the effectiveness analysis 

and may suggest breakdown of blinding. The review should discuss any concerns about 

dropouts and the methods employed by the reviewer to address them. 

7.1.3.2 Adverse Events Associated with Dropouts 

The analysis of adverse events associated with dropouts is important for two distinct reasons. 

First, it identifies the type and frequency of adverse events that patients were unable to tolerate 

even in a clinical trial setting, where there is arguably more support for enduring adverse events 

than in a clinical practice setting. This provides important prescribing information that can 

contribute to dose selection, and in some cases, to choosing a method of titration. In most cases, 

there will be little doubt about which of these events are attributable to the drug because the 

events will be of relatively high frequency, even if withdrawals because of them are not, and the 

main issue will be their frequency and importance. It is usually not necessary to review these 

events case by case. 

Second, and the reason CRFs for dropouts due to adverse events are provided automatically to 

reviewers, these adverse dropouts may provide a clue to unexpected, but important, adverse 

reactions, (e.g., fibrosing intra-abdominal or pulmonary illnesses, progressive liver or kidney 

diseases, cardiac valve damage, neurological diseases, arteritis, thromboembolic diseases, all of

which have been caused by drugs) that can easily be dismissed as intercurrent illness. The 

frequency of these events is likely to be very low, and the review should contain an analysis of 

each such adverse event that resulted in withdrawal from the study, whether or not the event was 

attributed to the drug. The reviewer should avoid dismissing such events as intercurrent illness 

and specifically consider the possibility that each dropout not due to a known effect of the drug 

might reflect an unexpected effect of the drug. The applicant will usually provide a line listing 

of adverse dropouts (Table 7.1.3.2.1) and this listing (which need not be attached to the review) 

can serve to identify events needing further scrutiny. Review of the CRFs can often provide 

critical insights. The reviewer should describe how she or he analyzed these events. 

With respect to the more common adverse events leading to discontinuation of treatment, the 

review should present: 

• The incidence of adverse events associated with dropouts. Ideally, incidence would be 

presented in a table or tables appended to the safety review with separate tables for subsets of 

the overall clinical data pool in which there were clinically meaningful differences in dropout 

incidence (Table 7.1.3.2.2). Tables displaying incidence of events should include each event 

that led to a dropout even if a single patient had more than one such event. 

• Whether the event can reasonably be considered drug-related; this conclusion will be based 

on comparisons between treatment groups in controlled trials and can be informed by the 

overall rate of the adverse event (Section 7.1.5), and the known pharmacology of the drug. 

• The dose response and time dependency of the drop-outs and drug-demographic, drugdisease, and drug-drug interactions (see section 7.4 General Methodology). 

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For the rarer events that could suggest an important adverse reaction, the critical review 

determination is whether any of these events suggest drug-induced injury. These events need to 

be considered individually, with narratives and reference to other databases as appropriate. 

Where the review contains applicant-generated tables, it is important for the reviewer to 

determine and describe how the tables were created. A table may identify one or more adverse 

events as having caused a particular patient to withdraw, in which case it would represent the 

actual incidence of specific adverse events that led to dropout. This approach is preferred. 

Alternatively, a table may list the adverse events that a subject experienced at the time of 

dropout and not identify any event (or events) as causing the dropout. This approach does not 

provide the actual incidence of adverse events associated with dropouts and is of less value. The 

reviewer should make clear in the review which of these approaches was used, or whether an 

alternative approach was used. 

7.1.3.3 Other Significant Adverse Events 

If a submission separates out information on adverse events that led to dose reduction or 

significant additional concomitant therapy,16 but not to discontinuation of treatment, those 

findings should be described using an approach similar to that proposed above for adverse 

dropouts. 

7.1.4 Other Search Strategies 

In addition to reviewing deaths, serious adverse events, and adverse events associated with 

dropouts, it may be useful to construct algorithms involving combinations of clinical findings 

that may be a marker for a particular toxicity (e.g. serotonin syndrome, cough, chest congestion 

and shortness of breath that may constitute drug-related bronchospasm, or drug-induced 

Parkinsonism). When such algorithms are used, the algorithm and results of the search using the 

algorithm should be described in the review. Generally, and where possible, such searches 

should be done while the reviewer is blinded to treatment, as this will minimize bias when 

identifying cases. 

It should be noted that the causal relation of a drug to uncommon serious adverse events may be 

supported by less serious events that are more common. For example, the likelihood that a drug 

caused a small number of cases of serious liver toxicity may be supported by a higher rate of 

transaminase elevation. 

7.1.5 Common Adverse Events 

This section of the review focuses on establishing the common adverse reaction profile for the 

drug and determining the content of the adverse reaction table(s) to be included in labeling. 

NDAs typically contain numerous tables and analyses of adverse event incidence (e.g., by study, 

by various pools of studies, and for the overall database). In general, what are included are 

TESS, treatment emergent signs and symptoms (i.e., signs and symptoms not present at baseline, 

 

16 This is recommended in the ICH E3 guidance. 

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Contains Nonbinding Recommendations

or not present at the severity seen on treatment). To approach these data, the reviewer should 

generally go through the steps outlined in sections 7.1.5.1-7.1.5.5. 

7.1.5.1 Applicant’s Approach to Eliciting Adverse Events in the Development Program 

Adverse events can be elicited by open-ended questions or checklists with varying degrees of 

specification. Each approach has advantages and disadvantages, but results can differ greatly 

and may lead to marked differences in reported adverse event rates across studies (it would not 

usually be appropriate to pool results obtained using both methods). The reviewer should 

describe the applicant’s method or methods of eliciting adverse event data in clinical trials, 

including whether checklists were used, the frequency with which patients were assessed, and 

whether the approaches differed among studies. Identification of signs (abnormal findings 

observed by a clinician) would seem to be less of a problem, as these are elicited by physical 

examination, but use of a physician exam checklist could lead to a different result from a more 

general requirement for physical exam. If different approaches were used (e.g., checklists in 

studies conducted in the United States, open-ended inquiries in European studies), the reviewer 

should consider and discuss in the review the effect, if any, on the adequacy of adverse event 

information collected. 

7.1.5.2 Establishing Appropriate Adverse Event Categories and Preferred Terms 

Although investigator adverse reaction terms are provided as part of study reports and are listed 

in case report tabulations, the integrated analysis of the ISS requires the applicant to use some

way of grouping closely related events to obtain an overall rate for a category of events. This is 

accomplished by using a so-called dictionary of preferred terms, such as COSTART,17 

MedDRA,18 the latter a more granular listing developed under the auspices of ICH. These 

dictionaries are in fact lists of preferred terms and leave (especially COSTART and other older 

dictionaries) considerable discretion to the classifier to choose the term that best reflects the 

verbatim term reported by the investigator. The categorization of such systems, however, may 

not capture, or can dilute, the true meaning of certain events. In addition, terms used in 

COSTART may not be informative (e.g., pain, tooth disorder). It is expected that as MedDRA 

becomes more widespread, this will no longer be such a problem. It is critical that the reviewer 

assess the appropriateness of the applicant’s categories and the coding of adverse event verbatim

terms to preferred terms and understand how the verbatim terms (including terms in languages 

other than English) were classified. 

In assessing the applicant’s coding of events, the reviewer should compare the applicant’s 

preferred terms to the verbatim terms used by investigators and patients, focusing on the events 

leading to dropouts or other changes in treatment as well as to serious adverse events. The 

applicant will usually provide (ideally this will have been agreed to at the pre-NDA/BLA 

meeting, but if not, it should be sought early in the review) the following tables and listings for 

 

17Food and Drug Administration, Coding Symbols for Thesaurus of Adverse Reaction Terms, 5th ed., FDA, 

Rockville, MD, 1995. 

18 MedDRA (Medical Dictionary for Regulatory Activities), http://www.meddramsso.com/NewWeb2003/index.htm.

20
Contains Nonbinding Recommendations

assistance with this assessment; they should be provided in a form the reviewer can manipulate, 

such as a SAS transport file, not just in PDF format: 

 

• Adverse event tables in individual study reports based on investigator terms for events 

• A comprehensive line listing of all adverse events in phase 2 and 3 studies with a column

containing investigator terms coded under a preferred term (see Table 7.1.5.2.1. This table 

is for reference only; it would not be included in the review) 

• Listing of preferred terms and the investigator and patient terms that were subsumed under 

the preferred term. This table is for reference only; it would not be included in the review, 

although parts of it might be). 

The reviewer should consider the following: 

 

• Whether terms are too narrow (splitting), resulting in an underestimation of the true 

incidence for a particular event or syndrome (e.g., somnolence, drowsiness, sedation, and 

sleepiness probably all refer to the same event) 

 

• Whether the terms are too broad or over-inclusive (lumping), so that important events that 

should be examined separately are diluted by less important events (e.g., loss of 

consciousness and syncope subsumed under hypotensive events or hypotension) 

• Whether terms used lack a commonly understood meaning (e.g., mouth disorder, tooth 

disorder, GI disorder) and, if so, whether the incidence of individual events subsumed under 

these terms should be expressed separately or mapped to a different preferred term

• Whether terms exaggerate a finding (acute liver failure for a transaminase elevation) or 

minimize the importance of an event (hypotension for a syncope episode) 

• Whether the coding of adverse events is similar across treatment groups 

In any of these cases, the reviewer (or the applicant at the request of the reviewer) may have to 

recalculate rates using alternative terms or different groups of terms. 

Usually it will be impossible to evaluate all or even most adverse event terms in this much detail. 

However, certain preferred terms should always have the subsumed verbatim terms examined 

because they may conceal important events. For example, accidental injury often includes 

fractures and/or lacerations related to falls. The fall, itself, however, may not have been captured 

as an adverse event. Additionally, edema may sometimes include facial edema. Since facial 

edema often represents an allergic reaction, one would not want allergic events lumped together 

with peripheral edema events. In general, adverse event terms associated with discontinuation or 

serious consequences deserve the closest scrutiny, but other classifications should be at least 

spot-checked. The review should comment on how this issue was addressed. 

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7.1.5.3 Incidence of Common Adverse Events — Assessment of Various Databases 

Applicants typically prepare a wide variety of tables of adverse event rates for individual studies 

and pools of various studies. Those tables generally include investigator causality assessments 

and severity ratings. The tables the reviewer considers useful should be appended to the review. 

 Incidence rates for common adverse events may be estimated from the relatively small portion 

of the overall database that is contained in the controlled (especially placebo-controlled) trials. 

For these more common events, the ability to compare rates on drug with a control outweighs the 

disadvantage of basing the rate estimates on fewer subjects. In determining incidence rates for 

common adverse events, the reviewer should identify the subset of trials in the phase 2 and 3 

database that will provide the best estimate of rates and develop tables of event rates based on 

that judgment. 

• If possible, the reviewer should rely on pooled data from studies using the same comparator 

group (e.g., only placebo-controlled trials) and of roughly similar duration. If some of the 

trials also had an active control, rates for that group (pooled) can also be included (see Table 

7.1.5.3.1). If different doses were used, both a pooled all doses group and individual dose 

groups can be shown. The best comparison is of the groups included in all studies (drug at a 

particular dose and placebo), but the others (active controls, individual dose groups) may 

also be useful (also see Section 7.4 for broader discussion of pooling). 

• If there are not adequate numbers of patients in such trials to give meaningful rate estimates, 

the reviewer should consider pooling placebo-controlled trials, active control trials, and three 

arm trials (i.e., trials that do not all have the same control group). Even when this approach 

is needed overall, smaller subsets of studies, or even individual studies, can be used to 

examine high-frequency events. 

• Most applicants will construct adverse event tables by compiling and presenting the numbers 

and/or percentages of patients experiencing an adverse event in a study (or the absolute 

number of adverse events experienced in a group), without regard to the duration of 

treatment received. This is often satisfactory for relatively short-term studies. If studies of 

significantly different durations are pooled, however, or if there is a different discontinuation 

rate in the treatment arms and the risk of the adverse reaction persists over time, one must 

consider these durations to understand the real occurrence rate that patients will experience. 

One way to deal with the problem of different durations is to use the total person-time 

exposure for each treatment group and calculate the rate of the adverse event per period of 

exposure (# of patients with adverse event total person-time exposure), rather than the risk (# 

of patients with adverse event total number of patients). This is particularly useful for the 

more important adverse reactions and reactions that occur at a fairly constant rate over time, 

but the person-time approach can also be used when the hazard rate changes over time. In 

this case, however, the observation period must be broken into component periods (e.g., 

evaluating person-time rates for each treatment for month 1, month 2, ....). 

• If concurrently controlled data are unavailable, overall rates from well-monitored, single-arm

databases can be used to provide some indication of rates that were observed in treated 

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patients, but there is little ability to establish causality except insofar as reactions are 

predicted by the known pharmacology of the drug. 

For the most part, attributions of causality by the investigators should be discounted, and adverse 

events should be assessed without regard to attribution. Also, in general, tables should give rates 

for all severities of a given effect, although in some cases (notably cytotoxic drugs), it is 

important to distinguish more and less severe reactions, as the former may be therapy-limiting or 

may affect the overall benefit-risk conclusion for the drug. For events with high background 

rates (e.g., headache, fatigue, and other events that occur frequently independent of drug 

therapy), however, display of all reported events can result in a high event rate that obscures 

drug-relatedness. This can be a particular problem when time on drug is prolonged. For 

example, it is common for studies of 4 to 6 weeks duration to report headache at a high (20 to 25 

percent) rate. In that case, considering the severity or causality assessment of such events may 

allow a better assessment (e.g., if severe headaches are found only in the drug-treated group). 

Events that are more severe and for which subjects have multiple occurrences while on drug 

therapy are more likely drug-related. In determining incidence, however, both single occurrence 

and multiple occurrence events should be counted as one event. 

Some categories of adverse events (e.g., decreased cognitive or sexual function) are notoriously 

difficult to detect without special efforts, such as targeted questionnaires. If the database 

includes special studies intended to identify these events, they should generally be given more 

credence than nontargeted studies, which tend to substantially underestimate rates (See Section 

7.1.9). Incidence rates should be based on findings from the targeted studies. 

7.1.5.4 Common Adverse Event Tables 

The review should contain a table (or tables) that presents the best overall display of commonly 

occurring adverse events, generally those occurring at a rate of 1 percent or more (but lower 

rates can be presented for very large databases). The table, or tables, will form the basis for the 

adverse reaction table in labeling. The table may use a higher cut off than 1 percent if doing this 

does not lose important information. Adverse events that are equally common on drug and 

placebo, or more common on placebo, are usually omitted. The frequency cut-off for inclusion 

of adverse events in the table (e.g., > 1%) is inherently arbitrary. If one is used, the review 

should explain how the threshold was determined. It may also be informative to include tables 

that distinguish between common adverse events on the basis of severity. It is most common to 

group adverse events within body systems, but a display by descending frequency may also be 

useful. 

7.1.5.5 Identifying Common and Drug-Related Adverse Events 

For common adverse events, the reviewer should attempt to identify those events that can 

reasonably be considered drug related. Although it is tempting to use hypothesis-testing 

methods, any reasonable correction for multiplicity would make a finding almost impossible, and 

studies are almost invariably underpowered for statistically valid detection of small differences. 

The most persuasive evidence for causality is a consistent difference from control across studies, 

and evidence of dose response. The reviewer may also consider specifying criteria for the 

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minimum rate and the difference between drug and placebo rate that would be considered 

sufficient to establish that an event is drug related (e.g., for a given dataset, events occurring at 

an incidence of at least 5 percent and for which the incidence is at least twice, or some other 

percentage greater than, the placebo incidence would be considered common and drug related). 

The reviewer should be mindful that such criteria are inevitably arbitrary and sensitive to sample 

size. 

7.1.5.6 Additional Analyses and Explorations 

For adverse events that seem drug related (the analyses suggested can have no value for 

unrelated events), the reviewer should perform the following additional analyses (see Section 

7.4, General Methodology, for discussion of methods for the explorations and analyses identified 

below), as appropriate: 

• Explorations for dose dependency. These are important. The reviewer should ordinarily rely 

on fixed dose studies, as titration studies tend to show that those who tolerate higher doses 

have lower adverse reaction rates, but in some cases titration studies may show a clearly 

increased rate of adverse reactions with dose. It may also be useful to evaluate safety as a 

function of weight-adjusted dose, body surface-adjusted dose, or cumulative dose. Dose 

increases may be associated with adverse reactions or the severity of adverse reactions. 

• For events that occur commonly, explorations of time to onset 

• For common, troublesome events (e.g., somnolence, nausea) explorations of adaptation to 

develop information on the time course of, and tolerance for, such events 

• Explorations for demographic interactions (rates and comparisons with control for 

demographic and other subsets) for at least the more common and important adverse events. 

The applicant will have provided such analyses under 21 CFR 314.50(d)(5)(vi). Note that 

this analysis may require use of less optimal tables of pooled results (see section 7.1.5.3). 

• Explorations for drug disease and drug-drug interactions if there is a strong signal for an 

interaction or good rationale for expecting an interaction

• Selective exploration of certain adverse events in an attempt to better characterize them. For 

example, if rash appears to be drug related, the reviewer may want to look more closely at 

individual cases of rash. The applicant’s line listing of all adverse events across the entire 

phase 2 to 3 databases would be a good source for identifying individual cases of rash. If a 

subject dropped out because of rash, the applicant should have provided a narrative 

discussion of the event, which would also be a good source for attempting to better 

characterize the event. Although the data collected on nonserious adverse events is usually 

sparse, the reviewer could still request additional information from the applicant on 

commonly occurring adverse events that require further characterization. 

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• When adverse events of a given type vary markedly in severity, separate analyses of each 

severity may be useful. 

A description of the methods used in such additional explorations should be provided, with all 

results, interpretations, and pertinent discussion. Where an applicant’s analysis is considered 

inadequate, this should be noted and an alternate developed by the reviewer or requested from

the applicant. 

7.1.6 Less Common Adverse Events 

In general, a fairly large database is needed to evaluate less common adverse events. To identify 

relatively rare events of significant concern, the reviewer has to examine the occurrence of 

adverse events over the entire phase 2 to 3 database, including data for which there is no useful 

concurrent control. The overall database is typically heterogeneous, including uncontrolled 

exposure for varying durations and at varying doses, and is unlikely to lend itself to meaningful 

estimates of rates or assessment of causality (except where there has been rechallenge). Thus, it 

may be sufficient for the reviewer to group these data in gross categories of incidence and by 

body system. For example, it may be useful to categorize less common events in order of 

decreasing frequency within the following incidence ranges: 

• Adverse events occurring at rates less than or equal to 1/100 

• Adverse events estimated to occur at rates between 1/100 and 1/1000 

• Adverse events estimated to occur at rates less than 1/1000 

The reviewer should then develop a condensed list of reactions to be included in the Adverse 

Reactions section of labeling.19 This list should eliminate events that are common in the general 

population and not likely to be drug related and adverse events characterized by terms that are 

too vague to be helpful, unless the reviewer is able to identify a more meaningful term that was 

subsumed into the vague term when the adverse event was coded by the applicant (see Section 

7.1.5.2 above). 

Some of the reactions in the condensed list may be of particular concern, but insufficiently clear 

as to whether they are caused by the drug to lead to a Warning/Precaution in the labeling. In that 

case, it is useful to notify the safety evaluator in the Office of Drug Safety who will be 

monitoring the drug after marketing. 

7.1.7 Laboratory Findings 

The approach to review of laboratory findings (chemistry, hematology, and urinalysis) is 

generally similar to that suggested for the other categories of safety data. As considered in 

greater detail below, the review should identify laboratory tests performed in the clinical studies, 

describe the dataset from which laboratory findings information is obtained, describe the 

 

19 A draft guidance for industry and reviewers, Content and Format of the Adverse Reactions Section of Labeling for 

Human Prescription Drugs and Biologics, was issued in June 2000. Once finalized, it will represent the Agency's

thinking on this topic. 

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methods used to assess findings, discuss pertinent findings, and review the more important 

findings in depth. Laboratory findings discussed in detail in other sections of the review (e.g., 

Section 7.1.2 Other Serious Adverse Events, Section 7.1.3 Dropouts and Other Significant 

Adverse Events) need not be discussed in detail in this section. This section should refer to the 

more detailed discussions of such findings elsewhere in the review. 

7.1.7.1 Overview of Laboratory Testing in the Development Program 

The review should provide an overview of what laboratory testing (chemistry, hematology, and 

urinalysis) was carried out. It is preferable to summarize the overall approach, rather than 

provide detailed comments about laboratory testing for each study. The review should contain 

the following to the extent relevant to the data: 

• Discussion of any discrepancies between planned analyses and analyses that were done (e.g., 

tests omitted or added, changes in planned frequency of testing) 

• Discussion of procedures used to evaluate abnormal values (e.g., whether patients were 

followed until their values normalized, whether any patients were rechallenged, the 

procedures used for sample analysis (i.e., central or local labs, windows of time in which lab 

values were considered20) 

• A summary table identifying the numbers of patients exposed to test drug who had baseline 

laboratory values and follow-up assessments 

• Whether results of unscheduled lab tests were included in the principal analyses and tables 

The reviewer should note that laboratory tests obtained at unscheduled visits (e.g., when a patient 

is hospitalized for an adverse event) are often not included in the NDA/BLA laboratory database. 

In those cases, the only place a reviewer would learn of an abnormal laboratory value might be a 

narrative summary (or occasionally a CRF). Too often, however, the narrative summary includes 

only a preferred or verbatim term (e.g., acute renal failure) and does not include the laboratory 

value of interest (e.g., BUN/creatinine). In such cases, the laboratory data of interest should be 

requested from the applicant. 

7.1.7.2 Selection of Studies/Analyses for Drug-Control Comparisons of Laboratory Values 

Controlled comparisons generally provide the best data for deciding whether there is a signal of 

an effect of a drug on a laboratory test. Placebo-controlled trials are generally short term, 

however, and therefore unsuitable for assessing late-developing abnormalities, so that longer 

term data also need to be examined. If there is no concomitant control, comparison may need to 

be made with similar populations outside the NDA (e.g., in other applications). In identifying 

the sample population for comparison of laboratory values, the reviewer should pool relevant 

 

20 Applicants may consider only lab values obtained within a certain window around the protocol-specified date for 

collection. In some cases, the laboratory data obtained outside the window may be available, but the applicant may 

choose not to include it. 

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studies. The review should explain how the studies to be pooled were selected. In comparing 

laboratory values, there are additional considerations when using pooled data (in addition to 

those discussed in Section 7.4.1 Methodology, Pooling), including: 

• The methods of sample collection and handling in different studies 

• The assay methods used in different studies 

• The reference ranges used in different studies 

Several analyses may be needed. Separate analyses should be performed for patients with 

normal values at baseline, for patients with abnormal values at baseline, and for patients without 

baseline values. In general, there will need to be at least one analysis that includes all data (data 

from planned or unplanned visits, values collected as follow-up to abnormal findings). 

7.1.7.3 Standard Analyses and Explorations of Laboratory Data 

This review should generally include three standard approaches to the analysis of laboratory 

data. The first two analyses are based on comparative trial data. The third analysis should focus 

on all patients in the phase 2 to 3 experience. Analyses are intended to be descriptive and should 

not be thought of as hypothesis testing. P-values or confidence intervals can provide some

evidence of the strength of the finding, but unless the trials are designed for hypothesis testing 

(rarely the case), these should be thought of as descriptive. Generally, the magnitude of change 

is more important than the p-value for the difference. 

7.1.7.3.1 Analyses Focused on Measures of Central Tendency 

The central tendency analysis generally compares mean or median changes from baseline across 

treatment groups, and the review should contain the results of these analyses for all laboratory 

measurements. Although marked outliers are typically of greatest interest from a safety 

standpoint (see below), at times a potentially important effect may be revealed only in analyses 

looking at differences in mean change from baseline. For example, several drugs that cause 

modest decreases in uric acid because of a uricosuric effect have caused acute renal failure 

(ticrynafen, suprofen) in inadequately hydrated patients. Suprofen was withdrawn from the 

market for this reason. Mean changes in electrolyte levels can also signal risks. 

It is generally useful to include as appendices tables providing data on central tendency (see 

Table 7.1.7.3.1.1). The reviewer should note and discuss signals that emerge from these tables 

and indicate those for which further study is needed, if any. 

7.1.7.3.2 Analyses Focused on Outliers or Shifts from Normal to Abnormal 

The review should focus on patients whose laboratory values deviate substantially from the 

reference range. Applicants usually include displays and analyses designed to detect such 

outliers. The relevant data would come from shift tables, scatter plots, box plots, cumulative 

distribution displays, and tables providing incidence of patients across treatment groups who had 

a potentially clinically important deviation from normal on one or more laboratory parameters 

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while on treatment (see Tables 7.1.7.3.2.1). In analyzing outliers, the reviewer should be aware 

of the following: 

• Regression to the mean (and an apparent upward shift) can be expected if patients are 

screened for normality, giving a shift even if there is no drug effect; comparison with control 

groups is critical. 

• If there are more measurements performed during treatment than baseline and abnormal 

values are randomly occurring, there is more opportunity for outliers during treatment. 

Again, comparison with a control group is critical. 

• For important laboratory parameters, the reviewer should carefully consider the cut-points 

used by the applicant to define normal and abnormal. 

• If values used to identify outliers are too extreme, important findings may not be identified. 

• If values used to identify outliers are not large enough, important findings may be obscured 

by grouping important outliers and trivial findings (e.g., values greater than two times upper 

limit of normal for transaminase are common in many datasets and may not distinguish 

hepatotoxic from non-hepatotoxic agents; 3-fold and higher elevations appear to be more 

discriminating). 

Decisions about what criteria to use to identify outliers should, if possible, be made at the preNDA meeting. Because it is not possible to know in advance what criteria will be optimal for 

detecting between-group differences, it may be useful to conduct analyses using cut points other 

than those chosen by the applicant. In addition, it may be useful to consider between-group 

comparisons of the following: 

• Cumulative or other distributions of data, rather than solely proportions of patients meeting 

some arbitrary criterion 

• Patients with large shifts within the normal reference range 

• Patients who meet outlier criteria for more than 1 variable simultaneously (e.g., transaminase 

and bilirubin) 

• Patients having persistent abnormalities (more likely to be real deviations) 

Analyses of outliers should serve as a source of signals for events to explore in more depth. The 

reviewer should discuss signals that emerge and indicate those for which further exploration is 

needed. The details of the explorations carried out and the results should be provided in 

subsection 7.1.6.4 as described below. 

7.1.7.3.3 Marked Outliers and Dropouts for Laboratory Abnormalities 

The reviewer should carefully analyze individual patients with large changes in laboratory 

values. These changes are much more likely to identify significant problems than mean or 

median changes from baseline. Applicants typically provide a list that identifies patients with 

extreme changes, usually specified in advance. Individual patient data displays should be 

available to the reviewer for all such patients. Even for relatively uncommon events, it is helpful 

to compare rates in treatment and control groups. 

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Discontinuation of treatment for a laboratory abnormality may be considered a marker of 

perceived clinical importance of the finding. It is again useful to compare treatment groups, 

taking into account duration of treatments, for rates of discontinuation for particular laboratory 

abnormalities. Because of the importance of looking at dropouts for laboratory changes (even a 

small number of marked abnormalities, such as liver function or WBC count, may signal major 

problems), all such dropouts in the phase 2 to 3 population should be identified. The reviewer 

should generally analyze and comment on each individual patient identified as dropping out for 

any significant laboratory abnormalities. In some cases, it is critical to note whether appropriate 

testing has been carried out to rule out non-drug-related mechanisms (e.g., viral hepatitis 

serological testing in patients with transaminase elevation or more severe liver injury) and 

whether appropriate additional tests have been performed (e.g., bilirubin in patients with 

transaminase elevation). 

7.1.7.4 Additional Analyses and Explorations 

Additional analyses may be appropriate for certain laboratory findings, including analyses for 

dose dependency, time dependency, and also drug-demographic, drug-disease, and drug-drug 

interactions (see Section 7.4 Methodology). The review should discuss the rationale for 

additional explorations, the methods used, and the results and interpretations. 

7.1.7.5 Special Assessments: Hepatotoxicity, QTc, Others 

Certain laboratory assessments are so critical to the safety assessment that they deserve special 

attention in any review. For example, hepatotoxicity has been an important cause of drug 

marketing withdrawals from the 1950s (iproniazid) to the present (ticrynafen, benoxaprofen, 

troglitizone, bromfenac) and has led to important limitations on the use of many more drugs 

(isoniazid, labetalol, trovafloxacin, tolcapone, nefazodone, felbamate). At present, it appears 

that a potential for severe hepatotoxicity may be signaled by a set of findings sometimes called 

Hy’s Law, based on the observation by Hy Zimmerman, a major scholar of drug-induced liver 

injury, that a pure hepatocellular injury leading to jaundice had serious implications, a 10 to 50 

percent mortality. Over the years, this observation has led to the following proposition: 

In a drug development database, a potential for severe hepatotoxicity is signaled by the 

following set of findings: 

1. An increased rate of transaminase elevations (3x ULN, 5x ULN, 10x ULN, etc.) 

in treated patients compared to control 

2. No significant evidence of obstruction (elevated AP), although some elevation 

may follow severe hepatocellular injury 

3. A very small number of cases (two, perhaps even one) of transaminase elevation 

accompanied by a rise in bilirubin to 2x ULN 

The explanation for the usefulness of this signal is the high capacity of the liver for bilirubin 

excretion; it takes a good deal of damage to the liver to impair bilirubin excretion (in the absence 

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of obstruction). This signal has been present for troglitizone, bromfenac, and dilevalol (never 

approved in the United States, but hepatotoxic in Portugal). 

Table 7.1.7.5.1 is an outline of a comprehensive assessment of available data pertinent to 

potential hepatotoxicity. A similar outline will be developed for assessment of

electrocardiographic QT abnormalities, a risk factor for potentially fatal arrhythmias (see section 

7.1.9).

7.1.8 Vital Signs 

Vital signs can be analyzed and reported using an approach essentially identical to that taken for 

laboratory data. This section should be organized in a similar manner to the laboratory section. 

7.1.8.1 Extent of Vital Signs Testing in the Development Program 

7.1.8.2 Selection of Studies and Analyses for Overall Drug-Control Comparisons 

7.1.8.3 Standard Analyses and Explorations of Vital Signs Data 

7.1.8.3.1 Analyses Focused on Measures of Central Tendency 

7.1.8.3.2 Analyses Focused on Outliers or Shifts from Normal to Abnormal 

7.1.8.3.3 Marked Outliers and Dropouts for Vital Signs Abnormalities 

7.1.8.4 Additional Analyses and Explorations 

7.1.9 Electrocardiograms (ECGs) 

ECG data can be analyzed and reported using an essentially identical approach to that taken for 

laboratory data. The adequacy of the assessment (see 7.2) may be especially important in this 

case, given recent experience with drugs that prolong the QT interval and cause the ventricular 

tachycardia known as Torsade de Pointes (TdP). A guidance document on the design, conduct 

and interpretation of clinical studies assessing the effects of drugs on the QT interval is under 

development as a part of the ICH effort. The current version, a step 2 guidance (E14: Clinical 

Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for NonAntiarrhythmic Drugs) can be found at http://www.ich.org. The safety review should provide in 

this section an overview of effects on the QT interval, organized in a similar manner to the 

laboratory section. This section of the safety review should summarize the results of any studies 

designed specifically to assess the effects of the drug on the QT interval. 

7.1.9.1 Extent of ECG Testing in the Development Program, Including Brief Review of 

Preclinical Results 

This section should describe the number of baseline and on-study ECGs obtained, who read the 

ECGs, and what methodology was used (e.g., automatic, blinded cardiologists). 

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7.1.9.2 Selection of Studies and Analyses for Overall Drug-Control Comparisons 

7.1.9.3 Standard Analyses and Explorations of ECG Data 

7.1.9.3.1 Analyses Focused on Measures of Central Tendency 

7.1.9.3.2 Analyses Focused on Outliers or Shifts from Normal to Abnormal 

7.1.9.3.3 Marked Outliers and Dropouts for ECG Abnormalities 

7.1.9.4 Additional Analyses and Explorations 

7.1.10 Immunogenicity 

Data on the impact of immunogenicity (if applicable) on safety, efficacy, and/or clinical 

pharmacology and pharmacokinetics may be summarized in this section and referenced 

throughout the review. 

All therapeutic proteins have the potential to elicit antibody responses. An antibody response to a 

protein may have no consequences or, in some cases, can lead to potentially serious sequelae. 

Adverse immune responses to a protein drug could result in one or more of the following 

outcomes: 

• For a product that is intended as replacement for a missing endogenous substance, antibodies 

could neutralize the replacement product and generate a clinical deficiency syndrome. 

• Neutralization of a protein product by blocking antibodies could reduce the efficacy of a lifesaving product. 

• Antibody development could result in a life-threatening hypersensitivity response. 

Factors that tend to increase the likelihood of an immune response include whether the protein is 

highly conserved in nature (less likely if it is), whether the protein product is administered via 

the subcutaneous route (more likely if it is), and whether the protein intended for chronic use. 

This section of the review should assess the adequacy of the immunogenicity data provided to 

address these issues. 

7.1.11 Human Carcinogenicity 

Although formal studies in humans of the carcinogenic effects of drugs and biologics are 

uncommon, reflecting the expectation that induction of cancer would occur over a very long 

period of exposure, a systematic assessment of human tumors reported during drug development 

can provide useful safety information in some cases. Such an assessment would be appropriate 

where controlled studies are of long duration (e.g., more than a year), especially for drugs or 

biologics that have positive genotoxicity or animal carcinogenicity findings or are known 

immune modulators. 

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7.1.12 Special Safety Studies 

The review should describe and discuss results of any studies designed to evaluate a specific 

safety concern or concerns. These studies may include: 

• Studies to assess whether a drug has safety concerns common to its pharmacologic class 

(e.g., a study to assess effects of a benzodiazepine hypnotic on driving, respiration, memory, 

or next day psychomotor functioning) 

• Studies in topical products (including systemic products delivered by a patch) to assess 

cumulative irritancy, contact sensitizing potential, photosensitivity, and photoallergenicity 

• Studies to characterize a drug’s effect on QT interval, part of most modern development 

efforts 

• Studies intended to demonstrate a safety advantage over therapeutic alternatives (less 

extrapyramidal effect for an antipsychotic, less sedation for an anti-histamine, less cough 

from an angiotensin II blocker than an ACE inhibitor). Such studies must include the 

comparator agent (a failure to see the side effect in a placebo-controlled study is usually not 

informative without the active control to demonstrate assay sensitivity). 

• Studies in special populations thought to be at increased risk and likely to use the drug. 

 

In labeling, the results of these studies should, as appropriate, supersede data from less targeted 

studies (e.g., observational safety data collected from efficacy trials). 

 

7.1.13 Withdrawal Phenomena/Abuse Potential 

The review should contain a discussion of abuse potential and any apparent withdrawal 

symptoms. For therapeutic classes with a history of abuse potential and withdrawal phenomena 

(e.g., sedative/hypnotics and anxiolytics), studies are usually performed to assess these issues. 

The review should comment on the adequacy and findings of these studies. For other drugs, 

adverse events that emerge after discontinuation of the drug should be assessed to determine 

whether they may indicate a withdrawal phenomenon. If the applicant evaluated the potential 

for withdrawal phenomena, the review should indicate whether there was a prospective or posthoc assessment of withdrawal emergent signs and symptoms (during drug taper or following 

discontinuation) and discuss the implications of the approach used on the reliability of the 

findings. 

7.1.14 Human Reproduction and Pregnancy Data 

Although formal studies in humans of the effects of drugs on reproduction, pregnancy, or 

lactation are uncommon, the review should summarize any drug exposure in pregnant or nursing 

women, including any inadvertent exposure during the drug’s development and exposure 

identified from secondary sources (e.g., postmarketing surveillance). If there is no information 

on drug exposure in pregnant or lactating women, the review should acknowledge that fact. The 

review should discuss positive and negative findings. 

7.1.15 Assessment of Effect on Growth 

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Increasingly, clinical reviewers are presented with analyses of height and weight data collected 

during studies of pediatric subjects. These data are generally inadequate to allow for definitive 

conclusions about an effect of drug on growth for several reasons. Assessment of the effect of 

drug on growth requires accurate measurements, particularly for height, and in most studies, 

height is not measured accurately. Growth is a process that occurs over long periods of time, 

and controlled trials of several weeks duration may not provide a sufficient period of observation 

to assess the effect of drug on growth. Open label studies can offer longer periods of time to 

observe effects on growth, but the lack of a control group limits the ability to separate the effect 

of drug and underlying disease on growth. Review of height and weight data for possible effects 

on growth makes use, in part, on approaches described above in the laboratory data section. 

Analysis of changes in central tendency and outlier analysis, for example, apply to the evaluation 

of the effect of a drug on growth. There are, however, some distinctive issues that must be 

considered. 

First, the sponsor should describe how weight and height were measured. The manner in which 

these measurements were made will bear on how much confidence the reviewer can have in the 

data provided. For example, a development program in which the measurement schedule and 

methodology were standardized and in which the study staff were trained in measurement, will 

result in more reliable data than a development program that did not standardize procedures. 

The review should therefore include a description of the measurement methodology. 

Second, growth is not constant throughout childhood and varies by age and sex. Without 

consideration of these factors at baseline, absolute mean changes in weight and height can give 

misleading results. Adjustment of growth for age and sex can be done by conversion of a child’s 

height and weight to a z-score, which is the number of standard deviations that an individual’s 

measurement is from the mean for age and sex matched children in the general population. A 

decrease in mean z-score for a group is interpreted as evidence of a lag in growth compared to 

what would be predicted using general population data. In a controlled trial, differences in mean 

z-score changes from baseline between treatment groups may provide evidence of an effect of 

drug on growth. Declines in mean z-scores in open label studies are less easily interpreted 

because these could result from the effect of drug or could be caused by the disease for which the 

treatment is being studied. 

Sponsors should provide analyses of height and weight data that assess measures of central 

tendency and outlier analyses using height and weight z-scores. Although results from these 

analyses will not provide definitive proof of drug related effects on growth in most cases, they 

may help identify candidates for prospective studies of the effect of drug on growth in children. 

The review team should request such analyses at the pre-NDA meeting. 

7.1.16 Overdose Experience 

The review should summarize all overdose experience with a drug in humans (including both 

information provided by the applicant and information obtained from secondary sources) and 

describe the constellation of signs, symptoms, and other abnormalities one might expect to see in 

association with overdose. Phase 1 data should be reviewed to identify subjects who may have 

received higher doses than those used in later phases of study. In addition, patients with certain 

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physiological differences that would compromise their ability to clear a drug (e.g., renal 

impairment, hepatic impairment, limited CYP4502D6 activity for a drug cleared by this 

isozyme) may provide data relevant to the clinical implications of overdose. 

7.1.17 Postmarketing Experience 

Relevant findings from postmarketing experience, if any, should be described briefly here and 

referenced in the summary section (Section 7.3). 

 

7.2 Adequacy of Patient Exposure and Safety Assessments 

Section 7.1 is an assessment of the adverse events seen during the development program. Section 

7.2 should provide the reviewer’s comments on the adequacy of drug exposure and the safety 

evaluations performed as part of the development program. This section addresses the 

regulatory question of whether or not all tests reasonably applicable were conducted to assess 

the safety of the new drug. Was there adequate experience with the drug in terms of overall 

numbers of patients and in appropriate demographic subsets of patients? Were doses and 

durations of exposure appropriate? Were all (or not all) appropriate tests performed in the 

exposed patients? Were all necessary and appropriate animal tests performed? Were all the 

appropriate clinical tests carried out (e.g., electrocardiographic assessment of effects on QT 

interval)? Was the drug adequately worked up metabolically? Were appropriate in vitro studies 

of drug-drug interaction carried out according to current guidelines? Were all potentially 

important findings adequately explored: for example, to what extent was psychomotor 

impairment specifically assessed in a drug that is sedating? 

If important data are missing, this could influence the regulatory action on the drug. A critical 

task of the reviewer in this section is identification of specific concerns that need to be addressed 

by the applicant, either before approval or postapproval. Even more than for most other parts of 

the review, the reviewer needs to be conscious of recent developments and discuss issues 

broadly. Finally, this section is the place for detailed comments on the quality and completeness 

of the data provided. 

The review should clearly describe the studies and overall extent of the data supporting the 

evaluation of safety. The reviewer should then make a judgment about the adequacy of the 

clinical experience with the new drug for assessing safety. 

7.2.1 Description of Primary Clinical Data Sources (Populations Exposed and Extent of 

Exposure) Used to Evaluate Safety 

In this section the reviewer should identify and characterize the primary safety data sources used 

in conducting the review. If these are described elsewhere in the review, this section can 

reference those sections. The primary source is generally the database derived from the 

applicant's development program. Studies in this program will generally have full study reports 

related to safety, or studies that are grouped for analysis of safety in an Integrated Summary of 

Safety; case report forms will be available. These studies usually will have been closely 

monitored. Secondary sources may also be available and may be of critical importance (e.g., for 

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a drug already available in other countries), and there may be some parts of the database that 

have had limited analyses (i.e., only for deaths and adverse dropouts); these are described in 

section 7.2.2. 

Tables and graphs are useful in describing the data sources for the safety review. Generally, the 

reviewer should use the tables and graphs in this section to characterize the overall database. 

The detailed tables and other displays for this subsection may be included in an appendix to the 

review, but summary tables and narrative statements should be included here. The reviewer 

should also characterize the per patient data (narratives, CRFs, CRTs and electronically 

accessible databases for baseline information. See section 7.4 for discussion of ability to link 

databases. 

7.2.1.1 Study Type and Design/Patient Enumeration 

The reviewer should include in an appendix a table, such as that illustrated in Table 7.2.1.1.1, 

enumerating all subjects and patients across the entire development program, phases 1 to 3. This 

is a critical table that identifies the important patient pools and denominators for subsequent 

analyses and incidence estimates. 

The reviewer should also include an appendix table that provides brief descriptive information 

for all individual studies, including study design (fixed dose vs. flexible dose, parallel vs. 

crossover), dosing schedule, study location (foreign vs. domestic), treatment groups and doses, 

sample sizes, patient population (elderly). Studies that were designed to assess a particular 

aspect of safety (e.g., ECG, ophthalmic) should be noted. Most NDAs/BLAs will include a table 

of all studies, as such a table is called for in the Clinical/Statistical guidline and in the Common 

Technical Document. 

Applicants sometimes segregate certain clinical trials from their primary source data (see 7.2.2, 

secondary source data), especially foreign data. This may be appropriate, especially if there is a 

basis for believing that these data differ substantially in quality and/or completeness or in critical 

aspects of investigator practice from the data included in the primary source database. This is a 

matter of judgment, however, and cannot be assumed to be valid. An explanation should be 

provided in the review describing the basis for decisions about what data were included and what 

excluded from the primary source data. 

An NDA/BLA generally includes data from patient samples that are at different levels of 

completeness in terms of data entry, information collected, and validation. Table 7.2.1.1.1 

should include patient counts (or estimates) from all studies contributing data, regardless of these 

factors. Data cutoff dates or database lock dates for the various databases comprising the 

NDA/BLA should be identified at this point in the review. For example, the cutoff date for the 

overall safety database derived from completed studies might be more distant, while the cutoff 

date for submitting serious adverse events from all studies may generally be more recent. These 

dates may likely need updating during the course of NDA/BLA review as more data become

available. 

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7.2.1.2 Demographics 

The reviewer should include appendix tables in a format similar to that illustrated in Table 

7.2.1.2.1 (showing percent distribution within treatments of patients by age, gender, and race as 

well as weight in various groups), providing overall demographic information for phase 1 and 

phase 2 to 3 study pools separately. It may be appropriate to provide demographic displays for 

subsets within these larger pools at other points in the review. 

7.2.1.3 Extent of Exposure (Dose/Duration) 

There are many ways to summarize the dose and duration experience with a new drug. Either 

can be expressed as mean, median, maximum, with histograms or other displays that give the 

numbers exposed at various doses or for various durations. A particularly useful approach is to 

provide combined dose and duration information. It is suggested that the review contain tables 

in the format illustrated in Table 7.2.1.3, enumerating patients on the basis of mean daily dose of 

the NDA/BLA drug and duration of administration for phase 1 and phase 2 to 3 study pools 

separately. If the study used a titration design, the modal dose (if 2 different doses were used for 

the same duration, the larger, or maximal modal dose) may be the more useful summary statistic. 

It is particularly important to examine the subgroup of patients who received a dose at least as 

large as the dose intended for marketing. 

It may also be useful to provide similar tables based on maximum dose, modal dose, dose 

expressed as mg/kg or mg/m,2 or even plasma concentrations, if such data are available. 

It may also be useful to provide similar tables for various subgroups (e.g., males and females 

separately, various age groups separately, and patients with various comorbid illnesses of 

interest separately). There should be similar displays for active control drugs if any were 

included in trials for the new drug. 

Finally, it may be useful for the review to include an appendix table providing total person time 

exposure data for the NDA/BLA drug, active control, and placebo, for the phase 2 to 3 database. 

 

7.2.2 Description of Secondary Clinical Data Sources Used to Evaluate Safety 

Secondary source data are (1) data derived from studies not conducted under the applicant's IND 

and for which CRFs and full study reports are not available,21 or studies so poorly conducted 

(e.g., poor ascertainment for adverse events), that they cannot be reasonably included in the 

primary source database, (2) postmarketing data, and (3) literature reports on studies not 

conducted under the IND. Often the applicant may have made the distinction between the data 

considered primary source data and other data, and the reviewer needs to examine the rationale 

for this distinction. 

 

21If CRFs are available from any such studies and the data quality is comparable to that of data from studies 

conducted under the applicant's IND, these data would ordinarily be included in the primary source database. 

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The secondary sources should be briefly described. It is worth emphasizing that secondary 

source data may be a critical source of information for review, despite the generally lower 

quality of these data, because they often provide the larger database needed to look for less 

common serious adverse events and may be reliable with respect to deaths and serious adverse 

events. 

7.2.2.1 Other Studies 

The NDA/BLA should be clear in describing exactly what other studies provided data and what 

the basis was for not integrating such data with the primary source data (e.g., no CRFs, no study 

reports, not adequately monitored). Lack of clarity in this should be noted by the reviewer. 

7.2.2.2 Postmarketing Experience 

If postmarketing data are available, this section should describe briefly the type of information 

available for review. An example of such a description would be a comment that a line listing 

for (a specified number of) spontaneous reports from marketing in (country) was provided, along 

with narrative summaries for the serious adverse events among the reports and an estimate of 

product use in (country) during that time period. As is the case for most spontaneous reports, 

these reports are likely to be difficult to interpret. Important events will be described in 

appropriate sections (e.g., 7.1.1 and 7.1.2, Deaths and Other Serious Events). 

7.2.2.3 Literature 

Relevant literature may be incorporated in various sections of the NDA, but is ordinarily 

included in section 5.4 of the Common Technical Document (M4: The CTD — Efficacy). The 

NDA/BLA may include a separate literature section or the literature may be provided or 

referenced as called for in various places in the Clinical/Statistical guidline in section II F, Other 

Studies and Information. The applicant should have provided a description of the search strategy 

to assess the world literature (e.g., databases used, key search words), the personnel who carried 

it out (their credentials) and whether the search relied on abstracts or full texts (including 

translations) of articles. A cutoff date for the literature search should also have been provided. A 

copy (translated as required) should have been submitted for any report or finding judged by the 

applicant to be potentially important. 

This section of the review should describe what information from the literature search was 

provided for review, the extent to which the above description of an ideal presentation was met, 

and whether any missing information is important (and/or was obtained by the reviewer). 

Independent literature reviews conducted by the reviewer should be described here as well. 

Actual safety findings should be described in appropriate sections of the safety review to present 

from the literature reports in this section of the review. 

7.2.3 Adequacy of Overall Clinical Experience 

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In evaluating the adequacy of clinical experience with the drug, the reviewer should refer to 

current ICH guidance on extent and duration of exposure needed to assess safety22 as well as the 

draft guidance on Pre-Marketing Risk Assessment.

23 The review should specifically address the 

following: 

• Whether an adequate number of subjects were exposed to the drug, including adequate 

numbers of various demographic subsets and people with pertinent risk factors 

• Whether doses and durations of exposure were adequate to assess safety for the intended 

use 

• Whether the design of studies (open, active-control, placebo-control) was adequate to 

answer critical questions 

• Whether potential class effects were evaluated (e.g., for anti-arrhythmic effects, 

evaluation of the potential for pro-arrhythmic effects) and whether problems suggested 

by pre-clinical data were assessed 

• Whether patients excluded from the study limit the relevance of safety assessments (e.g., 

diabetics, people over 75, people with recent myocardial infarction, people with renal or 

hepatic functional impairment, or people on other therapy). This may depend on the 

signals of toxicity that were observed in the patients who were studied. 

7.2.4 Adequacy of Special Animal and/or In Vitro Testing 

The clinical reviewer should not attempt a general assessment of the preclinical program, but 

rather, comment on whether preclinical testing was adequate to explore certain potential adverse 

reactions, using preclinical models based either on a drug’s pharmacology or on clinical findings 

that emerged early in clinical development. For example, for a drug anticipated to cause QT 

prolongation because of its drug class or because QT prolongation was seen in phase 1 studies, 

there are in vitro models to evaluate this potential. The reviewer should note whether such 

studies were done. If such studies were performed, the results would be summarized in the 

Pharmacology Review. 

7.2.5 Adequacy of Routine Clinical Testing 

The reviewer should comment on the adequacy of routine clinical testing of study subjects, 

including efforts to elicit adverse event data and monitor laboratory parameters, vital signs, and 

ECGs. In assessing the adequacy of clinical testing, the reviewer should consider the adequacy 

of the methods and tests used and the frequency of testing. The adequacy of specific testing 

intended to assess certain expected or observed reactions should be discussed under subsection 

7.2.7. 

 

22ICH E1A The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-Term 

Treatment of Non-Life-Threatening Conditions (http://www.fda.gov/cder/guidance/iche1a.pdf ) recognizes possible 

differences in expected exposure (e.g., more patient exposure would be expected for drugs with small effects, or 

drugs that are used prophylactically in well populations, where only a small fraction of patients will benefit). 

23 A draft guidance Premarketing Risk Assessment was issued in May 2004. Once finalized, it will represent the 

Agency's thinking on this topic. 

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The reviewer should be alert to the absence of data in an NDA laboratory database for analytes 

that are typically included in routine laboratory monitoring. For example, it was discovered after 

approval that the NDA laboratory database for the anti-epileptic drug zonisamide did not have 

data on serum bicarbonate. It was later determined that this drug is associated with a non-anion 

gap metabolic acidosis. The serum bicarbonate data would have been helpful in identifying this 

adverse reaction earlier. 

7.2.6 Adequacy of Metabolic, Clearance, and Interaction Workup 

Knowledge of how a drug is metabolized and excreted is critical to anticipating safety problems 

in patients with impaired excretory or metabolic function and problems resulting from drug-drug 

interactions. 

Drug-drug interaction assessment is a critical part of a modern drug development program and 

should evaluate the drug both as a substrate for interactions (interference with its clearance) and 

as an inducer or inhibitor of the clearance of other drugs. The reviewer should comment on the 

adequacy of in vitro and in vivo testing carried out by the applicant to identify the following: 

• The enzymatic pathways responsible for clearance of the drug and the effects of inhibition of 

those pathways, notably CYP450 enzymes and p-glycoproteins 

• The effect of the drug on CYP450 enzymes (inhibition, induction) and the effects of the drug 

on the PK of model compounds 

• The major potential safety consequences of drug-drug interactions 

Details of these assessments will be found in the Clinical Pharmacology Review and in the 

summary of that evaluation in the Medical Officer’s Review. 

7.2.7 Adequacy of Evaluation for Potential Adverse Reactions for Any New Drug and 

Particularly for Drugs in the Class Represented by New Drug; Recommendations for 

Further Study 

The reviewer should discuss the adequacy of the applicant’s efforts to detect specific adverse 

reactions that are potentially problematic and might be expected with a drug of any class (e.g., 

QT prolongation or hepatotoxicity) or that are predicted on the basis of the drug class (e.g., 

sexual dysfunction with SSRI antidepressants). The reviewer should also discuss whether the 

applicant should have made efforts to assess certain events that it did not assess. The reviewer 

should also discuss pertinent negative findings (absence of findings) for a drug in this section of 

the review (see examples below). 

 

The adverse events that warrant specific attention will vary depending on the characteristics of

the drug and the drug class. The known pharmacology of the drug would suggest some

evaluations (e.g., first dose effects for peripheral alpha blockers, tolerance and withdrawal 

effects for central alpha agonists, urinary retention with anti-cholinergics, QT prolongation with 

type III anti-arrhythmics, extrapyramidal effects with antipsychotics, muscle pain with statins), 

while experience with other members of the class would suggest others (e.g., hepatotoxicity with 

thiazolidinedione PPAR gamma agonists (glitizones), tendon problems with fluoroquinolones). 

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There should be a subheading for each adverse reaction that warrants special consideration (even 

if not observed) and, under each subheading, a discussion of what was done to detect the reaction 

and the adequacy of the approach. The following list of potential adverse reactions, and some of 

the drug and therapeutic classes that might trigger higher interest in them, may be a useful 

starting point in assembling a list (it is also important to examine labeling for other members of 

the drug’s pharmacologic class): 

Hepatotoxicity (NSAIDs, thiazolidinedione PPAR gamma agonists) 

Pancreatic toxicity 

QT prolongation (any antiarrhythmic, antipsychotic, antihistamine, fluoroquinolone) 

Vasodilator effects, such as hypotension (alpha blockers) or edema (dihydropyridine 

calcium channel blockers) 

Withdrawal effects (beta blockers, central alpha agonists, SSRIs, narcotics) 

Orthostatic hypotension (any antihypertensive, antipsychotics) 

Hypertension (any sympathomimetic or phosphodiesterase inhibitor) 

Tachycardia 

Neutropenia (drugs related to ticlopidine, procainamide, clozapine) 

Bleeding (drugs inhibiting any aspect of clotting or platelet function, NSAIDs) 

Aplastic anemia 

Increased coagulation times 

Muscle injury (any HMG CoA Reductase Inhibitor (statin) or other lipid-lowering drug) 

Sedation (any psychotropic drug) 

CNS stimulation 

Anticholinergic activity 

Allergic reactions 

Sexual dysfunction (any antidepressant, sedating drug) 

Elevated intraocular pressure 

Cataracts 

Retinopathy 

Worsening glucose tolerance/diabetes (diuretics, atypical antipsychotics) 

Pro-arrhythmic effects and increased mortality (most nonbeta blocker anti-arrhythmics) 

Increased CHF and SD mortality (any inotrope, some negative inotropes such as calcium

channel blockers) 

Nephropathy (NSAIDs) 

Example 1: If orthostatic hypotension was an expected adverse reaction, but was not observed, 

the reviewer should determine whether the applicant made efforts to detect it and, if so, whether 

the applicant’s approach (e.g., timing and frequency of vital signs testing) was adequate to detect 

it. 

Example 2: If QT prolongation was observed in phase 1 studies, the reviewer should ascertain 

whether the applicant made efforts, beyond routine ECG testing, in phases 2 and 3 to explore the 

consequences in patients of the observed QT prolongation and, if so, whether those efforts were 

adequate, including adequate exposure to higher doses. For example, how did the applicant 

follow-up patients who experienced clinical events that may be manifestations of torsade de 

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pointes (e.g., syncope, dizziness, or palpitations)? Holter monitoring, for example, might have 

been appropriate in such patients. 

7.2.8 Assessment of Quality and Completeness of Data 

The reviewer should provide general overall assessments of the quality and completeness of the 

data available for conducting the safety review and describe the bases for these assessments. 

More than that, attention to completeness and quality of assessment is important throughout the 

review. The reviewer should recognize that quality may differ from the primary source data and 

for data over which the applicant had less control. The following examples illustrate some of the 

ways in which applicants can differ in the quality and completeness of data they provide: 

• Applicants may differ in what they include in a CRF. For example, if additional laboratory 

data are collected at unscheduled visits or after the normal end of a trial, some do not include 

these data. Such data may be stored in some other place (a correspondence file). Sometimes 

additional information is attached to the front of the CRF as queries. If CRFs do not indicate 

any additional testing beyond the routine assessments, the reviewer should ascertain whether 

additional testing was done to reassess abnormal values before the next routine visit (e.g., at 

an unscheduled visit). If the CRFs do not indicate that additional testing was performed, the 

reviewer should ask the applicant if additional laboratory data are available. 

• If it is apparent that the CRF contains insufficient information about an adverse event (e.g., if 

a patient was hospitalized for an adverse event), the reviewer needs to determine whether 

there is additional information available. Such an observation also raises the general 

question of whether all pertinent data have been included in CRFs. 

• The reviewer should be concerned about patients with abnormal clinical or laboratory 

findings who are lost to follow up, particularly if there are significant numbers of such 

patients. In these situations, the reviewer may consider asking the applicant to attempt to 

obtain the needed follow up information. If the information cannot be obtained, it may be 

appropriate to perform sensitivity analyses to assess the possible impact of missing data, 

assuming a worst-case outcome. 

• The reviewer should be particularly alert to situations in which applicants make changes in 

CRFs to reclassify adverse events or reasons for subjects dropping out without the 

investigator's agreement. There is greater concern where serious adverse events are 

reclassified and reclassifications are done without blinding. The reviewer should ask the 

applicants about procedures used (if unclear) and attempt to assess the impact of multiple 

changes on the safety evaluation. 

• For electronic data, the reviewer should clarify what information is, and is not, included in 

the electronic files. For example, if a reviewer is relying on electronic files from the case 

report forms, it is important to know what, if any, information from the CRFs was not 

included. A separate file may be needed for any missing data. 

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7.2.9 Additional Submissions, Including Safety Update 

The initial NDA/BLA submission may not contain all information pertinent to the safety 

evaluation. Further data submissions may be planned at the time of initial submission and filing 

(e.g., results of additional long-term follow-up), may represent responses to specific questions or 

discipline review letters, or may be part of the safety update required under regulations (21 CFR 

314.50(d)(5)(vi)(b)). It is critical to review these data to determine whether safety conclusions 

are affected, particularly with respect to serious or fatal events. 

This section should: 

• Describe safety submissions, noting whether the results have been incorporated into 

the rest of the review or are considered in this section 

• For those safety matters not incorporated into the rest of the review, discuss any data 

with important implications for safety. In general, this will involve deaths, adverse 

dropouts and other serious events, and these should be considered as in sections 7.1.1, 

7.1.2, 7.1.3, as appropriate to the (usually) small numbers. Only if these events alter 

the overall safety picture will a more detailed discussion of the entire area (e.g., 

deaths, liver injury) be needed. 

Any reports of important changes in foreign labeling or new studies that give insight into more 

common events should also be noted. 

7.3 Summary of Selected Adverse Reactions, Important Limitations of Data, and 

Conclusions 

This section of the review should briefly summarize each of the adverse reactions that the 

reviewer considers important and drug-related (i.e., this should constitute a problem list for the 

drug). For each adverse reaction, there should be a separate subheading followed by a brief 

summary of the reaction and references to sections of the review (e.g., other parts of the safety 

section, Clinical Pharmacology, studies described in the Efficacy section) containing more 

detailed information about the adverse reaction generally, or specific aspects of the reaction. The 

review should integrate by reference all relevant details about the reaction, including patient 

identifying numbers for certain patients (e.g., for deaths). Below is a sample summary section 

entry for QT prolongation: 

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QT Prolongation

Dose-related QT prolongation compared to control was seen in all controlled trials, 

with a mean change of 20 msec at 100 mg/day (peak), the recommended maximum

dose, and smaller changes at lower doses; 5 percent of patients had QTc values over 

500 msec at some point, compared with ___ percent on placebo. The drug’s 

metabolism is predominately via CYP4503A4, so that moderate inhibitors of this 

enzyme could lead to greater QTc prolongation. The QTc effects of doses greater than 

100 mg have not been studied. 

• See Section 7.1.1 (Deaths) at page __ for discussion of deaths that may be 

related to QT prolongation and detailed discussion of the finding 

• See Section 7.1.9 (ECGs) at page __ for discussion of ECG changes 

• See Section 7.1.10 (Special Studies) at page __ for dose response study of 

QT prolongation (doses of 10, 40 and 100 mg) 

• See Section 7.2.4 (Metabolic and Interaction Workup) at page __ for 

discussion of the adequacy of the applicant’s in vivo and in vitro 

assessments of the metabolism of (Drug) and potential relation of drugdrug interactions to QT prolongation 

• See Section 3.2 (Animal Pharmacology/Toxicology) at page __ for 

discussion of the animal models used to evaluate effects on K channels, and 

 QT prolongation 

• See Section 7.2.1.1.2.3 (Literature) at page __ for published articles about 

similar products and methodological suggestions. 

• See Section 7.1.13 (Overdose) at page __. 

• Patient ID numbers for possibly relevant deaths: ______, ______, ______. 

As the QT prolongation example shows, it is useful to identify the various sections of the clinical 

review that can be referenced for additional details about an identified adverse event. If the 

review is converted into a PDF file, bookmarking can be used to electronically link the text in 

the problem list to earlier sections of the review. 

In addition, in this section the reviewer should provide summary recommendations for further 

studies, with a reference to section 7.2 for more details. 

The review should also provide overall conclusions about the safety of the drug, including: 

• Overall assessment of the available safety information, referring both to what it 

has shown and its adequacy 

• The limitations of the available data 

• Additional information needed, including both further analyses and additional 

studies. 

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• Comparison, to the extent possible, of the safety of the drug under review to the 

safety of other available products, and the basis for that comparison (direct 

comparative data vs. clinical opinion) 

• Whether a risk management program (beyond labeling) is needed and why 

• Analysis of likely uses beyond labeling, (e.g., in more severe patients, in other 

diseases, in children) 

• Whether there is a need for postmarketing safety studies 

7.4 General Methodology 

This section of the guidance describes analytical methods that have general application to the 

safety review and provides a location in the review for any general discussion of methodological 

issues not discussed elsewhere, organized by the subsections listed here, with additional sections 

as needed. It is important to consider early in the review whether the available patient level data 

will allow the analyses the reviewer intends. For example, in examining whether particular 

baseline risk factors are related to an adverse event, the reviewer will either need to extract the 

baseline characteristics from case report tabulations or be sure the information is available in a 

retrievable form. Similarly, it may be important to link individual safety observations with other 

on therapy data, such as dose, duration of treatment, concomitant therapy, other adverse events, 

lab data or effectiveness results (it is obviously best if such issues are considered at preNDA/BLA meetings). 

7.4.1 Pooling Data Across Studies to Estimate and Compare Incidence 

7.4.1.1 Pooled Data vs. Individual Study Data 

Before estimating the incidence of adverse events, the reviewer must select the patient sample of 

interest. Pooling data from different studies can improve the precision of an incidence estimate 

(i.e., narrow the confidence intervals by enlarging the sample size). Better precision is 

particularly important for lower frequency events, which can be difficult to detect and may not 

occur in some studies. Pooling can also provide the larger database that will permit explorations 

of possible drug-demographic or drug-disease interactions in subgroups of the population. 

Pooling can also, however, obscure real potentially meaningful differences between studies. The 

review should explain why any pooling used in the review was chosen. When making decisions 

about pooling, the reviewer should consider the following: 

• It is most appropriate to combine data from studies that are of similar design, that is, similar 

in dose, duration, choice of control, methods of ascertainment, and population (checklist vs. 

general inquiries vs. no prompt at all; in psychiatric drug trials it is typical for obsessive 

compulsive patients to spontaneously report adverse events more frequently than 

schizophrenic patients. It is also possible that different populations may have different 

vulnerabilities to a drug, and therefore, different risk profiles.) When the studies are similar 

in design but differ in duration, it may be critical to account for exposure duration and to 

look for time-dependent events. 

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• Even when the pooled analysis is the primary one, it is important to explore the range of 

incidences across the studies being pooled. For a specific adverse event, if the incidence 

differs substantially across the individual studies in a pool, the pooled value should not be 

used, as it is probably not meaningful and, in some cases, could obscure important 

information about predictors for that event. (In one case, for example, several studies were 

combined and a reassuringly low estimate of phototoxicity was obtained. Subsequent 

examination of individual study results found one study with a substantial rate of 

phototoxicity. The study was the only outpatient study done (i.e., the only one in which 

patients had an opportunity to be exposed to sunlight).) In some situations, the incidence 

may be best described by the range in the various studies. For the photoxicity example 

above, however, the most relevant data are those from the outpatient study, the only study 

that was conducted under conditions pertinent to intended use. 

• In some cases, observed differences in rates in various studies can be explained (e.g., better 

ascertainment, different populations), so that a consistent rate can be determined from a 

subset of studies. 

• Formal tests for extreme values may be useful to assess appropriateness of assay pooled data 

(e.g., test of heterogeneity such as the Breslow-Day Chi-Square test could be used). 

Alternatively, the reviewer might use a more subjective approach, such as determining if the 

direction of the difference is always the same across studies, or use a graphic display of 

incidence by study to informally consider the extent of variability and to identify outliers; 

outliers may be important in identifying subgroups of patients who are at particular risk for 

certain adverse reactions. 

7.4.1.2 Combining Data 

In pooling data, usually the numerator events and denominators for the selected studies are 

simply combined. Other more formal weighting methods can be used (e.g., weighting studies on 

the basis of study size or inversely to their variance). The review should describe how the 

pooling was performed, as well as the rationale for selection of the method used. 

7.4.2 Explorations for Predictive Factors 

Adverse reaction rates may differ considerably from one patient population to another and may 

change over time. Factors that may affect the safety profile of a drug should be explored during 

the review. Explorations for common predictive factors, such as dose, plasma level, duration of 

treatment and concomitant medications, and patient-predictive factors such as age, sex, race, 

concomitant illnesses, are considered below. In general, these explorations are meaningful only 

for adverse events that appear to be drug-related (see Section 7.4.3). 

7.4.2.1 Explorations for Dose Dependency for Adverse Findings 

If data from randomized, parallel, fixed-dose studies (or data from studies in which patients were 

randomized to fixed dose ranges), are available, they should be analyzed for evidence of dose 

dependency for any adverse reactions. If plasma concentration data are available, it may be 

45
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useful to explore plasma concentration effect relationships as well. It may also be useful to 

reconfigure dose as mg/kg or mg/m2

, to decrease the effect of size or weight differences on drug 

exposure. Dose-response relationships should also be examined in demographic subgroups (e.g., 

females, blacks, elderly patients). Dose-dependency analyses are usually performed by simple 

inspection of incidence rates across different doses or different weight or body surface areaadjusted doses. Formal statistical testing can also be used. If formal statistical tests are 

performed for a study that includes placebo control as well as different doses, and a drug-placebo 

difference is apparent, it may be desirable to focus on between-dose group differences. 

Flexible Dose Titration Studies

Although it is tempting to try to extract dose-response or plasma level-response data from

flexible dose (titration) studies, and the ICH dose-response guideline24 encourages this, there are 

many potential problems with such analyses. In particular, many adverse reactions show 

considerable time dependency, some occurring early, some late. It is easy to confound dose (or 

plasma concentration) with duration when dose is increased over time. In some cases, such as 

anticancer drugs or drugs that are known to produce anti-cholinergic or sedating reactions, the 

drug is dose-adjusted to toxicity, which will often obscure any dose-response relationship. In 

addition, if dose is increased only in patients without adverse effects (i.e., subjects who are 

resistant to them), the higher doses will be associated with lower adverse effect rates. On the 

other hand, if dose is titrated to clinical effect, and adverse reactions occur late (so that they do 

not affect the dose given), analysis of the rate with respect to dose may be useful. For example, 

erythropoietin, used to treat anemia in patients with chronic renal failure or cancer, is titrated to 

maintain hemoglobin within a specific range. Given the delayed therapeutic response 

(erythropoesis), analysis of adverse events by dose or cumulative dose prior to a reaction can 

give insight into dose-related toxicity. 

Cumulative Dose Dependency

For certain adverse reactions, it may be possible to demonstrate a relationship between 

cumulative dose and the occurrence of the reaction (e.g., liver fibrosis and cirrhosis with 

methotrexate, cardiotoxicity with doxorubicin, renal toxicity with Amphotericin B). For drugs 

that are used chronically, the reviewer should consider the possibility that cumulative dose may 

predict toxicity and discuss this in the review. 

7.4.2.2 Explorations of Time-Dependency for Adverse Findings 

The reviewer should explore time dependency of adverse reactions in two ways — time to onset 

of the finding and duration of the finding: 

Time of Onset

 

24 See ICH E4Dose-Response Information to Support Drug Registration 

(http://www.fda.gov/cder/guidance/iche4.pdf). 

46
Contains Nonbinding Recommendations

Although most adverse reactions occur early in treatment and may be best characterized by a 

crude incidence rate (number with the reaction divided by number exposed), others may occur 

only after some delay of weeks, months, or longer. A crude incidence rate, based on a patient 

population exposed predominantly for short periods, will understate the importance of such 

adverse reactions for chronically used drugs. For important adverse reactions that occur later in 

treatment, there should be explorations of the time dependency of the reaction. Possible methods 

include: 

• A life table (Kaplan-Meier graph) describing risk as a function of duration of exposure (i.e., 

cumulative incidence) 

• Plotting risk for discrete time intervals over the observation period (i.e., a hazard rate curve) 

reveals how risk changes over time. 

 

• Adjusting for duration of exposure by expressing the adverse reaction rate in terms of 

person-time (person-time is duration of exposure summed across all patients, e.g., 2 patients 

each exposed for 6 months = 1 patient-exposure-year). This approach is useful only when 

one can safely assume that the hazard rate is constant over time. 

Duration of Adverse Event

Certain adverse events that occur at initiation of treatment may appear to diminish in frequency 

with continued use. Possible explanations for this phenomenon include adaptation or tolerance, 

decreased reporting of the event even by patients though it is still occurring at the same rate, and 

reduced dose or dropping out in patients with the event. For drugs used chronically and for 

which there was an adverse event that seemed to diminish in frequency over time, it may be 

useful to characterize and quantify the change. It would be important, for adverse events of 

interest, to determine whether the decreased rate simply reflected discontinuation by affected 

patients or real adaptation. One way to make this distinction is to identify a cohort that 

experienced an event of interest during a specified period of a trial, but nonetheless completed 

the trial, and observe the rate of the event in that cohort over time. This cohort of survivors could 

be compared to a similar cohort of placebo recipients who experienced the same event at 

baseline. The same approach could be used for adverse events occurring later in treatment. It is 

usually sufficient to do such analyses for those adverse reactions that are relatively common and 

likely to be drug related (see Section 7.1.5.4 for methods to identify drug-related events). 

7.4.2.3 Explorations for Drug-Demographic Interactions 

Numerous methods can be used to analyze age, gender, and race implications for safety, and 

applicants must present analyses of safety information for these population subsets. In most 

cases, there will be pharmacokinetic information available for some or all of these subsets, which 

may help in interpreting adverse event rates. In some cases, it may be useful to construct 

subgroups based on more than one factor. For example, bleeding is the principal risk associated 

with use of thrombolytic agents in patients with acute myocardial infarction. Women tend to 

have more bleeding than men, and risk is inversely related to weight. Thus, an analysis by 

47
Contains Nonbinding Recommendations

gender weight subgroups can identify the group at greatest risk of bleeding (thin women). It 

may also be useful to consider age-gender or race-gender subgroups. Formal analysis should be 

limited to events considered common (e.g., occurring at an incidence of at least 2 percent) and 

that occur at a clearly greater rate on drug than placebo. In small studies or for low frequency 

events, there will usually not be sufficient power to detect differences between groups, so that 

these analyses will usually be based on pooled data. In general, these analyses are descriptive, 

comparing risk of an event in one subset with the risk in another (men vs. women, old vs. young, 

black vs. white); as these comparisons obviously do not reflect randomization to the subset 

(baseline characteristic) of interest, formal statistical comparisons are usually not warranted. For 

these descriptive comparisons, two approaches deserve consideration; when the control rates of 

adverse events differ for population subsets these approaches can provide quite different results: 

 (1) evaluation of relative risk (RR) (cumulative risk on drug/cumulative risk on comparison 

drug or placebo) and (2) evaluation of attributable risk (AR) (cumulative risk on drug - 

cumulative risk on comparison drug or placebo). 

When background event rates differ by demographic subgroup, relative risk analysis will provide 

a quantitative estimate of the difference in effect of the drug, but the attributable risk may be a 

better estimate of the importance of the risk in the subsets. To illustrate, consider a comparison 

of drug-induced nausea for males versus females. Suppose the rate of nausea on placebo is 1 

percent for men and 3 percent for women and that on drug it is 3 percent for men and 9 percent 

for women. The risk ratios (RR) for both sexes are 3 and the relative risk for men and women 

(RRf/RRm) is one (no difference), yet the attributable risk is much greater for women than men 

(6 percent vs. 2 percent), a finding of possible importance in treatment. Such a difference has 

been observed for several adverse reactions of amlodipine, a calcium channel blocker, and is 

described in labeling as a gender difference, even though the RR’s are the same. 

7.4.2.4 Explorations for Drug-Disease Interactions 

The reviewer should be alert to the possibility that co-morbidity will affect the adverse reaction 

profile of the drug (i.e., a drug-disease interaction). Such interactions can arise from

abnormalities of excretory function (renal or hepatic disease), and typically, the applicant will 

have carried out formal pharmacokinetic studies in patients with hepatic and renal disease to 

indicate the potential for such reactions. The reviewer needs to consider, in that case, whether 

PK differences are manifested as differences in adverse reaction rates. Apart from differences in 

adverse reaction rates related to PK differences, differences in rates can also reflect true 

differences in susceptibility to adverse reactions (i.e., real pharmacodynamic differences). In 

general, the same methods described for exploring drug-demographic interactions can be applied 

here. 

7.4.2.5 Explorations for Drug-Drug Interactions 

The clinical reviewer should be alert to the potential of drug-drug interactions to affect the safety 

profile of the drug. Again, these interactions could be either pharmacokinetic (affecting 

elimination of the drug) or pharmacodynamic, in either case leading to observed differences in 

adverse reaction rates for the subgroups receiving or not receiving co-administered drugs. 

Typically, there will be formal interaction studies to evaluate potential pharmacokinetic effects 

48
Contains Nonbinding Recommendations

of concomitant therapy on drugs metabolized by CYP450 enzymes, but PK interactions can also 

occur through effects on renal excretion and transport (P-glycoprotein) proteins. True 

pharmacodynamic interactions are less frequently recognized but can be important (e.g., marked 

hypotension when sildenafil is given with organic nitrates). In general, the same methods 

described for exploring drug demographic interactions can be applied here. 

7.4.3 Causality Determination 

In assessing the critical question of whether an adverse event is caused by a drug, whether the 

drug is capable of causing that adverse event in the population is usually of greater interest than 

whether the drug caused the event in each patient who reported the event, but the approach to 

causality is distinctly different for relatively common events and relatively rare, serious events. 

Common Events

Where events are common and occur in multiple patients in controlled trials, it is usually not 

necessary or helpful to consider each case individually. Rather, all reported cases can be 

considered potentially drug-related, and causality is assessed by comparing the rates of reports in 

patients treated with test drug and in control groups. If an event is clearly more frequent with 

test drug than the control, it can be attributed to treatment with the test drug. 

Uncommon, Serious Events

Causality judgments are much more difficult for uncommon (e.g., < 1/1000) serious events 

where there are, in most cases, no useful comparisons to control groups. The reviewer therefore 

must form a judgment as to the plausibility of drug-relatedness for the individual cases. 

• The following questions should be considered: 

1. Was the patient in fact exposed to drug and did the adverse event occur after drug 

exposure? 

2. Did the patient have a clinical experience that meets the criteria for the adverse 

event of interest? (Establishing a standard case definition may be helpful here.) 

3. Is there a reasonably compelling alternative explanation for the event? (For 

example, recent benzene exposure for a case of aplastic anemia; the event is a wellrecognized consequence of the patient’s underlying illness.) 

4. Is the adverse event of a type commonly associated with drug exposure, such as 

hematologic, hepatic, renal, dermatologic or pro-arrhythmic events? (But also see 

below caution about discarding events that do not seem plausibly drug related.) 

• After assessing individual cases to identify events that could be drug-related and for which 

there are no compelling alternative explanations, the reviewer should compare the observed 

rate of occurrence of the event in the database with a best estimate about the background 

rate for the event for the population being studied. For an event like aplastic anemia, with a 

background rate of perhaps 1 per million person years, finding even one case suggests a 

causal relationship. For events that occur more frequently in the absence of drug therapy 

49
Contains Nonbinding Recommendations

(e.g., MI, stroke, sudden death, seizure, which could occur at rates of 0.1 to 1 percent, 

depending on the population), the finding of one or two cases may be very difficult to 

interpret in the absence of a substantial controlled trial database. 

• The reviewer should also evaluate any other information about the drug that bears on causality 

including: 

1. Whether the drug is a member of a class of drugs known to be causally associated 

with the event of interest 

2. Presence of other adverse events in the database that may be associated with the 

event of interest (e.g., a general finding of drug associated transaminitis or animal 

findings suggestive of hepatotoxicity would substantially strengthen the signal 

generated by the finding of a single case of hepatic failure) 

3. Positive re-challenge with the drug (although it would be unusual to deliberately rechallenge for a serious event, there may occasionally be inadvertent re-exposures that 

are informative) 

• Caution Concerning Relative Plausibility of Uncommon, Serious Events 

The reviewer should be cautious about dismissing uncommon, serious events that don’t seem

plausibly drug-related and should consider differences in common less serious adverse reactions 

that might predict the uncommon serious reactions with longer use. There are numerous 

examples of uncommon, serious adverse reactions that are uniquely associated with a drug or 

drug class: 

- tendon rupture associated with the quinolone antibiotics 

- heart valve lesions associated with fenfluramine 

 - practolol syndrome 

- retroperitoneal fibrosis with Sansert 

- pulmonary hypertension with Aminorex (a European weight loss drug), and 

various other drugs 

- suicidal ideation with interferons, Accutane 

- intussusception with rotovirus vaccine 

- pulmonary fibrosis with amiodarone 

50
Contains Nonbinding Recommendations

List of Tables 

TABLE 7.0.1 INDEX FOR LINKING IDENTIFIED PATIENTS WITH 

SUPPLEMENTARY PATIENT INFORMATION IN THE NDA 

(CRFS, NARRATIVE SUMMARIES, AND PATIENT DATA 

LISINGS)..................................... ERROR! BOOKMARK NOT DEFINED. 

TABLE 7.1.1.1 DEATHS LISTING...................... ERROR! BOOKMARK NOT DEFINED. 

TABLE 7.1.1.2 MORTALITY BY TREATMENT GROUP FOR POOL OF PHASE 2-3 

STUDIES WITH NEW DRUG.. ERROR! BOOKMARK NOT DEFINED. 

TABLE 7.1.2.1 SERIOUS ADVERSE EVENT LISTING..... ERROR! BOOKMARK NOT 

DEFINED. 

TABLE 7.1.3.1.1 DROPOUT PROFILE: INCIDENCE OF DROPOUT BY 

TREATMENT GROUP AND REASON FOR PHASE 2 TO 3 

STUDIES WITH NEW DRUG.. ERROR! BOOKMARK NOT DEFINED. 

TABLE 7.1.3.2.1 ADVERSE EVENT DROPOUT LISTING. ERROR! BOOKMARK NOT 

DEFINED. 

TABLE 7.1.5.2.1 TREATMENT EMERGENT ADVERSE EVENT LISTING.....ERROR! 

BOOKMARK NOT DEFINED. 

TABLE 7.1.5.3.1 TREATMENT EMERGENT ADVERSE EVENT INCIDENCE FOR 

POOL OF 6-WEEK PLACEBO-CONTROLLED TRIALS.......ERROR! 

BOOKMARK NOT DEFINED. 

TABLE 7.1.7.3.1.1 MEAN CHANGE FROM BASELINE FOR SERUM CHEMISTRY 

PARAMETERS IN POOL OF PLACEBO-CONTROLLED STUDIES .

 .................................................. ERROR! BOOKMARK NOT DEFINED. 

TABLE 7.1.7.3.2.1 INCIDENCE OF POTENTIALLY CLINICALLY SIGNIFICANT 

CHANGES IN SERUM CHEMISTRY PARAMETERS FOR POOL 

OF PLACEBO CONTROLLED STUDIES FOR NEW DRUG .ERROR! 

BOOKMARK NOT DEFINED. 

TABLE 7.1.7.5.1 HEPATOTOXICITY EVALUATION ........ ERROR! BOOKMARK NOT 

DEFINED. 

TABLE 7.2.1.1.1 ENUMERATION OF SUBJECTS/PATIENTS FOR NEW DRUG 

DEVELOPMENT PROGRAM. ERROR! BOOKMARK NOT DEFINED. 

TABLE 7.2.1.2.1 DEMOGRAPHIC PROFILE FOR PHASE 2-3 STUDIES WITH NEW 

DRUG........................................... ERROR! BOOKMARK NOT DEFINED. 

TABLE 7.2.1.3.1 NUMBER (PERCENT) OF PATIENTS RECEIVING NEW DRUG 

ACCORDING TO MEAN DAILY DOSE AND DURATION OF 

THERAPY IN PHASE 2-3 STUDIES (N=2500).. ERROR! BOOKMARK 

NOT DEFINED. 

51
Contains Nonbinding Recommendations

52
Contains Nonbinding Recommendations

Table 7.0.1 

Index for Linking Identified Patients with Supplementary Patient Information in the NDA (CRFs, Narr

and Patient Data Listings1

Case Report Forms Narrative Summaries 

Patien

Study 

Number2

Patient 

Number3

Volume4 Pages5 Volume Pages Volum

1Separate indices should be provided for patients exposed to new drug, active control drugs, and placebo. 2Study numbers should be numerically ordered and tabbed as separate sections within the index. 3Patient numbers should be numerically ordered within each study section. 4The volume number provided in this index should be the unique volume number assigned to the volume as part of the comple

separate volume number assigned to the volume as part of a section of the NDA. 

5The page numbers provided in this index should be the unique page numbers assigned for the entire volume, and not separate 

the separate sections that might be included in any particular volume.

53
Contains Nonbinding Recommendations

Table 7.1.1.1 

Deaths Listing1,2,3

Treatment = New Drug4

Cutoff Date5

Trial Center Patient Age 

(yrs) 

Sex Dose6

(mg) 

Time7

(Days) 

Source8 Person 

Time9 Desc

1A footnote should describe the rule for including deaths in the table (e.g., all deaths that occurred during a period of drug exposure or w

following discontinuation from drug and also those occurring later but resulting from adverse events that had an onset during drug expup period). Other rules may be equally appropriate. 

2Deaths occurring outside the time window for this table should be listed elsewhere. 3This table should be provided by the sponsor in electronic format. The exact design of the table and the preferred electronic format sho

between the sponsor and the reviewing division. 

4Similar lists should be provided for patients exposed to placebo and active control drugs. 5This is the data lock date for entering data into this table (i.e., the date beyond which additional exposed patients were not available for 

be no more than several months prior to the submission date for an NDA. This date as well as this table may likely need to be updated as more data become available. 

6Dose at time of death, or if death occurred after discontinuation, note that, as well as last dose before discontinuation. 7Days on drug at time of death; or if death occurred after discontinuation, note how many days on drug before discontinuation and also 

death. 

8This listing should include all deaths meeting the inclusion rule, whether arising from a clinical trial or from any secondary source (e.g

source should be identified in this column (i.e., 10 for deaths arising from primary source clinical trials and 20 for those arising from se

9This column should identify patients (yes/no) for whom person-time data are available, so the reviewer can know which patients were 

calculations. 

10Since narrative summaries should be available for all deaths, the description can be very brief (e.g., myocardial infarction, stroke, pan

drowning).

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Contains Nonbinding Recommendations

Table 7.1.1.2 

Mortality by Treatment Group 

for Pool of Phase 2-3 Studies with New Drug1,2,3

Cutoff Date4

Treatment 

Group5

Total Number 

of Patients6

Total Number 

 of Deaths7

Crude 

 Mortality8

Patient Exposure 

Years (PEY)9

Total Death

Person-Ti

New DrugActive ControlPlacebo

1This table provides data comparing overall mortality across treatment groups for the pool of all phase 2 to 3 studies in the development 

appropriate for other subgroups within the phase 2 to 3 program (e.g., a table may be provided for a pool of all similarly designed shorSimilar tables may be appropriate for certain individual trials of interest. All deaths should be counted, regardless of the investigator's 

causality, including (1) any deaths occurring during participation in any of the studies in the target pool, (2) any deaths occurring after studies, whether prematurely or after completion to the nominal endpoint, if the death is (a) the result of a process initiated during the s

occurs, or (b) occurs within 4 weeks of a patient leaving a study, or longer for drugs with particularly long elimination half-lives or fro

occurring effects. The actual rule used for including deaths should be provided in a footnote to the table. In case there are substantial appropriate to provide data for cause specific mortality as well. 

2Patients participating in crossover trials should be enumerated for each of the pertinent columns of the table (e.g., a patient receiving tr

a 3-way crossover study comparing new drug, active control, and placebo would be included in all three columns. 

3This table should be provided by the sponsor in electronic format. The exact design of the table and the preferred electronic format sho

between the sponsor and the reviewing division. 

4This is the data lock date for entering data into this table (i.e., the date beyond which additional exposed patients were not available for 

be no more than several months prior to the submission date for an NDA. This date as well as this table may likely need to be updated as more data become available. 

55

5In the sample table, only 1 row is provided for an active control group. One such category may suffice for certain NDAs, but may not 

regarding how to categorize active control patients should be made in consultation with the reviewing division. Similarly, for this tabldrug, with the implication that all new drug patients, regardless of dose, should be included in the calculations for that column. Other patients on the basis of dose) may be equally appropriate. 
Contains Nonbinding Recommendations

6The Ns in these rows should match the N’s in Table 5.1.1.1., and if not, an explanation should be provided in a footnote. 7This is the total number of deaths for each group. 8This is simply the total number of deaths divided by the total number of patients exposed in each group. 9This column should provide person-time in patient exposure years (PEY). This table assumes a constant hazard rate; however, in certa

to stratify by increments of exposure. 

10This is the subset of total deaths for which person-time is available. 11This is the number of deaths for whom person-time is available divided by PEY for each group, and multiplied by 100.

56
Contains Nonbinding Recommendations

Table 7.1.2.1 

Serious Adverse Event Listing1,2,3

New Drug Clinical Trials 

Source: Phase 2-3 Trials4

Sorting A: Randomized Treatment, Trial #, Investigator/Center #, Patient #5

Treatment = New Drug6

Cutoff Date7

Trial Center Patient Age 

(yrs) 

Sex Dose8

(mg) 

Time9

(days) 

Body

System

Prefrrd

Term 

Adv

Eve

1This is a line listing of all reported adverse events that met the sponsor’s definition of being a serious adverse event, regardless of whet

for all patients participating in the phase 2 to 3 trials in the development program. This listing is a critical component of the integrated 

2The variables included in this listing include: 

-Trial # -Center # -Patient # (a unique number that identifies this patient in the NDA database) -Age -Sex -Dose (in mg) at time of event onset -Time, i.e., duration, of exposure (in days) at time of event onset -Body system category for event (using COSTART or other thesaurus) -Preferred term for event -Adverse event as reported by investigator and/or patient -An indication of whether or not the event led to withdrawal -Serious Adverse Event Type (e.g., fatal, life-threatening). 

The following additional variables may be considered for inclusion as well: 

-Race -Weight -Height 

57
Contains Nonbinding Recommendations

-Dose expressed as mg/kg, mg/mm2, or even plasma concentration, if available 

-Other drug treatment -Severity of adverse event (mild, moderate, severe) -Action taken (e.g., none; decrease dose; discontinue treatment) -Outcome-Causality assessment by investigator (definitely; probably; possibly; unlikely related) -Location in NDA of CRF (e.g., patient narrative summary) 

3The exact design of the table and whether or not it needs to be provided in electronic format should be established in discussions betwe

division. 

4Similar listings may be provided for individual studies as part of full reports for such studies, and possibly for other pools that are subs5It is essential to provide this listing in two different forms (i.e., sorting A (by patient) and sorting B (by adverse event)). This listing is 

permits the reviewer to explore all the serious adverse events reported for each individual patient. Sorting B (by adverse event) should Treatment, Body System, Preferred Term, Adverse Event, Trial, Center, Patient #, Age, Sex, Dose, Time, W/D. Sorting B permits the 

serious adverse events of a similar type. 

6This sample listing is for all new drug patients across all studies in the phase 2 to 3 development program. Similar listings should be p

placebo patients. 

7This is the data lock date for entering data into this table (i.e., the date beyond which additional exposed patients were not available for 

be no more than several months prior to the submission date for an NDA. This date as well as this table may likely need to be updated as more data become available. 

8This column should include the dose being administered (in mg/day) at the time the event occurred. 9This column should include the time (i.e., duration of exposure (in days)), at the time the event occurred. If the event occurred after di

should note how long after discontinuation. 

10This column should include the adverse event in the language reported by the investigator and/or patient (i.e., before coding).11This column should include an indication of whether or not the adverse event led to discontinuation of the assigned treatment. 

58
Contains Nonbinding Recommendations

Table 7.1.3.1.1 

Dropout Profile: Incidence of Dropout by Treatment Group and Reason 

for Phase 2 to 3 Studies with New Drug1,2,3

Cutoff Date4: 

Treatment Groups6

Reasons for 

Dropout5 New Drug 

N = 

Placebo 

N = 

Active Control 

N = 

Lack of Efficacy %7 % % 

Adverse Event % % % 

Lost to Follow up % % % 

Other % % % 

Total Dropouts % % % 

1

This sample table should be based on a pool of all trials in the phase 2 to 3 development program. Similar 

tables may be appropriate for other subgroups within the phase 2 to 3 program (e.g., a table should be provided 

for a pool of all similarly designed short-term placebo controlled trials). Similar tables may be appropriate for 

certain individual trials of interest. 

2

Patients participating in crossover trials should be enumerated for each of the pertinent columns of the table 

(e.g., a patient receiving treatment in each of the three arms of a 3-way crossover study comparing new drug, 

active control, and placebo would be included in all three columns). 3

This table should be provided by the sponsor in electronic format. The exact design of the table and the 

preferred electronic format should be established in discussions between the sponsor and the reviewing 

division. 

4

This is the data lock date for entering data into this table (i.e., the date beyond which additional exposed 

patients were not available for entry). Generally this date should be no more than several months prior to the 

submission date for an NDA. This date as well as this table may likely need to be updated during the course of 

NDA review as more data become available. 5

This sample table includes 4 categories for dropout, but a more detailed breakdown may be of interest as well. 

• The adverse event category here would include all patients identified as dropping out for adverse events, 

regardless of whether or not the events were judged by the investigator or sponsor to be drug related and 

regardless of what other reasons may have been identified in association with dropout. Patients identified 

as dropping out for intercurrent illness would ordinarily be included under this adverse event category. 

Similarly, a patient identified as dropping out for an adverse event and lack of efficacy would also 

ordinarily be included under this adverse event category. 

• Lost-to-follow up is an important outcome to track, since it reflects on the overall conduct of the studies. 

• The other category is intended to include all other reasons that may generally be considered nontreatment 

related. This category is often identified as administrative, and includes such reasons as patient refused 

further participation, patient moved away, patient improved, patient not eligible, protocol violation, 

unknown. 

• Decisions about what categories to include should be made in consultation with the reviewing division. 6

In the sample table, only 1 column is provided for an active control group. One such category may suffice for 

certain NDAs, but may not for others, and the decision regarding how to categorize active control patients 

should be made in consultation with the reviewing division. Similarly, for this table, only 1 column is provided 

for new drug, with the implication that all new drug patients, regardless of dose, should be included in the 

calculations for that column. Other approaches (e.g., distinguishing patients on the basis of dose) may be 

59
Contains Nonbinding Recommendations

equally appropriate. The N’s in these column headings should match the N’s in Table 5.1.1.1., and if not, an 

explanation should be provided in a footnote. 

7

Numbers for this table should be rounded to the nearest integer. 

60
Contains Nonbinding Recommendations

Table 7.1.3.2.1 

Adverse Event Dropout Listing1,2,3

New Drug Clinical Trials 

Source: Phase 2-3 Database4

Sorting A: Randomized Treatment, Trial #, Investigator/Center #, Patient #5

Treatment = New Drug6

Cutoff Date7: 

Trial Center Patient Age 

(yrs) 

Sex Dose8

(mg) 

Time9

(days) 

Body

System

Prefrrd

Term 

Adverse 

Event10

61
Contains Nonbinding Recommendations

1This is a line listing of all reported adverse events identified as leading to discontinuation, regardless of whether or not they were c

for all patients participating in trials identified as sources for this listing. Thus, all events categorized as intercurrent illness leadinwould, nevertheless, be included in this listing, and any judgments about attribution can be included in the narrative summary. Thcomponent of the integrated safety summary. 

2The variables included in this listing include: 

-Trial # -Center # -Patient # (a unique number that identifies this patient in the NDA database) -Age -Sex -Dose (in mg) at time of event onset -Time (i.e., duration, of exposure (in days) at time of event onset) -Body system category for event (using COSTART or other thesaurus) -Preferred term for event -Adverse event as reported by investigator and/or patient -An indication of whether or not the event met definition for serious -Outcome

The following additional variables may be considered for inclusion as well: 

-Race -Weight -Height -Dose expressed as mg/kg, mg/mm2, or even plasma concentration, if available 

-Other drug treatment -Severity of adverse event (mild, moderate, severe) -Action taken (e.g., none; decrease dose, discontinue treatment) -Causality assessment by investigator (related, not related) -Location in NDA of CRF, patient narrative summary) 

3The exact design of the table and whether or not it needs to be provided in electronic format should be established in discussions b

the reviewing division. 

4Similar listings may be provided for individual studies as part of full reports for such studies and, possibly, for other pools that are 

pool. 

5It is essential to provide this listing in two different forms (i.e., sorting A (by patient) and sorting B (by adverse event)). This listin

patient, and permits the reviewer to explore all the adverse events reported as leading to discontinuation for each individual patienevent) should be as follows: Randomized Treatment, Body System, Preferred Term, Adverse Event, Trial, Center, Patient #, Age, Sorting B permits the reviewer to explore all the adverse events of a similar type reported as leading to discontinuation. 

6This sample listing is for all new drug patients across all studies in the phase 2 to 3 development program. Similar listings should 

control and placebo patients. 

62

7This is the data lock date for entering data into this table (i.e., the date beyond which additional exposed patients were not availabl

this date should be no more than several months prior to the submission date for an NDA. This date as well as this table may likel

during the course of NDA review as more data become available. 
Contains Nonbinding Recommendations

8This column should include the dose being administered (in mg/day) at the time the event occurred. 9This column should include the time (i.e., duration of exposure (in days)), at the time the event occurred. 10This column should include the adverse event in the language reported by the investigator and/or patient, i.e., before coding. 11This column should include an indication of whether or not the adverse event met the criteria for serious as defined for the develo12This column should categorize the outcome upon follow up evaluation for the adverse event leading to discontinuation, as follow

(R) Resolved (P) Persisting (U) Unknown

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Table 7.1.5.2.1 

Treatment Emergent Adverse Event Listing1,2,3

New Drug Clinical Trials 

Source: Phase 2-3 Database4

Sorting A: Randomized Treatment, Trial #, Investigator/Center #, Patient #5

Treatment = New Drug6

Cutoff Date7: 

Trial Center Patient Age 

(yrs) 

Sex Dose8

(mg) 

Time9

(days) 

Body

System

Preferred

Term 

Adverse 

Event10

1This is a line listing of all reported treatment emergent adverse events, regardless of whether or not they were considered drug rela

participating in trials identified as sources for this listing. A footnote should identify all studies contributing to this pool. 

2The variables included in this listing include: 

-Trial # -Center # -Patient # (a unique number that identifies this patient in the NDA database) -Age -Sex -Dose (in mg) at time of event onset -Time (i.e., duration, of exposure (in days) at time of event onset) -Body system category for event (using COSTART or other thesaurus) -Preferred term for event -Adverse event as reported by investigator and/or patient -An indication of whether or not the event met definition for serious -An indication of whether or not the event led to withdrawal 

64

The following additional variables may be considered for inclusion as well: 
Contains Nonbinding Recommendations

-Race -Weight -Height -Dose expressed as mg/kg, mg/mm2, or even plasma concentration, if available 

-Other drug treatment -Duration of adverse event -Timing of adverse event relative to last dose -Severity of adverse event (mild, moderate, severe) -Action taken (none, decrease dose, discontinue treatment) -Outcome-Causality assessment by investigator (definitely, probably, possibly, or unlikely related) -Location in NDA of CRF, patient narrative summary 

3The exact design of the table and whether or not it needs to be provided in electronic format should be established in discussions b

the reviewing division. 

4Similar listings may be provided for individual studies as part of full reports for such studies, and possibly for other pools that are 5It is essential to provide this listing in two different forms (i.e., sorting A (by patient) and sorting B (by adverse event)). This listin

patient, and permits the reviewer to explore all the adverse events reported for each individual patient. Sorting B (by adverse evenoccurrence of each adverse event)) should be as follows: Randomized Treatment, Body System, Preferred Term, Adverse Event, TAge, Sex, Dose, Time, Serious, W/D. Sorting B permits the reviewer to explore all the reported adverse events of a similar type. 

6This sample listing is for new drug patients (i.e., for all patients exposed to New Drug in the phase 2 to 3 studies that are part of th

Database). Similar listings should be provided for active control and placebo patients. 

7This is the data lock date for entering data into this table (i.e., the date beyond which additional exposed patients were not availabl

this date should be no more than several months prior to the submission date for an NDA. This date as well as this table may likel

during the course of NDA review as more data become available. 

8This column should include the dose being administered (in mg/day) at the time the event occurred. 9This column should include the time (i.e., duration of exposure (in days)), at the time the event occurred. 10This column should include the adverse event in the language reported by the investigator and/or patient (i.e., before coding).11This column should include an indication of whether or not the adverse event met the criteria for serious as defined for the develo

12This column should include an indication of whether or not the adverse event led to discontinuation of the assigned treatment. 

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Contains Nonbinding Recommendations

Table 7.1.5.3.1 

Treatment-Emergent Adverse Event Incidence 

for Pool of 6-Week Placebo-Controlled Trials1-10

Cutoff Date11: 

Percentage of Patients Reporting Event15

Body System/ 

 Adverse Event12-14 New Drug 

N16

= 

Active Control 

N= 

Placebo 

N= 

Body as a Whole 

Headache 

Etc. 

Cardiovascular System 

Postural Hypotension 

Etc. 

Gastrointestinal System 

Constipation 

Etc. 

. 

. 

Urogenital System 

Impotence17

Etc. 

. 

. 

1

This table compares the incidence of treatment emergent adverse events across treatment groups for a pool of 

similarly designed placebo-controlled trials of new drug. Generally, an arbitrary threshold incidence for new 

drug patients is used as a criterion for selecting adverse events to include; > 1% for new drug is a commonly 

used rule, but others may be equally appropriate. The criterion used should be noted in the table title or in a 

footnote. 

2

Study pools other than those described for this sample table may be equally appropriate, and similar tables 

useful for individual trials may also be of interest. 3

In the sample table, only 1 column is provided for an active control group. One such category may suffice for 

certain NDAs, but may not for others, and the decision regarding how to categorize active control patients 

should be made in consultation with the reviewing division. 4

Similarly, for this table, only 1 column is provided for new drug, with the implication that all new drug 

patients, regardless of dose, should be included in the calculations for that column. Other approaches (e.g., 

dividing patients on the basis of dose), may be equally appropriate. If the studies used were fixed-dose studies, 

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Contains Nonbinding Recommendations

it is generally most informative to preserve the dose categories in constructing this table. However, dose 

categories that are not relevant to the doses that are being recommended for use may reasonably be omitted 

from this table. It is generally not useful to try to artificially construct dose categories from dose titration 

studies, since there is often confounding of dose and time. 5

Data are often available on the investigator’s opinion regarding whether or not any particular adverse event was 

in fact related to the drug being taken. Some reviewers consider this useful information and may construct 

tables that include only those events considered possibly, probably, or definitely drug-related by the 

investigator. Others ignore such judgments and include all reported adverse events, with the view that the 

control groups, especially placebo if present, should permit one to make causality decisions, regardless of the 

investigators’ judgments about drug-relatedness. Either approach can be acceptable, but it is critical that a 

footnote indicate clearly when adverse events are not included due to investigators’ judgments that they were 

not drug-related, since this approach may reduce the adverse event rates that appear in the table. 6

Data are also often available on the intensity of the reported adverse events, generally including categories of 

mild, moderate, or severe. Adverse event tables may ignore such classifications and pool all events together, 

or some attempt may be made to focus only on a subset of reported events (e.g., only those classified as 

severe). Again, either approach is acceptable, but it is important to describe in a footnote what approach was 

taken. 

7

Not uncommonly, a new drug is developed for more than one indication. If adverse event rates appear to be to 

occur at similar rates across the indications, it may be reasonable to pool the data in creating an adverse events 

table, possibly one providing greater precision. However, it is not inconceivable that adverse event rates may 

vary depending on the population studied, and if this appears to be the case, pooling may not be appropriate. 8

Adverse events that occur at a rate for placebo that is > the rate for new drug should be removed from the table 

and noted only as a footnote. 

9

Patients participating in crossover trials should be included in the calculations for each of the pertinent columns 

of the table (e.g., a patient receiving treatment in each of the three arms of a 3-way crossover study comparing 

new drug, active control, and placebo would be included in the calculations for all three columns). 10This table should be provided by the sponsor in electronic format. The exact design of the table and the 

preferred electronic format should be established in discussions between the sponsor and the reviewing 

division. 

11This is the data lock date for entering data into this table (i.e., the date beyond which additional exposed 

patients were not available for entry). Generally this date should be no more than several months prior to the 

submission date for an NDA. This date as well as this table may likely need to be updated during the course of 

NDA review as more data become available. 12Adverse events should be organized under body system categories. 13Within each body system category, adverse events should be ordered according to decreasing frequency. 14Adverse events during exposure are generally obtained by spontaneous report and recorded by clinical 

investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful 

estimate of the proportion of individuals experiencing adverse events without first grouping similar types of 

events into a smaller number of standardized event categories. Generally a table of this type should use these 

preferred adverse event terms, and a footnote should identify the system used for coding investigator terms. 

Adverse event terms that convey no useful information (e.g., joint disorder), should be replaced by more 

clinically useful terms or deleted. 15Percentages should be rounded to the nearest integer. Although not strictly hypothesis testing, p-values give 

some feeling for the strength of the finding and should be produced for all new drug/placebo pairwise 

comparisons and any p-values meeting a p < 0.05 level of significance should be noted by an asterisk (*) as a 

superscript to the %. 

16The N for each column should be provided at the column heading, so that only the percentage of patients 

having that adverse event need be included in the table, and not the actual number. 17The rates for gender specific adverse events (e.g., impotence) should be determined using the appropriate 

gender specific denominator, and this fact should be indicated with a footnote. 

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Contains Nonbinding Recommendations

Table 7.1.7.3.1.1 

Mean Change from Baseline for Serum Chemistry Parameters1

in Pool of Placebo-Controlled Studies2,3,4

Cutoff Date5: 

Treatment Groups7,8

New Drug Placebo 

Serum Chemistry Parameters 

and Units of Measure6

N9 BL10 Change from BL11 N BL Change from BL N 

Albumin (g/dl) Alkaline Phosphatase (U/L) Bilirubin, total (mg/dl) BUN (mg/dl) CK (U/L) Calcium (mg/dl) Cholesterol (mg/dl) Creatinine (mg/dl) GGT (U/L) Glucose (mg/dl) LDH (U/L) Phosphorus (mg/dl) Potassium (mmol/L) 

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Contains Nonbinding Recommendations

Sodium (mmol/L)Triglycerides (mg/dl) Uric Acid (mg/dl) 

1This table provides data comparing the mean change from baseline across treatment groups for serum chemistry parameters. An accep

would be to provide median change from baseline. The postmeasurement is generally the worst value during treatment. 

2This sample table is based on a pool of similarly designed placebo controlled trials. Other pools, as well as individual trials may also 3Patients participating in crossover trials should be enumerated for each of the pertinent columns of the table (e.g., a patient receiving t

three arms of a 3-way crossover study comparing New Drug, active control, and placebo would be included in all three columns).

4This table should be provided by the sponsor in electronic format. The exact design of the table and the preferred electronic format sh

discussions between the sponsor and the reviewing division. 

5This is the data lock date for entering data into this table (i.e., the date beyond which additional exposed patients were not available fo

this date should be no more than several months prior to the submission date for an NDA. This date as well as this table may likely n

during the course of NDA review as more data become available. 

6The parameters included in this list are for illustration. In general, the list should include all those serum chemistry parameters measu

of studies is the focus of the table. Similarly, the units of measure are for illustration, and these details should be worked out in consu

reviewing division. 

7In the sample table, only 1 column is provided for an active control group. One such category may suffice for certain NDAs, but may 

decision regarding how to categorize active control patients should be made in consultation with the reviewing division. 

8Similarly, for this table, only 1 column is provided for new drug, with the implication that all new drug patients, regardless of dose, sh

the calculations for that column. Other approaches (e.g., dividing patients on the basis of dose), may be equally appropriate. If the st

dose studies, it is generally most informative to preserve the dose categories in constructing this table. However, dose categories that doses that are being recommended for use may reasonably be omitted from this table. It is generally not useful to try to artificially cofrom dose titration studies, since there is often confounding of dose and time. 

9N represents the number of patients who had the serum chemistry parameter of interest assessed at baseline and at least one follow up 10This column should provide the baseline means for all the serum chemistry parameters of interest. 11This column should provide the mean change from baseline to patient’s worst on drug value for each of the serum chemistry paramet

not hypothesis testing, p-values provide some measures of the strength of the finding and should be produced for all new drug/placebo comparisons and any p-values meeting a p < 0.05 level of significance criterion should be noted by an asterisk (*) as a superscript to tbaseline. 

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Contains Nonbinding Recommendations

Table 7.1.7.3.2.1 

Incidence of Potentially Clinically Significant Changes in Serum Chemistry Parameters1 for 

Pool of Placebo Controlled Studies for New Drug2,3,4

Cutoff Date5: 

Treatment Groups6

New Drug Placebo A

Abnormal Abnormal 

Serum Chemistry Parameters 

and PCS Criteria 7 

L=Low; H=High; 

ULN=Upper Limits of Normal

Total 

Pts8

Nbr9 %10

Total 

Pts 

Nbr % 

Total 

Pts 

Albumin-L (< 2.5 g/dl) Alkaline P’tase-H (> 400 U/L) Bilirubin, total-H (> 2 mg/dl) BUN-H (> 30 mg/dl) CK-H (> 3XULN) Calcium-L (< 7 mg/dl) Calcium-H (> 12 mg/dl) Cholesterol-H (> 300 mg/dl) Creatinine-H (> 2 mg/dl) GGT-H (> 3XULN) Glucose-L (< 50 mg/dl) Glucose-H (> 250 mg/dl) 

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Contains Nonbinding Recommendations

LDH-H (> 3XULN)Phosphorus-L (< 2.0 mg/dl) Phosphorus-H (> 5.0 mg/dl) Potassium-L (< 3.0 mmol/L) Potassium-H (> 5.5 mmol/L) SGOT/AST-H (> 3XULN) SGPT/ALT-H (> 3XULN) Sodium-L (< 130 mmol/L) Sodium-H (> 150 mmol/L) Triglycerides-H (> 300 mg/dl) Uric Acid (F)-H (> 8.0 mg/dl) Uric Acid (M)-H (> 10.0 mg/dl) 

1This table provides data comparing the incidence across treatment groups of patients who were normal at baseline meeting criteria of having had 

serum chemistry parameters of potential clinical significance (PCS). Separate listings should be provided for patients who were abnormal at bacriteria. 

2This sample table is based on a pool of similarly designed placebo controlled trials. Other pools, as well as individual trials may also be of inter3Patients participating in crossover trials should be enumerated for each of the pertinent columns of the table (e.g., a patient receiving treatment i

way crossover study comparing New Drug, active control, and placebo would be included in all three columns). 

4This table should be provided by the sponsor in electronic format. The exact design of the table and the preferred electronic format should be e

between the sponsor and the reviewing division. 

5This is the data lock date for entering data into this table (i.e., the date beyond which additional exposed patients were not available for entry. G

more than several months prior to the submission date for an NDA. This date as well as this table may likely need to be updated during the coudata become available. 

6In the sample table, only 1 column is provided for an active control group. One such category may suffice for certain NDAs, but may not for ot

regarding how to categorize active control patients should be made in consultation with the reviewing division. Similarly, for this table, only 1 drug, with the implication that all new drug patients, regardless of dose, should be included in the calculations for that column. Other approachon the basis of dose), may be equally appropriate. 

71
Contains Nonbinding Recommendations

7The parameters included in this list are for illustration. In general, the list should include all those serum chemistry parameters measured in wha

focus of the table. Similarly, the proposed criteria for potentially clinically significant are for illustration, and these details should be worked oureviewing division. 

8The total number of patients for each parameter should represent the number of patients for the treatment group who (1) had that parameter asse

one follow up time and (2) for whom the baseline assessment was normal. 

9The number abnormal represents the subset of the total number who met the criterion in question at least once during treatment. A separate listi

identification for those patients meeting the criterion. 

10Percentage of the total number meeting the criterion should be rounded to the nearest integer. While not strictly hypothesis testing, p-values sh

drug/placebo pairwise comparisons and any p-values meeting a p < 0.05 level of significance should be noted by an asterisk (*) as a superscript 

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Contains Nonbinding Recommendations

Table 7.1.7.5.1 

Hepatotoxicity Evaluation 

I. Data Collection 

A. Overview of liver chemistry data (tests performed, frequency, specific follow-up plans 

for abnormal values) 

B. Specific follow-up plan if chemistry is elevated at end of treatment 

C. Re-challenge plan, if any 

D. Exclusions from studies because of liver chemistry abnormalities, if any 

II. Observations 

A. Abnormal liver chemistries seen in controlled trials (separate for pooled placebo 

controlled, active controlled) with greater than two week exposure. Rates can be given 

as events/exposed; positive findings can be also analyzed as events per patient year and 

examined for rates over time. 

1. Rates of 3x, 5x, 10x, 20x ULN elevations of AST (SGOT), ALT (SGPT), and 

either ALT or AST 

2. Rates of any elevations of bilirubin; rate of elevated bilirubin to >1.5x ULN 

3. Rates of alkaline phosphatase (AP) > 1.5x ULN 

4. Rates of elevated transaminase accompanied by elevated bilirubin. 

All rates should be given for both drug and control group. 

B. For total database with exposure > two weeks (i.e., including uncontrolled) 

Same as for controlled database (1-4) 

C. Individual events 

1. Listing of patients with any elevated transaminase (>3x ULN), without more 

than slight AP elevation, associated with increase in bilirubin to > ULN. 

2. Show time course of enzyme and bilirubin elevations 

3. For such patients, review clinical situation 

a. Ethanol history 

b. Evidence viral hepatitis 

c. Symptoms and course – follow-up is particularly important to detect 

underlying liver disease 

d. Special studies, notably Bx 

e. Possible confounding, including concomitant illness, concomitant 

medications (known hepatotoxins, including acetaminophen) 

III. Possible problems/signals 

A. Any patient with elevated transaminase (to at least 3x ULN, generally higher), no 

evidence of obstruction (elevated AP) and even modestly (2X ULN) elevated bilirubin. 

Greater elevation of bilirubin is stronger signal. 

B. Greater rate than control of 3x, 5x, 10x, etc. elevations of transamisne. 

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Contains Nonbinding Recommendations

Table 7.2.1.1.1 

Enumeration of Subjects/Patients for 

New Drug Development Program1,2,3,4 

Cutoff Date5: 

Treatment Groups 

Study 

Groups New Drug Active Control6 Placebo 

Completed Phase 1 (Clinical Pharmacology) 

Single Dose 120 30 30 

Multiple Dose 60 30 30 

Ph 1 Subtotal 180 60 60 

Completed Phase 2-3 (Studies of Proposed Indication) 

Placebo Control7 

 Fixed Dose 500 150 150 

 Flexible Dose 100 100 100 

Active Control 

 Fixed Dose 200 100 0 

 Flexible Dose 100 100 0 

Uncontrolled 

 Short Term 100 0 0 

 Long Term 700 0 0 

Ph 2-3 Subtotal 12008 450 250 

Ongoing Phase 2-3 Studies (Studies of Proposed Indication) 

Placebo Control 

 Flexible Dose 1509 0 1509

SD Subtotal 120 30 30 

MD Subtotal 1410 480 430 

Grand Total 1530 510 460 

1

This table provides a count by study type of the subjects/patients exposed to new drug, active control, and 

placebo across the entire set of studies in the development program that contributed safety and efficacy data for 

new drug. It should include all subjects/patients known or assumed to have received even a single dose of 

assigned treatment. It should exclude subjects/patients who are known not to have received any of the 

assigned treatments or for whom no follow up information is available subsequent to the assumed receipt of 

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Contains Nonbinding Recommendations

assigned treatment. A separate listing of all such patients should be provided. [Note: If this list includes more 

than a few patients, this may indicate a potentially important problem in the conduct of studies.] 

In creating this table, it is necessary to classify and group studies on the basis of several characteristics. For 

the purposes of this table, the following characteristics and distinctions were deemed important: 

-Phase 1 vs Phases 2 to 3 

-Completed vs Ongoing and Blinded 

-Single Dose vs Multiple Dose 

-Controlled vs Uncontrolled 

-Short-Term vs Long-Term

-Placebo-Controlled vs Active-Controlled 

-Fixed Dose vs Flexible Dose 

Obviously, there are other features that may be important as well, and that could lead to additional breakdowns 

within the table or to separate tables (e.g., different indications, inpatient vs outpatient status, differences in the 

quality and completeness of data collected across different studies, foreign vs domestic). The characteristics to 

be used in classifying studies for the purpose of this table should be decided in consultation with the designated 

reviewing division at FDA. 

In addition to this table that enumerates patients by category of study, it would be useful to have a table that 

enumerates patients by each individual study in the development program. This would be an expanded version 

of the above table that enumerates patients for each study (i.e., each of the categories in the above table would 

identify and provide data for the individual studies comprising that category). Sponsors ordinarily provide 

such a table. 

2

Patients participating in crossover trials should be counted in each of the pertinent columns of the table (e.g., a 

patient receiving treatment in each of the three arms of a 3-way crossover study comparing new drug, active 

control, and placebo would be counted in all three columns). 3

Footnotes to this table should identify by study number all those studies comprising the various study 

groupings for this table. For example, in the sample table, the fixed dose placebo controlled trials contributing 

to the counts for that category should be listed in a footnote, and similarly for all other categories. 4

This table should be provided by the sponsor in electronic format. The exact design of the table and the 

preferred electronic format should be established in discussions between the sponsor and the reviewing 

division. 

5

This is the data lock date for entering data into this table (i.e., the date beyond which additional exposed 

patients were not available for entry). Generally this date should be no more than several months prior to the 

submission date for an NDA. This date as well as this table likely need to be updated during the course of 

NDA review as more data become available. 6

In the sample table, only 1 column is provided for an active control group. One such category may suffice for 

certain NDAs, but may not for others, and the decision regarding how to categorize active control patients 

should be made in consultation with the reviewing division. 7

In this table, a decision was made to pool all studies having a placebo arm, whether or not an active control arm

was also included. Thus, the active control category includes only those active control studies that did not 

have a placebo control arm. Other approaches to grouping studies may be equally appropriate. 8

The intent of this table is to provide a count of unique subjects/patients exposed to new drug, etc. in the 

development program. Since patients often participate in more than 1 study in a development program, it is 

necessary to have an approach to avoid counting patients more than once for the subtotals and grand totals. 

The approach used in this table is to include in parentheses in the pertinent cells of the table a count of the 

patients in that cell total who have already been counted by virtue of having participated in a previous study 

(e.g., a patient in an open extension trial should have been previously counted in an acute, controlled phase). 

The subtotals of unique individuals exposed to the assigned treatment can then be calculated by subtracting the 

sum of all numbers in parentheses from the sum of all the cell totals for each column (e.g., in this table, the 

completed phase 2 to 3 subtotal for new drug is 1700 less the 500 patients already counted in short-term

controlled trials, or 1200). 

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Contains Nonbinding Recommendations

9

Frequently, some studies may be ongoing and blinded at the time of NDA submission, even though some

individual patients having experienced serious adverse events may have been unblinded. In these instances, 

the table should include estimates of the numbers of patients exposed to new drug, etc. from these studies, 

since exact counts may not be available. Footnotes should indicate when the table entries are based on 

estimates rather than exact counts. 

Table 7.2.1.2.1 

Demographic Profile for Phase 2-3 Studies with New Drug1,2,3,4,5

Cutoff Date6

: 

Treatment Groups7,8

Demographic 

Parameters New Drug 

N = 

Placebo 

N = 

Active Control 

N = 

Age (years) 

 Mean 

 Range 

 Groups9

 < 40 

 40-64 

 > 65 

% 

% 

% 

% 

% 

% 

% 

% 

% 

Sex 

 Female 

 Male 

% 

% 

% 

% 

% 

% 

Race10

 Caucasian 

 Non-Caucasian 

% 

% 

% 

% 

% 

% 

Weight (kg) 

 Mean 

 Range 

1

This table should be based on a pool of all trials in the phase 2 to 3 development program. Similar tables may 

be appropriate for other subgroups within the phase 2 to 3 program and also for certain individual trials of 

interest. The specific trials included should be listed. 

2

Patients participating in crossover trials should be included in the calculations for each of the pertinent columns 

of the table (e.g., a patient receiving treatment in each of the three arms of a 3-way crossover study comparing 

New Drug, active control, and placebo would be included in the calculations for all three columns). 3

Numbers for this table should be rounded to the nearest integer. 4

This sample table includes 4 demographic categories of obvious interest, however, others may be of interest as 

well (e.g., height, severity on baseline measures of disease severity). It may also be of interest to look at 

combinations of characteristics, such as gender and age (e.g., women under 50). 5

This table should be provided by the sponsor in electronic format. The exact design of the table and the 

preferred electronic format should be established in discussions between the sponsor and the reviewing 

division. 

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Contains Nonbinding Recommendations

6

This is the data lock date for entering data into this table (i.e., the date beyond which additional exposed 

patients were not available for entry). Generally this date should be no more than several months prior to the 

submission date for an NDA. This date as well as this table may likely need to be updated during the course of 

NDA review as more data become available. 7

In the sample table, only 1 column is provided for an active control group. One such category may suffice for 

certain NDAs, but may not for others, and the decision regarding how to categorize active control patients 

should be made in consultation with the reviewing division. Similarly, for this table, only 1 column is provided 

for new drug, with the implication that all new drug patients, regardless of dose, should be included in the 

calculations for that column. Other approaches (e.g., distinguishing patients on the basis of dose), may be 

equally appropriate. 

8

If, as is often the case, the Ns available for calculating any particular demographic parameter are less than the 

Ns in the column headings, these Ns should be provided, along with an explanation, in footnotes. 9

If there are pediatric exposures, these should be broken out as well. 

10Other approaches to racial categorization may be substituted for that proposed in this sample table. 

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Contains Nonbinding Recommendations

Table 7.2.1.3.1 

Number (Percent) of Patients Receiving New Drug According to Mean1,2,3,4,5,6,7 Daily Dose 

Duration of Therapy in Phase 2-3 Studies (N=2500) Cutoff Date8: 

Dose9 Duration (mg) 

(Weeks) 

0<Dos<5 5<Dos<10 10<Dos<20 20<Dos<30 30<Dos<50 50<Dos 

(

0<Dur<1 6 19 31 31 25 13 1<Dur<2 6 19 31 31 25 13 2<Dur<4 13 37 62 63 50 25 

4<Dur<12 31 94 156 156 125 63 

12<Dur<24 25 75 125 125 100 50 24<Dur<48 25 75 125 125 100 50 48<Dur<96 13 37 62 63 50 25 

96<Dur 6 19 31 31 25 13 

Total 

(AnyDur) 

125 375 623 625 500 252 

(%) (5%) (15%) (25%) (25%) (20%) (10%) 

1This table is calculated by first categorizing patients on the basis of the interval of exposure for each (e.g., a patient exposed for 6 

in the 4<Dur<12 row). The mean daily dose is then calculated for each patient for dose categorization (e.g., a 6-week patient with 

mg would be counted in the 10<Dos<20 column). Patients are enumerated in only 1 cell of the matrix (i.e., this is a mutually excl

and duration intervals need to be designed specifically for the drug of interest. The specific trials included should be listed. As w

78
Contains Nonbinding Recommendations

79

data from disparate sources, it does not address all information needs, and it should be interpreted with caution (e.g., mean doses imean doses over 0-12 weeks, not 4-12 as one might think). Nevertheless, the information provided provides useful information. 

2Similar tables can be prepared for median, for modal, and for maximum dose. 3The same table can be generated for any individual study or for any pool of studies. 4The same table can be generated for any subgroup of interest (e.g., on the basis of age, sex, race, comorbid condition, concomitant 

combination of these factors). 

5Similar tables should be provided for active control drugs and placebo. 6If the total N for this table does not match the total N from Table 5.1.1.1, as may be the case (e.g., if dose or duration data are not a

patients counted in Table 5.1.1.1, a footnote should provide an explanation for the discrepancy). 

7This table should be provided by the sponsor in electronic format. The exact design of the table and the preferred electronic forma

discussions between the sponsor and the reviewing division. 

8This is the data lock date for entering data into this table (i.e., the date beyond which additional exposed patients were not availabl

this date should be no more than several months prior to the submission date for an NDA. This date as well as this table may likelduring the course of NDA review as more data become available. 

9Dose may also be expressed as mg/kg, mg/m2, or in terms of plasma concentration if such data are available.