Guidance for Industry 

Integrated Summary of 

Effectiveness 

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only. 

Comments and suggestions regarding this draft document should be submitted within 60 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and 

Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments 

should be identified with the docket number listed in the notice of availability that publishes in 

the Federal Register. 

For questions regarding this draft document contact (CDER) Howard Chazin at 301-796-0700, 

or (CBER) Leonard Wilson at 301-827-0373. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

August 2008 

Procedural 

I:\7694dft.doc 

8/8/2008 
Guidance for Industry 

Integrated Summary of 

Effectiveness 

Additional copies are available from: 

Office of Training and Communications 

Division of Drug Information 

Center for Drug Evaluation and Research 

Food and Drug Administration 

10903 New Hampshire Ave., Bldg. 51, rm. 2201 

Silver Spring, MD 20993-0002 

(Tel) 301-796-3400 

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

or 

Office of Communication, Training, and 

Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research 

Food and Drug Administration 

1401 Rockville Pike, Rockville, MD 20852-1448 

(Tel) 800-835-4709 or 301-827-1800

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

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

August 2008 

Procedural 
TABLE OF CONTENTS 

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

II. BACKGROUND ............................................................................................................... 2

III. FORMAT AND CONTENT OF THE ISE..................................................................... 3

A. Background and Overview of Clinical Efficacy ..........................................................................3

B. Tabular Results of Individual Studies.......................................................................................... 5

C. Comparisons and Analyses of Efficacy Results Across Studies.................................................5

1. Demographics of Efficacy Study Populations..................................................................................5

2. Efficacy Results................................................................................................................................6

3. Analysis Issues .................................................................................................................................7

4. Integrated Data Analyses.................................................................................................................7

D. Comparison of Results in Subpopulations...................................................................................9

E. Analysis of Clinical Information Relevant to Dosing Recommendations ...............................10

F. Persistence of Efficacy and/or Tolerance Effects ......................................................................11

G. Exploratory Investigations..........................................................................................................11

IV. TABLES AND FIGURES .............................................................................................. 12

REFERENCES............................................................................................................................ 13
Contains Nonbinding Recommendations 

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Guidance for Industry1 1 

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Integrated Summary of Effectiveness 

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7 This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 

8 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 

9 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 

10 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

11 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

12 the appropriate number listed on the title page of this guidance. 

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I. INTRODUCTION 

This guidance describes how an integrated summary of effectiveness (ISE) should be prepared 

by industry for inclusion in a new drug application (NDA) or biologics license application 

(BLA)2

 submitted to the Food and Drug Administration (FDA). The recommendations in this 

guidance reflect the FDA’s current thinking regarding what industry should include in an ISE to 

provide a truly integrated analysis, rather than a summary of efficacy results from individual 

clinical trials, and to satisfy FDA regulatory requirements.3 Although there are no corresponding 

regulations requiring an ISE for BLA submissions, applicants are encouraged to provide these 

analyses in their applications. 

This guidance supersedes section G, Integrated Summary of Effectiveness Data, of the 1988 

guidance on Format and Content of the Clinical and Statistical Sections of an Application (ClinStat guidance). It also incorporates the conceptual framework of section 2.7.3, Summary of 

Clinical Efficacy (SCE), from the ICH guidance for industry M4E The CTD — Efficacy.

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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 

1

 This guidance has been prepared by the Office of New Drugs and the Office of Biostatistics in the Center for Drug 

Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at 

the Food and Drug Administration. 

2

 This guidance does not apply to medical devices regulated as biologics under the Public Health Service Act. 

3

 See 21 CFR 314.50(d)(5)(v). 

4

 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER 

guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 

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cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required. 

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II. BACKGROUND 

The ISE is an overall integrated analysis that comprehensively examines the effectiveness data 

from individual clinical studies. In addition to the adequate and well-controlled studies that 

should be submitted as the basis for approval, the ISE should include other controlled trials (e.g., 

incomplete trials or trials that do not support the claim) and the results of any other studies, 

published or unpublished, not conducted by the applicant, of which the applicant has become 

aware. 

Under 21 CFR 314.50(d)(5)(v), the ISE must include: 

• An integrated summary of the data demonstrating substantial evidence of effectiveness 

for each claimed indication 

• Evidence that supports the dosage and administration section of the labeling, including 

support for the recommended dosage and dose interval 

• Effectiveness data analyzed by sex, age, and racial subgroups 

• Evidence that is pertinent to individualization of dosing and the need for modifications of 

dosing for specific subgroups 

Since 1985, the ISE has been required as part of an NDA submission, but the regulation does not 

describe the specific components of the ISE in detail except for the components listed above. 

The FDA provided recommendations for what should be in an ISE in the Clin-Stat guidance, as 

follows: 

“The individual controlled studies to a great extent speak for themselves with respect to 

their ability to provide the evidence of effectiveness required by law. This section should 

provide an overview of the results, showing that they do satisfy the regulatory 

requirements for approval, i.e., represent adequate and well-controlled studies 

demonstrating the claimed effect, particularly if results are inconsistent or marginal. For 

example, the sponsor would explain here his basis for seeking to rely on a single study. 

Equally important, this section should include an examination of study-to-study 

differences in results, effects in subsets of the treated population, dose-response 

information from all sources, any available comparisons with alternative drugs, and any 

other information, so that the nature of the drug’s effectiveness can be as fully defined as 

possible, and the user of the drug can be given the best possible information on how to 

use the drug and what results to expect.” 

Since the Clin-Stat guidance was published, several International Conference on Harmonisation 

(ICH) guidances, including the ICH guidances for industry E3 Structure and Content of Clinical 

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Study Reports, E9 Statistical Principles for Clinical Trials, E10 Choice of Control Group and 

Related Issues in Clinical Trials, and M4E The CTD — Efficacy,

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5

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recommendations for describing individual trials and providing an efficacy analysis. The 

recommendations in this guidance reflect the FDA’s current thinking regarding what should be 

included in an ISE to provide a truly integrated analysis, rather than a summary of efficacy 

results from individual clinical trials, and to satisfy FDA regulatory requirements. 

The draft guidance for industry Integrated Summaries of Effectiveness and Safety: Location 

Within the Common Technical Document6 outlines where to place the ISE within the framework 

of the common technical document (CTD) and electronic common technical document (eCTD). 

That guidance is intended to resolve the confusion concerning the difference between the 

document that should be included in Module 2, section 2.7.3, SCE, and the document that should 

be located in Module 5, section 5.3.5.3, Reports of Analyses of Data from More than One Study 

(Including Any Formal Integrated Analyses, Meta-Analyses, and Bridging Analyses). Although 

one of the goals of the ISE is to summarize the available effectiveness data, the ISE primarily is 

an integrated analysis of these data, going beyond a simple summary. For example, the 

regulatory requirements in 21 CFR 314.50(d)(5)(v) for support of dosing recommendations and 

analyses of demographic subset responses usually involve overview approaches that need both 

detailed explanation and documentation. The document in section 2.7.3 should summarize these 

analyses, but, in most cases, the ISE will be substantially larger than what would be appropriate 

for the section 2.7.3 summary of these data and analyses. 

III. FORMAT AND CONTENT OF THE ISE 

A. Background and Overview of Clinical Efficacy 

The format (including section titles) of the ISE should be flexible, but in many cases (and as 

broken down below) it can closely follow the format of the SCE that appears in Module 2, 

section 2.7.3, of the CTD. Applicants should take note of the following suggestions for content 

but should choose the format that best suits the data. 

The ISE should not recapitulate detailed results of single studies, which are described in 

individual study reports, but instead should provide a comprehensive, detailed, in-depth analysis 

of the efficacy results in aggregate, with a clear rationale for the methods used in the analysis. 

Studies should be presented briefly while noting critical design and analytic features as well as 

important differences between studies (e.g., population, dose, duration, endpoints). 

The background and overview section of the ISE should show clearly why individual studies 

should be considered adequate and well-controlled studies that demonstrate the claimed effect, 

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 Specifically, sections 2.5, Clinical Overview, and 2.7, Clinical Summary, in Module 2, and Module 5: Clinical 

Study Reports. 

6

 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent version of a 

guidance, check the CDER guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 

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and thus fulfill the legal requirements for approval. This demonstration is particularly important 

if results are inconsistent or marginal. 

Critical study design features of the controlled studies supporting effectiveness should be 

discussed and compared among studies, especially when results are inconsistent. Examples of 

these features are as follows (see ICH E3 for additional important study characteristics): 

• Randomization 

• Blinding 

• Choices of control treatment, particularly noninferiority designs 

• Statistical approaches 

• Dosing modifications 

• Choice of patient population, and use of enrichment approaches to identify patients with 

high likelihood of events or high likelihood of response 

• Particular design features such as crossover or randomized withdrawal designs 

• Use of run-in periods as a method of enrichment 

• Handling of dropouts in the study and analysis 

• Choice of study endpoints (with particular attention to use of surrogate endpoints) 

• Study duration 

• Prespecified plans for analysis of the study results, with attention to multiplicity and 

primary and secondary endpoints 

• Other features that may be critical in particular cases 

As part of a comprehensive summary of experience related to efficacy, the ISE also can refer to 

nonclinical data and clinical pharmacology data as appropriate. 

Particular attention should be paid to any recognized limitations of the efficacy studies. Thus, if 

an effectiveness claim is based on a surrogate endpoint, the basis for choice of the endpoint 

should be discussed and its validity as a predictor of clinical outcome should be supported. In 

some cases, this discussion may not be needed if the surrogate endpoint has been sufficiently 

validated and relied upon as the basis of approval for previously approved drugs (e.g., 

antihypertensive, oral hypoglycemic, and lipid-lowering drugs generally have been approved on 

the basis of demonstrated effects on blood pressure, blood sugar and HgA1c, and LDL 

cholesterol or triglycerides, respectively, without evidence, at the time of approval, of an effect 

of the particular drug on survival or morbidity). Nevertheless any novel surrogate endpoint (e.g., 

not used previously by the FDA as a basis for approval) should be discussed and supported. 

If the objective of some of the studies was to show equivalence or noninferiority to an active 

control, the basis for the choice of noninferiority margin and support for the assay sensitivity of 

the trial, including support for the constancy assumption, should be provided in detail. The 

results should be evaluated by using the predefined criteria for defining equivalence or 

noninferiority, and any modification of plans should be explained (see ICH E10). 

Graphs, technical discussion, mathematical derivations, or presentation of formulae should be 

included in an appendix, rather than in the main body of the ISE. 

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168 B. Tabular Results of Individual Studies 

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Generally, a tabular listing of all studies with data relevant to drug efficacy should be provided, 

together with study narrative descriptions. Both positive and negative studies should be 

included. The study narrative descriptions should be brief (e.g., similar in level of detail to an 

abstract for a journal article) and describe critical design features and critical results, including 

the prospectively identified endpoints and statistical analysis plan for each study. Similar studies 

can be described together, noting the individual study results and any important differences 

among the studies. These brief study narrative descriptions should include references or 

electronic links to the full study reports. 

C. Comparisons and Analyses of Efficacy Results Across Studies 

Using text, figures, and tables as appropriate, the Comparison and Analysis of Results Across 

Studies section should present all available data that characterize the efficacy of the drug. These 

comparisons and analyses should use appropriate methods for comparing studies of similar 

design, controlling for design differences, weighting by sample size, and examining by common 

covariates or stratifications. This section should include analyses of all data, irrespective of the 

strength of evidence of their support for the overall conclusion, and should discuss the extent to 

which the results of the relevant studies reinforce or do not reinforce each other. Any major 

inconsistencies in the data regarding efficacy should be addressed, and any areas needing further 

exploration should be identified. Data should be examined with respect to control groups, 

duration of exposure, patient populations enrolled, endpoints (including how defined), dropout 

profiles and analyses, and statistical methods (time-to-event versus cumulative rates). 

Generally, this section should use two kinds of analyses: comparison of results of individual 

studies, and analysis of data combined from various studies. 

1. Demographics of Efficacy Study Populations 

The demographic and other baseline characteristics of study populations across all efficacy 

studies should be described. The following information should be included: 

• The disease characteristics (e.g., severity, duration), prior treatment of the study subjects, 

concomitant treatment allowed or required, and study inclusion and exclusion criteria, 

including concomitant illness. 

• Differences in baseline characteristics of the study populations in different studies or 

groups of studies, which may include any differences in age, sex, race, and geographic 

region (United States versus non-U.S. regions). 

• Any differences among all populations included in critical efficacy analyses and the 

overall patient population expected to receive the drug when it is marketed. 

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• Assessment of the number of subjects who dropped out of the studies (separately for each 

treatment group), time of withdrawal (a defined study day or visit during treatment or 

follow-up period), and reasons for discontinuation. 

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2. Efficacy Results 

Results from all controlled studies, including those controlled studies that did not favor the study 

treatment and other pertinent controlled studies that were included under clinical pharmacology, 

should be summarized, examined, and compared as appropriate using tables and figures (such as 

forest plots). Important differences in study design (such as endpoints, control group, study 

duration, patient population, dose, and statistical methods) should be identified. 

Comparisons of results across studies should focus on prespecified primary endpoints. When the 

primary endpoints involved different variables, exposure durations, or time points in different 

efficacy studies, it can be useful to provide cross-study comparisons of important data elements 

that can be found in all studies even if not the primary endpoint in some of them. If results over 

time are important, study results can be displayed in a figure that illustrates the change over time 

in each study. Important secondary endpoints, particularly when examined appropriately after 

success on a primary endpoint, also should be shown. 

The analysis should be consistent with the report of individual study results and can be 

accomplished with the help of tables that show major study design features, number of subjects, 

number of dropouts, and major outcomes. 

When comparing study results for those cases in which many variables or time points were 

analyzed, representative ones (usually those that were identified as the primary endpoints in the 

individual studies) should be selected for display and evaluation. 

Ordinarily, studies with similar controls (placebo control, active control) should be discussed 

together. A variety of methods have been used to display study results including tables, although 

graphic displays are more often helpful. It is increasingly common to use forest plots to display 

each study result on a common vertical axis, giving results (absolute effect versus placebo or 

hazard ratio) measured on the X axis. These plots can show p-values. To aid in the 

interpretation of point estimates, confidence intervals for treatment effects also should be given. 

If differences in change from baseline are shown for placebo and test drugs, the baseline values 

and the magnitude of effect in all treatment groups, including placebo and active controls (if 

used), generally should be presented in the table or in text accompanying a figure. 

If there are important differences in outcome among studies of generally similar design, these 

differences should be displayed and an attempt should be made to explain why results were 

different, even though doing this can be difficult. Factors such as differences in subjects (disease 

definition, disease stage, severity, prior treatment, genetic differences among populations), drug 

dose or regimen, methods of observation, adherence to protocol or inadequate power (high beta 

error rate) may offer such an explanation and should be considered. Often such analyses will 

raise questions for future exploration rather than provide definitive answers. 

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Studies may exist that can serve as bridging studies intended to allow reliance on studies 

conducted outside the United States by showing that the clinical effect can be demonstrated in a 

U.S. population (see the ICH guidance for industry E5 Ethnic Factors in the Acceptability of 

Foreign Clinical Data). These studies should be particularly noted in this section. There also 

should be an analysis of the similarity of efficacy for subjects in different regions either study by 

study, subsets of studies, or pooled analyses. Any other information that may support 

extrapolation of the efficacy data to the new region also should be provided. 

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3. Analysis Issues 

Support for the proposed claim should be described in terms of the strength of statistical 

evidence (including consistency of findings, individual study strength, p-value, and confidence 

interval) and findings that appear to weaken the actual claim. The applicant should include a 

summary and discussion of the analyses of each individual study, the extent of evidence in 

support of claims, statistical issues that may affect the conclusion on efficacy, and any related 

comments. Statistical issues should be summarized study by study, as well as collectively, for all 

studies conducted. Resolution of these issues and any effect on overall efficacy assessment 

should be discussed. 

The following are examples of important statistical issues that may affect the results: 

• Breaking the blind 

• Unblinded or unplanned interim analyses 

• High percentage of dropouts 

• Inappropriate methods of imputation for missing values 

• Change of primary endpoints during conduct of trial 

• Dropping or adding treatment arms 

• Sample size modification 

• Adaptations to the design not planned in advance 

• Inconsistency of results across subgroups 

• Type I error inflation caused by multiplicity 

4. Integrated Data Analyses 

For the purposes of this guidance, the term integrated analysis refers to synthesizing the results 

of individual studies in an appropriate manner to collectively provide support for the claimed 

effectiveness of the study drug. Statistical literature formally uses the term meta-analysis, which 

was defined by Gene V. Glass as “the statistical analysis of a large collection of analysis results 

from individual studies for the purpose of integrating findings.”7

 Examples of related terms used 

in literature include: analysis of combined data, combined analysis, analysis of pooled data, and 

pooled analysis. No matter what term is used, the objective is to use appropriately sound 

methods when formulating an integrated analysis. 

7

 Glass, GV, 1976, Primary, Secondary and Meta-Analysis of Research, Educational Researcher, 5(10):3-8. 

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As a general rule, when individual studies fail to show effectiveness on the basis of their planned 

analyses, a meta-analysis will not provide persuasive evidence of effectiveness. The decision to 

pool data usually is made after the fact and is potentially biased. In some cases, however, metaanalyses involving the entire study populations can provide useful information in an efficacy 

evaluation. Interpretability of meta-analyses depends upon the ability to minimize biases during 

the selection of studies for the analyses. Careful prospective planning is necessary to reduce 

these selection biases. 

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Meta-analyses or pooled analyses of clinical trials can provide useful information in a number of 

cases including: 

• When examining various patient subgroups, such as those based on demographics,8

etiology or severity of disease, or geographical regions, where individual studies might be 

expected to lack power. 

• When assessing the dose-response relationship, especially if individual studies were 

conducted using different doses, and particularly in demographic subgroups. 

• When assessing the drug effects on a secondary endpoint or on a component of a 

composite endpoint. 

It is particularly important to plan such analyses in study protocols. For example, a mortality 

effect can be a planned pooled analysis of two studies using a composite outcome measure for 

each study. Pooled analyses also can be useful in evaluating time to effect and response rates 

(where the primary endpoint is a continuous variable). 

Such results also can be used to design future trials including trials used to satisfy phase 4 

commitments. 

If a pooled analysis (or meta-analysis) of the clinical studies is performed, it should be clearly 

stated in the ISE whether this analysis was performed according to a predefined protocol or was 

a post hoc exercise. To avoid producing potentially biased results, decisions on how data will be 

analyzed should be done prospectively, before the results are known. It also should be clear 

whether including or excluding studies based on their observed outcomes will introduce bias.

Any differences in trial designs or populations, or in efficacy measurements, between studies 

should be described to allow an appropriate assessment of the relevance and validity of the 

results and conclusions (see ICH E9). A detailed description of the methodology and results of 

the meta-analysis should be provided. 

It is important that the analysis avoid pooling studies with drastic heterogeneity, and it is also 

important to maintain the randomization procedure. Therefore, studies having different 

allocation ratios generally should not be lumped together and analyzed as a single study. 

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 Demographic analyses are required under 21 CFR 314.50 and are expected to be reported in labeling. 

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In summary, the points to consider with respect to meta-analyses are as follows: 

• A meta-analysis without positive individual studies is not likely to be accepted as support 

for a claim unless a pooled analysis is specified as the primary endpoint. 

• The measures and/or endpoints used in pooled or meta-analysis, such as survival, effects 

on less common endpoints, and dose response, should be specified and justified. 

• Heterogeneity of the measure across trials should be considered and summarized. 

• Measure and effect of the weight or influence of each study on the overall estimate of the 

measures should be given. 

• The effect of varying trial durations, possibly including nonconstant hazard functions, 

should be considered. How duration is considered is critical to understanding therapies 

used in chronic diseases. 

D. Comparison of Results in Subpopulations 

The results of individual studies or overview analyses of efficacy in specific populations should 

be summarized in this section. The purpose of these comparisons is to evaluate the observed 

treatment effect across all studies and to show whether the claimed treatment effects observed 

are not drastically inconsistent across all relevant subpopulations, especially those populations 

where there are special reasons for concern. 

The comparisons can highlight apparent variations in efficacy that call for further investigation 

and discussion. However, the limitations of such analyses should be recognized (see ICH E9), 

and it is important to note that their purpose is not to provide the basis for specific claims or to 

attempt to improve the evidence of efficacy in situations where the individual study results are 

disappointing. 

Given the limited sample sizes in individual studies, pooled analyses across multiple studies 

should be performed to evaluate effects of major demographic factors (e.g., age, sex, and race) 

and of other predefined or relevant intrinsic and extrinsic factors (e.g., disease severity, prior 

treatment, concomitant illness, concomitant drugs, alcohol, tobacco, body weight, renal or 

hepatic functional impairment) on efficacy. This analysis should be stratified and weighted by 

study size to minimize the chance of confounding caused by inherent differences in design 

specifications including baseline characteristics of the patient populations and use of 

concomitant medications across the studies to be pooled. Regional differences may need to be 

evaluated in multinational studies. 

Factors of special interest can arise from general concerns (e.g., regarding the use of drugs in the 

elderly) or from specific issues that are related to the pharmacology of the drug or that have 

arisen during earlier drug development. If the application is being submitted for a new active 

ingredient, new indication, new dosage form, new dosing regimen, or new route of 

administration, the Pediatric Research Equity Act of 2007 (21 U.S.C. 355c) requires that the 

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safety and efficacy of the drug be assessed in all relevant pediatric populations. A deferral 

and/or waiver of the pediatric study requirements may be appropriate in some cases, and 

pediatric studies do not necessarily need to be conducted before seeking approval of a drug for 

use in adults. 

The comparison of results should be displayed using tables or figures/plots and should refer to 

the number of exposed subjects in the major subsets (e.g., age, race, sex). The examination of 

subsets need not routinely involve formal inferential statistical analysis. 

Of interest are differences of clinically meaningful size. If these differences are not observed, 

there may be minor differences that reflect the fact that multiple subsets have been analyzed. 

These minor differences should be described although they need not be analyzed further. If a 

tendency toward a difference in the pooled analysis is seen, it also may be useful to look at 

study-by-study results. Differences that are consistently large across studies may generate a 

hypothesis for further study. 

There might be cases in which formal inferential statistical analysis for specific subgroups may 

be needed to provide useful information in the drug label. For instance, the treatment effect may 

be most attributed to a specific subgroup. For such a labeling purpose, the integrated analysis 

should follow the clinical trial principle and statistical principle. The following issues that merit 

statistical consideration include: 

• Whether or not the treatment effect in the overall population is conclusive 

• Whether the integrated analysis is pre-planned 

• Whether the studies pooled are drastically different with respect to patient population, 

dosage and study duration, pattern of missing values, among others 

• How each individual study is weighted in the integrated analysis (usually it should be 

weighted by the study size) 

• Whether proper multiple comparison adjustments are made for testing the multiple 

hypotheses (e.g., primary versus secondary endpoints) in the integrated analysis 

• Whether the pooled study is acceptable as one randomized clinical study equivalent 

• Whether the results of the integrated analysis are reproducible, if this analysis is 

acceptable for generating one-study worth evidence 

For many NDA or BLA submissions, a well-constructed presentation of the results of several 

individual studies should be adequate to summarize the effectiveness results. Even in this case, 

however, a combined analysis usually will be needed to look at effects in demographic subsets 

and other subsets of the overall population. Interpretability of such a combined analysis rests 

upon careful prospective planning before commencement of the combination process. Careful 

prospective planning is needed to reduce the biases resulting from the combination process that 

is influenced by examination of study results. 

E. Analysis of Clinical Information Relevant to Dosing Recommendations 

This section should provide an integrated summary and analysis of all data, including data from 

individual dose-response clinical studies, relevant pooled analyses, and clinical pharmacological 

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studies, that pertain to the dose-response or blood level-response relationships of effectiveness 

(including dose-blood level relationships). These data contribute importantly to dosing 

recommendations, including the choice of dose interval. The individual study results and any 

cross-study analyses that will be used to support the dosing recommendations (including the 

recommended starting and maximal doses, the method of dose titration, schedule, and any other 

instructions regarding individualization of dosage) should be summarized here. These results 

and analyses should include descriptions of relatively simple dose-response or blood levelresponse relationships as well as any identified deviations caused by nonlinearity of 

pharmacokinetics, delayed effects, tolerance, or enzyme induction. Limitations of the data (e.g., 

because titration designs were used instead of fixed-dose designs) should be candidly assessed. 

Any evidence of differences in dose-response relationships that result from a subject’s age, sex, 

race, disease, or other factors should be described. Any evidence of different pharmacokinetic or 

pharmacodynamic responses also should be discussed, or discussions in section 2.7.2, Summary 

of Clinical Pharmacology Studies, CTD Module 2, can be cross-referenced. The ways in which 

such differences were looked for, even if no differences were found, should be described (e.g., 

specific studies in subpopulations, analysis of efficacy results by subgroup, or blood level 

determinations of the test drug). 

F. Persistence of Efficacy and/or Tolerance Effects 

Assessments of treatment response over time can be of interest. For example, is the persistence 

of efficacy over a time interval erratic or fairly consistent and how does the response over time 

relate to the dose? Therapeutic effects of a treatment can decline over time because of 

tolerability issues (patients who experience adverse events and refuse treatment) or from the 

development of drug resistance or tolerance. In such cases, all available information on 

persistence of efficacy over time should be summarized. The number of subjects for whom longterm efficacy data are available, the dose, duration of exposure, and the reason for censoring 

should be provided. Any evidence of tolerance (loss of therapeutic effects over time) should be 

noted. Examination of any apparent relationships between dose changes over time and long-term 

efficacy can be useful. 

The primary focus should be on controlled studies specifically designed to collect efficacy data. 

These studies should be clearly differentiated from other, less rigorous studies, such as open 

extension studies. This distinction also applies to specific studies designed for evaluation of 

tolerance and withdrawal effects. Data concerning withdrawal or rebound effects pertinent to 

drug safety should be presented in the appropriate safety sections. Extension studies that enroll 

subjects who leave the controlled studies can provide valuable information and can permit true 

intent-to-treat analysis. Such analyses provide important information about the sensitivity of the 

analysis, especially for mortality or irreversible morbidity. 

G. Exploratory Investigations 

Results of exploratory analyses on nonspecified endpoints, patient subgroups, and pooled data 

can be reported. However, if such exploration was not prospectively defined, it will not meet the 

regulatory criteria for adequate and well-controlled clinical study, and, therefore, cannot be used 

as substantial evidence of efficacy (21 CFR 314.126). Nevertheless, these analyses can lead to 

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proposals for additional studies and in some cases in which the analyses refine evidence of 

effectiveness that has already been established (e.g., demographic subset analyses), they can 

provide useful labeling information as well. 

IV. TABLES AND FIGURES 

Tables and figures should be embedded in the text when they enhance understanding of the 

document. Lengthy tables can be placed in the appendix at the end of the section. For eCTDs, 

hyperlinks to tables can be provided within the body of the ISE. 

Tables should identify all studies pertinent to the evaluation of efficacy (including studies that 

were terminated or are not yet completed, studies that failed to show effectiveness for any 

reason, studies available as publications only, studies reported in full technical reports (ICH E3), 

and studies described in abbreviated reports) and should provide the most important results of 

those studies. However, it should be noted that unplanned interim analyses on ongoing studies 

generally are not needed and are not encouraged. When more than one ISE is provided for an 

application with more than one indication, usually each section should have its own appendix 

with tables. 
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Guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and 

Biological Products

ICH guidance for industry E3 Structure and Content of Clinical Study Reports

ICH guidance for industry E5 Ethnic Factors in the Acceptability of Foreign Clinical Data

ICH guidance for industry E9 Statistical Principles for Clinical Trials

ICH guidance for industry E10 Choice of Control Group and Related Issues in Clinical Trials

ICH guidance for industry M4E The CTD — Efficacy, Section 2.7.3, Summary of Clinical 

Efficacy 

MAPP 4000.8 BLA Biostatistics Biologics Licensing Application Template 

MAPP 4000.8 NDA Biostatistics New Drug Application Review Template 

MAPP 6010.3 Clinical Review Template, Attachment A, Section 6, Integrated Review of 

Efficacy 

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