Guidance for Industry
M4E: The CTD — Efficacy
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 2001
Guidance for Industry
M4E: The CTD — Efficacy
Copies of this Guidance are available from: Office of Training and Communications
Division of Drug Information, HFD-240 Center for Drug Evaluation and Research 5600 Fishers Lane, Rockville, MD 20857 Internet: http://www.fda.gov/cder/guidance/index.htm. Office of Communication, Training and Center for Biologics Evaluation and Research 1401 Rockville Pike, Rockville, MD 20852-1448 Internet: http://www.fda.gov/cber/guidelines.htm. Fax: 1-888-CBERFAX or 301-827-3844 Mail: the Voice Information System at 800-835-4709 or 301-827-1800. U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
August 2001
Table of Contents
The CTD .2
Preparing and Organizing the CTD .2
Organization and Format of the ICH Guidances for Industry .7
Numbering .7
Preamble .8
Guidances Referenced .9
Table of Contents.9
Detailed Discussion of Content of the Clinical Overview Sections .10
2.5.7 REFERENCES. 15
Preamble .16
Table of Contents .16
Detailed Guidance on Sections of the Clinical Summary .17
ANALYTICAL METHODS. 17 Background and Overview .17 Summary of Results of Individual Studies.17 Comparison and Analyses of Results Across Studies.17 Appendix .18
SUMMARY OF CLINICAL PHARMACOLOGY STUDIES. 18 Background and Overview .18 Summary of Results of Individual Studies.19 Comparison and Analyses of Results Across Studies.19 Special Studies .20 Appendix .21
SUMMARY OF CLINICAL EFFICACY. 22 Background and Overview of Clinical Efficacy.22 Summary of Results of Individual Studies.23 Comparison and Analyses of Results Across Studies.23 Study Populations . Comparison of Efficacy Results of all Studies . Comparison of Results in Subpopulations.25 Analysis of Clinical Information Relevant to Dosing Recommendations.25 Persistence of Efficacy and/or Tolerance Effects .26 Appendix .26
SUMMARY OF CLINICAL SAFETY. 27 Exposure to the Drug .27 Overall Safety Evaluation Plan and Narratives of Safety Studies. Overall Extent of Exposure . Demographic and Other Characteristics of Study Population .28 Adverse Events.29 Analysis of Adverse Events . Narratives .34 Clinical Laboratory Evaluations .34 Vital Signs, Physical Findings, and Other Observations Related to Safety.35 Safety in Special Groups and Situations.35 Intrinsic Factors.352. Extrinsic Factors .352. Drug Interactions .352. Use in Pregnancy and Lactation .362. Overdose.362. Drug Abuse .362. Withdrawal and Rebound .362. Effects on Ability to Drive or Operate Machinery or Impairment of Mental Ability .36 Postmarketing Data .36 Appendix .37
Preamble .50
Detailed Organization of Clinical Study Reports and Related Information in Module 5.50
5.3.1 Reports of Biopharmaceutic Studies .51 Bioavailability (BA) Study Reports .515.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports .525.3.1.3 In Vitro – In Vivo Correlation Study Reports.525.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies .52 5.3.2 Reports of Studies Pertinent to Pharmacokinetics Using Human Biomaterials.52 Plasma Protein Binding Study Reports.525.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies.535.3.2.3 Reports of Studies Using Other Human Biomaterials .53 5.3.3 Reports of Human Pharmacokinetic (PK) Studies .53 Healthy Subject PK and Initial Tolerability Study Reports.545.3.3.2 Patient PK and Initial Tolerability Study Reports .545.3.3.3 Intrinsic Factor PK Study Reports .545.3.3.4 Extrinsic Factor PK Study Reports .545.3.3.5 Population PK Study Reports .54 5.3.4 Reports of Human Pharmacodynamic (PD) Studies.54 Healthy Subject PD and PK/PD Study Reports.555.3.4.2 Patient PD and PK/PD Study Reports .55 5.3.5 Reports of Efficacy and Safety Studies.55 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication.555.3.5.2 Study Reports of Uncontrolled Clinical Studies.565.3.5.3 Reports of Analyses of Data from More than One Study (Including Any Formal IntegratedAnalyses, Meta-Analyses, and Bridging Analyses).565.3.5.4 Other Study Reports.56 5.3.6 Reports of Postmarketing Experience .57
5.3.7 Case Report Forms and Individual Patient Listings .57
Guidance for Industry1
M4E: The CTD — Efficacy
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. Itdoes not create or confer any rights for or on any person and does not operate to bind FDA or the public.
An alternative approach may be used if such approach satisfies the requirements of the applicablestatutes and regulations.
This is one in a series of guidances that provide recommendations for applicants preparing theCommon Technical Document for the Registration of Pharmaceuticals for Human Use (CTD) forsubmission to the U.S. Food and Drug Administration (FDA). This guidance presents the agreedupon common format for the preparation of a well-structured Efficacy section of the CTD forapplications that will be submitted to regulatory authorities. A common format for the technicaldocumentation will significantly reduce the time and resources needed to compile applications forregistration of human pharmaceuticals and will ease the preparation of electronic submissions. Regulatory reviews and communication with the applicant will be facilitated by a standarddocument of common elements. In addition, exchange of regulatory information betweenregulatory authorities will be simplified.
For information on the Quality and Safety sections of the CTD, see the individual guidances forindustry that discuss those parts of the CTD. For general information about the CTD, as well asspecific information about Module 1 (regional administrative information), see the Agency'sguidance for industry, General Considerations for Submitting Applications According to the 1 This guidance was developed within the Expert Working Group (Efficacy) of the International Conference on Harmonisation ofTechnical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by theregulatory parties, in accordance with the ICH process. This document was endorsed by the ICH Steering Committee at Step 4of the ICH process, November 9, 2000. At Step 4 of the process, the final draft is recommended for adoption to the regulatorybodies of the European Union, Japan, and the United States.
ICH/CTD Format (General Considerations guidance).2 The CTD guidances are intended to beused together with other ICH and Agency guidances. Please refer to those guidances for detailedinformation about the contents of an application.
Through the ICH process, considerable harmonization has been achieved among the three regions(Japan, Europe, and the United States) in the technical requirements for the registration ofpharmaceuticals for human use. However, until now, there has been no harmonization of theorganization of a submission. Each region has its own requirements for the organization of thetechnical reports in the submission and for the preparation of the summaries and tables. In Japan,the applicants must prepare the GAIYO, which organizes and presents a summary of the technicalinformation. In Europe, expert reports and tabulated summaries are required, and writtensummaries are recommended. The U.S. FDA has guidance regarding the format and content of thenew drug application submission. To avoid the need to generate and compile different registrationdossiers, this guidance describes a format for the Efficacy section of the CTD that will beacceptable in all three regions.
Preparing and Organizing the CTD
This guidance primarily addresses the organization of the information to be presented in theEfficacy section of an application for new pharmaceuticals (including biotechnology-derivedproducts). Guidances also are available that discuss the Quality and Safety sections of the CTD.
These guidances are not intended to indicate what studies are required. The guidances merelyindicate an appropriate format for the data that have been acquired. Applicants should not modifythe overall organization of the CTD. However, in the Nonclinical and Clinical Summariessections of the CTD, applicants can modify individual formats, if needed, to provide the bestpossible presentation of the technical information to facilitate the understanding and evaluation ofthe results.
Throughout the CTD, the display of information should be unambiguous and transparent, tofacilitate the review of the basic data and to help a reviewer become quickly oriented to theapplication contents. Text and tables should be prepared using margins that allow the document tobe printed on both A4 paper (E.U. and Japan) and 8.5 x 11” paper (U.S.). The left-hand marginshould be sufficiently large that information is not obscured through binding. Font sizes for textand tables should be of a style and size that are large enough to be easily legible, even afterphotocopying. Times New Roman, 12-point font is recommended for narrative text. Acronymsand abbreviations should be defined the first time they are used in each module. Referencesshould be cited in accordance with the current edition of the Uniform Requirements for 2 A draft version of the General Considerations guidance is currently available. Once it has been finalized, it will represent theAgency's thinking on this topic.
Manuscripts Submitted to Biomedical Journals, International Committee of Medical JournalEditors (ICMJE).3 The CTD should be organized into five modules. Module 1 is region specific. Modules 2, 3, 4,and 5 are intended to be common for all regions. Conformance with the CTD guidances shouldhelp ensure that these four modules are provided in a format acceptable to the regulatoryauthorities (see the figure and overall outline on the following pages).
Module 1. Administrative Information and Prescribing Information
This module should contain documents specific to each region; for example, application
forms or the proposed label for use in the region. The content and format of this module
can be specified by the relevant regulatory authorities. For information about this module
see the General Considerations guidance.
Module 2. Common Technical Document Summaries
Module 2 should begin with a general introduction to the pharmaceutical, including its
pharmacologic class, mode of action, and proposed clinical use. In general, the
Introduction should not exceed one page.
Module 2 should contain 7 sections in the following order: • Nonclinical Written and Tabulated Summaries The individual organization of these summaries is described in three separate documents: • M4E: The CTD — Efficacy.
Module 3. Quality
Information on Quality should be presented in the structured format described in the
guidance M4Q.
Module 4. Nonclinical Study Reports
The Nonclinical Study Reports should be presented in the order described in the guidance
3 The first edition of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals was conceived by theVancouver Group and was published in 1979.
Module 5. Clinical Study Reports
The human study reports and related information should be presented in the order
described in the guidance M4E.
Diagrammatic Representation of the ICH Common Technical
The CTD should be organized according to the following general outline.
Module 1: Administrative Information and Prescribing Information
Table of Contents of the Submission Including Module 1 Documents Specific to Each Region (for example, application forms, prescribing Module 2: Common Technical Document Summaries
Nonclinical Written and Tabulated Summary Biopharmaceutics and Associated Analytical MethodsClinical Pharmacology StudiesClinical EfficacyClinical SafetySynopses of Individual Studies Module 3: Quality
Module 4: Nonclinical Study Reports
Module 5: Clinical Study Reports
Organization and Format of the ICH Guidances for Industry
Although the CTD is organized by modules, the guidances for industry that providerecommendations for applicants on preparing the CTD have been organized by topic. As a result,guidance discussing Module 2 is divided among the three guidances.
Guidance on the Quality section of the CTD (Module 2, Quality Overall Summary (QOS),and Module 3) can be found in the guidance for industry M4Q: The CTD — Quality. Guidance on the Safety section of the CTD (Module 2, the Nonclinical Overview and theNonclinical Written and Tabulated Summaries, and Module 4) can be found in the guidancefor industry M4S: The CTD — Safety Guidance on the Efficacy section of the CTD (Module 2, the Clinical Overview and theClinical Summary, and Module 5) can be found in the guidance for industry M4E: TheCTD — Efficacy. Numbering
In the guidances for industry on the Quality, Safety, and Efficacy sections of the CTD, Arabicnumbers have been assigned to designate those specific sections that should be included in theCTD. The Arabic numbers used in the guidances also should be used when assembling the CTDfor submission. For specific information on numbering the pages and volumes of the submission,see the guidance for industry, General Considerations for Submitting Marketing ApplicationsAccording to the ICH/CTD Format. Sections in the guidance documents that are not numberedprovide guidance on how to prepare those sections. In this guidance for industry, sections thatshould be included in Module 2 and Module 5 of the CTD have been numbered using the Arabicnumbers 2 and 5, respectively.
It is possible that information for more than one indication will be submitted. In such cases, pleasecontinue the use of Arabic numbers by repeating the specific section’s numbering, making it clearthat the data are for an additional indication. For example, if more than one indication issubmitted, repeat section 2.7.3, including the name of the indication(e.g., 2.7.3 pneumonia, 2.7.3 URI). The same approach should be used in the Quality section of theapplication for additional drug substances (2.3.S) and drug products (2.3.P).
The Clinical Overview is intended to provide a critical analysis of the clinical data in theCommon Technical Document (CTD). The Clinical Overview will refer to application dataprovided in the comprehensive Clinical Summary, the individual clinical study reports (ICH E3),and other relevant reports; but it should primarily present the conclusions and implications of thosedata and should not recapitulate them. Specifically, the Clinical Summary should provide adetailed factual summarization of the clinical information in the CTD, and the Clinical Overviewshould provide a succinct discussion and interpretation of these findings together with any otherrelevant information (e.g., pertinent animal data or product quality issues that may have clinicalimplications).
The Clinical Overview is primarily intended for use by regulatory agencies in the review of theclinical section of a marketing application. It should also be a useful reference to the overallclinical findings for regulatory agency staff involved in the review of other sections of themarketing application. The Clinical Overview should (1) present the strengths and limitations ofthe development program and study results, (2) analyze the benefits and risks of the medicinalproduct in its intended use, and (3) describe how the study results support critical parts of theprescribing information.
To achieve these objectives, the Clinical Overview should do the following.
• Describe and explain the overall approach to the clinical development of a medicinal product, including critical study design decisions • Assess the quality of the design and performance of the studies and include a statement regarding good clinical practice (GCP) compliance • Provide a brief overview of the clinical findings, including important limitations (e.g., lack of comparisons with an especially relevant active comparator; absence of information on somepatient populations, on pertinent endpoints, or on use in combination therapy) • Provide an evaluation of benefits and risks based on the conclusions of the relevant clinical studies, including interpretation of how the efficacy and safety findings support the proposeddose and target indication and an evaluation of how prescribing information and otherapproaches will optimize benefits and manage risks • Address particular efficacy or safety issues encountered in development and how they have • Explore unresolved issues, explain why they should not be considered barriers to approval, • Explain the basis for important or unusual aspects of the prescribing information The Clinical Overview should be a relatively short document (about 30 pages). The length,however, will depend on the complexity of the application. The use of graphs and concise tablesin the body of the text is encouraged for brevity and to facilitate understanding. It is not intendedthat material presented fully elsewhere be repeated in the Clinical Overview; cross-referencing tomore detailed presentations provided in the Clinical Summary or in Module 5 is encouraged.
Guidances Referenced
The following ICH guidances referenced in M4E – Efficacy are referred to by ICH topicdesignation in the text.
The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended forLong-Term Treatment of Non-Life-Threatening Conditions (March 1995) Clinical Safety Data Management: Definitions and Standards for Expedited Reporting(March 1995) Structure and Content of Clinical Study Reports (July 1996) Dose-Response Information to Support Drug Registration (November 1994) Ethnic Factors in the Acceptability of Foreign Clinical Data (June 1998) Studies in Support of Special Populations: Geriatrics (August 1994) Statistical Principles for Clinical Trials (September 1998) Choice of Control Group and Related Issues in Clinical Trials (May 2000) Clinical Investigation of Medicinal Products in the Pediatric Population (December2000) Table of Contents
We recommend that the Clinical Overview section contain a table of contents as shown here.
Detailed Discussion of Content of the Clinical Overview Sections

The discussion of the rationale for the development of the medicinal product should:• Identify the pharmacological class of the medicinal product • Describe the particular clinical/pathophysiological condition that the medicinal product is intended to treat, prevent, or diagnose (the targeted indication) • Briefly summarize the scientific background that supported the investigation of the medicinal product for the indications that were studied • Briefly describe the clinical development program of the medicinal product, including ongoing and planned clinical studies and the basis for the decision to submit the application at thispoint in the program. Briefly describe plans for the use of foreign clinical data (ICH E5).
• Note and explain concordance or lack of concordance with current standard research approaches regarding the design, conduct, and analysis of the studies. Pertinent publishedliterature should be referenced. Regulatory guidance and advice (at least from the region orregions where the Clinical Overview is being submitted) should be identified, with discussionof how that advice was implemented. Formal advice documents (e.g., official meetingminutes, official guidance, letters from regulatory authorities) should be referenced, withcopies included in the references section of Module 5.

The purpose of this section is to present a critical analysis of any important issues related tobioavailability that might affect efficacy and/or safety of the to-be-marketed formulations (e.g.,dosage form/strength proportionality, differences between the to-be-marketed formulation and theformulations used in clinical trials, and influence of food on exposure).
The purpose of this section is to present a critical analysis of the pharmacokinetic (PK),pharmacodynamic (PD), and related in vitro data in the CTD. The analysis should consider allrelevant data and explain why and how the data support the conclusions drawn. The analysisshould emphasize unusual results and known or potential problems, or note the lack thereof. Thissection should address: Pharmacokinetics (examples)
• Comparative PK in healthy subjects, patients, and special populations • PK related to intrinsic factors (e.g., age, sex, race, renal and hepatic impairment) and to extrinsic factors (e.g., smoking, concomitant drugs, diet) • Rate and extent of absorption; distribution, including binding with plasma proteins • Specific metabolic pathways, including effects of possible genetic polymorphism and the formation of active and inactive metabolites • Time-dependent changes in pharmacokinetics • Clinically relevant PK interactions with other medicinal products or other substances Pharmacodynamics (examples)
• Information on mechanism of action, such as receptor binding • Onset and/or offset of action; relationship of favorable and unfavorable pharmacodynamic effects to dose or plasma concentration (i.e., PK/PD relationships) • PD support for the proposed dose and dosing interval • Clinically relevant PD interactions with other medicinal products or substances • Possible genetic differences in response.
This section should also address interpretation of the results and implications of immunogenicitystudies, clinical microbiology studies, or other drug class specific PD studies summarized insection of the Clinical Summary.
The purpose of this section is to present a critical analysis of the clinical data pertinent to theefficacy of the medicinal product in the intended population. The analysis should consider allrelevant data, whether positive or negative, and should explain why and how the data support theproposed indication and prescribing information. Those studies deemed relevant for evaluation ofefficacy should be identified, and reasons that any apparently adequate and well-controlled studiesare not considered relevant should be provided. Prematurely terminated studies should be notedand their impact considered.
The following issues should generally be considered: • Relevant features of the patient populations, including demographic features, disease stage, any other potentially important covariates, any important patient populations excluded from criticalstudies, and participation of children and elderly (ICH E11 and E7). Differences between thestudied populations and the population that would be expected to receive the medicinalproduct after marketing should be discussed.
• Implications of the study designs, including selection of patients, duration of studies and choice of endpoints and control groups. Particular attention should be given to endpoints for which there is limited experience. Use of surrogate endpoints should be justified. Validation of anyscales used should be discussed. • For noninferiority trials used to demonstrate efficacy, the evidence supporting a determination that the trial had assay sensitivity and justifying the choice of noninferiority margin (ICH E10) • Statistical methods and any issues that could affect the interpretation of the study results (e.g., important modifications to the study design, including endpoint assessments and plannedanalyses, as they were specified in the original protocol; support for any unplanned analyses;procedures for handling missing data; and corrections for multiple endpoints) • Similarities and differences in results among studies, or in different patient subgroups within studies, and their effect on the interpretation of the efficacy data • Observed relationships between efficacy, dose, and dosage regimen for each indication in both the overall population and in the different patient subgroups (ICH E4) • Support for the applicability to the new region of data generated in another region, where • For products intended for long-term use, efficacy findings pertinent to the maintenance of long- term efficacy and the establishment of long-term dosage. Development of tolerance should beconsidered.
• Data suggesting that treatment results can be improved through plasma concentration monitoring, if any, and documentation for an optimal plasma concentration range • The clinical relevance of the magnitude of the observed effects • If surrogate endpoints are relied on, the nature and magnitude of expected clinical benefit and • Efficacy in special populations. If efficacy is claimed with inadequate clinical data in the population, support should be provided for extrapolating efficacy from effects in the generalpopulation.
The purpose of this section is to provide a concise critical analysis of the safety data, noting howresults support and justify proposed prescribing information. A critical analysis of safety shouldconsider: • Adverse effects characteristic of the pharmacological class. Approaches taken to monitor for similar effects should be described.
• Special approaches to monitoring for particular adverse events (e.g., ophthalmic, QT interval • Relevant animal toxicology and product quality information. Findings that affect or could affect the evaluation of safety in clinical use should be considered.
• The nature of the patient population and the extent of exposure, both for test drug and control treatments. Limitations of the safety database (e.g., related to inclusion/exclusion criteria andstudy subject demographics) should be considered, and the implications of such limitationswith respect to predicting the safety of the product in the marketplace should be explicitlydiscussed.
• Common and nonserious adverse events, with reference to the tabular presentations of events with the test drug and with control agents in the Clinical Summary. The discussion should bebrief, focusing on events of relatively high frequency, those with an incidence higher thanplacebo, and those that are known to occur in active controls or other members of thetherapeutic class. Events that are substantially more or less common or problematic(considering the duration and degree of the observed events) with the test drug than with activecontrols are of particular interest.
• Serious adverse events (relevant tabulations should be cross-referenced from the Clinical Summary). This section should discuss the absolute number and frequency of serious adverseevents, including deaths, and other significant adverse events (e.g., events leading todiscontinuation or dose modification) and should discuss the results obtained for test drugversus control treatments. Any conclusions regarding causal relationship (or lack of this) tothe product should be provided. Laboratory findings reflecting actual or possible seriousmedical effects should be considered.
• Similarities and differences in results among studies and their effect on the interpretation of the • Any differences in rates of adverse events in population subgroups, such as those defined by demographic factors, weight, concomitant illness, concomitant therapy, or polymorphicmetabolism • Relation of adverse events to dose, dose regimen, and treatment duration • Methods to prevent, mitigate, or manage adverse events • Reactions due to overdose; the potential for dependence, rebound phenomena, and abuse, or • World-wide marketing experience. The following should be briefly discussed: — The extent of the world-wide experience — Any new or different safety issues identified — Any regulatory actions related to safety • Support for the applicability to the new region of data generated in another region, where 2.5.6 BENEFITS AND RISKS CONCLUSIONS
The purpose of this section is to integrate all of the conclusions reached in the previous sectionsabout the biopharmaceutics, clinical pharmacology, efficacy, and safety of the medicinal productand to provide an overall appraisal of the benefits and risks of its use in clinical practice. Also,implications of any deviations from regulatory advice or guidance and any important limitations ofthe available data should be discussed here. This assessment should address critical aspects ofthe proposed prescribing information. This section should also (1) consider the risks and benefitsof the medicinal product as they compare to available alternative treatments or to no treatment inillnesses where no treatment may be a medically acceptable option and (2) clarify the expectedplace of the medicinal product in the armamentarium of treatments for the proposed indication. Ifthere are risks to individuals other than those who will receive the drug, these risks should bediscussed (e.g., risks of emergence of drug-resistant bacterial strains with widespread use of anantibiotic for minor illnesses). The analyses provided in previous sections should not bereiterated here. This section often can be quite abbreviated when no special concerns have arisenand the drug is a member of a familiar pharmacological class.
This analysis of benefits and risks is generally expected to be very brief but it should identify themost important conclusions and issues concerning each of the following points: • The efficacy of the medicinal product for each proposed indication • Significant safety findings and any measures that may enhance safety • Dose-response and dose-toxicity relationships; optimal dose ranges and dosage regimens • Efficacy and safety in subpopulations (e.g., those defined by age, sex, ethnicity, organ function, disease severity, and genetic polymorphisms) • Data in children in different age groups, if applicable, and any plans for a development • Any risks to the patient of known and potential interactions, including food-drug and drug-drug interactions, and recommendations for product use • Any potential effect of the medicinal product that might affect ability to drive or operate heavy Examples of issues and concerns that could warrant a more detailed discussion of benefits andrisks might include: • The drug is for treatment of a nonfatal disease but has known or potential serious toxicity, such as a strong signal of carcinogenicity, teratogenicity, pro-arrhythmic potential (effect on QTinterval), or suggestion of hepatotoxicity.
• The proposed use is based on a surrogate endpoint and there is a well-documented important • Safe and/or effective use of the drug calls for potentially difficult selection or management approaches that involve special physician expertise or patient training.
A list of references used, stated in accordance with the International Committee of MedicalJournal Editors’ Uniform Requirements for Manuscripts Submitted to Biomedical Journals orthe system used in Chemical Abstracts, should be provided. Copies of all references cited in theClinical Overview should be provided in Section 5.4 of Module 5.
The Clinical Summary is intended to provide a detailed, factual summarization of all of theclinical information in the CTD. This includes information provided in ICH E3 clinical studyreports; information obtained from any meta-analyses or other cross-study analyses for which fullreports have been included in Module 5; and postmarketing data for products that have beenmarketed in other regions. The comparisons and analyses of results across studies provided in thisdocument should focus on factual observations. (In contrast, the CTD Clinical Overviewdocument should provide critical analysis of the clinical study program and its results, includingdiscussion and interpretation of the clinical findings and discussion of the place of the test drug inthe armamentarium.) The length of the Clinical Summary will vary substantially according to the information to beconveyed, but it is anticipated that (excluding attached tables) the length will usually range from 50to 400 pages.
Table of Contents
We recommend that the Clinical Summary section contain a table of contents as shown here.
2.7.1 SUMMARY OF BIOPHARMACEUTIC STUDIES AND ASSOCIATED ANALYTICAL METHODS2.7.1.1 Background and Overview2.7.1.2 Summary of Results of Individual Studies2.7.1.3 Comparison and Analyses of Results Across Studies SUMMARY OF CLINICAL PHARMACOLOGY STUDIES2.7.2.1 Background and Overview2.7.2.2 Summary of Results of Individual Studies2.7.2.3 Comparison and Analyses of Results Across Studies2.7.2.4 Special Studies SUMMARY OF CLINICAL EFFICACY2.7.3.1 Background and Overview2.7.3.2 Summary of Results of Individual Studies2.7.3.3 Comparison and Analyses of Results Across Studies2.7.3.4 Analysis of Clinical Information Relevant to Dosing Recommendations2.7.3.5 Persistence of Efficacy and/or Tolerance Effects SUMMARY OF CLINICAL SAFETY2.7.4.1 Exposure to the Drug2.7.4.2 Adverse Events2.7.4.3 Clinical Laboratory Evaluations2.7.4.4 Vital Signs, Physical Findings, and Other Observations Related to Safety2.7.4.5 Safety in Special Groups and Situations2.7.4.6 Postmarketing Data Detailed Guidance on Sections of the Clinical Summary
ANALYTICAL METHODS Background and Overview
This section should provide the reviewer with an overall view of the formulation developmentprocess, the in vitro and in vivo dosage form performance, and the general approach and rationaleused in developing the bioavailability (BA), comparative BA, bioequivalence (BE), and in vitrodissolution profile database. Reference should be made to any guidance or literature used inplanning and conducting the studies. This section should also provide the reviewer with anoverview of the analytical methods used, with emphasis on the performance characteristics ofassay validation (e.g., linearity range, sensitivity, specificity) and quality control (e.g., accuracyand precision). This section should not include detailed information about individual studies. Summary of Results of Individual Studies
A tabular listing of all biopharmaceutic studies should be provided (see the Section 2.7.1Appendix), together with narrative descriptions of relevant features and outcomes of each of theindividual studies that provided important in vitro or in vivo data and information relevant to BAand BE. The narrative descriptions should be brief (similar to an abstract for a journal article)and should describe critical design features and critical results. Similar studies may be describedtogether, noting the individual study results and any important differences among the studies. These narratives may be abstracted from the ICH E3 synopsis. References or electronic links tothe full report of each study should be included in the narratives. Comparison and Analyses of Results Across Studies
This section should provide a factual summary of all in vitro dissolution, BA, and comparative BAstudies carried out with the drug substance or drug product, with particular attention to differencesin results across studies. This overview should summarize the findings in text and tables (see theSection 2.7.1 Appendix) and should consider the following: • Evidence of the effects of formulation and manufacturing changes on in vitro dissolution and BA and conclusions regarding BE. When manufacturing or formulation changes are made forproducts containing complex drug substances (e.g., a protein), pharmacokinetic (PK) studiescomparing the product before and after the changes can be performed to ensure that the PKcharacteristics have not changed as a result of product changes. Although such studies aresometimes referred to as BE studies, they generally do not focus on assessing release of drugsubstance from drug product. Nonetheless, such studies should be reported in this section. Note also that PK studies alone may not be sufficient to ensure similarity between such drugproducts. In many situations, pharmacodynamic (PD) studies or clinical trials may berecommended. Additionally, depending on the circumstances, antigenicity data may also beneeded. Results of these other types of studies should be reported in the appropriate places inthe application.
• Evidence of the extent of food effects on BA and conclusions regarding BE with respect to meal type or timing of the meal (where appropriate) • Evidence of correlations between in vitro dissolution and BA, including the effects of pH on dissolution, and conclusions regarding dissolution specifications • Comparative bioavailability, including BE conclusions, for different dosage form strengths • Comparative BA of the clinical study formulations (for clinical studies providing substantial evidence of efficacy) and the formulations to be marketed • The source and magnitude of observed inter- and intrasubject variability for each formulation Appendix
Tables and figures should be embedded in the text when they enhance the readability of thedocument. Lengthy tables can be provided in the appendix at the end of the section. For purposesof simplicity, the tables mentioned there are provided at the end of the section on Module 2.
Tables and are examples of tabular formats for reporting information and resultsrelated to bioavailability and in vitro dissolution studies respectively. These examples displayresults as well as the type and design of the study. Tables prepared for reporting the results of BEstudies can also include the mean ratios (test/reference) for Cmax and AUC and their 90 percentconfidence interval or the currently recommended metrics for BE assessments.
These tables are not intended to be templates; they illustrate the type of information that should beconsidered by an applicant in designing the tables for biopharmaceutic studies. Applicants shouldalso decide whether information and results from these studies are best presented in tables, text, orfigures to aid clarity. If, for example, results are best presented in text and figures, tables can beused simply to list the studies.
This section should provide the reviewer with an overall view of the clinical pharmacologystudies. These studies should include clinical studies performed to evaluate humanpharmacokinetics (PK) and pharmacodynamics (PD) and in vitro studies performed with human cells, tissues, or related materials (human biomaterials) that are pertinent to PK processes. Forvaccine products, this section should provide the reviewer with immune response data that supportthe selection of dose, dosage schedule, and formulation of the final product. Where appropriate,relevant data that are summarized in Sections 2.7.1, 2.7.3, and 2.7.4 can also be referenced toprovide a comprehensive view of the approach and rationale for the development of thepharmacokinetic, pharmacodynamic, PK/PD, and human biomaterial database. This section shouldnot include detailed information about individual studies.
This section should begin with a brief overview of the human biomaterial studies that wereconducted and that were intended to help in the interpretation of PK or PD data. Studies ofpermeability (e.g., intestinal absorption, blood brain barrier passage), protein binding, hepaticmetabolism, and metabolic-based drug-drug interactions are particularly relevant. Thisinformation should be followed by a brief overview of the clinical studies that were carried out tocharacterize PK and PD of the medicinal product, including studies of PK/PD relationships inhealthy subjects and patients and relevant effects of intrinsic and extrinsic factors on PK andPK/PD relationships.4 Critical aspects of study design and data analysis should be noted (e.g., thechoice of the single or multiple doses used, the study population, choice of the intrinsic or extrinsicfactors that were studied, the choice of PD endpoints, and whether a traditional approach or apopulation approach was used to collect and analyze data to assess PK or PD). Summary of Results of Individual Studies
A tabular listing of all clinical pharmacology studies should generally be provided (see the section2 appendix), together with a narrative description of the relevant features and outcomes of each ofthe critical individual studies that provided in vitro or in vivo data and information relevant to PK,PD and PK/PD relationships. The narrative descriptions should be brief (similar to an abstract fora journal article) and should describe critical design features and critical results. Similar studiescan be described together, noting the individual study results and any important differences amongthe studies. References or electronic links to the full report of each study should be included in thenarratives.
Summaries of dose-response or concentration response (PK/PD) studies with pharmacodynamicendpoints should generally be included in this section. In some cases, however, when well-controlled dose-response PD or PK/PD studies provide important evidence of efficacy or safety,they should be placed in Section 2.7.3 or 2.7.4 as appropriate and referenced, but not summarized,here. Comparison and Analyses of Results Across Studies
This section should use the results of all in vitro human biomaterial studies and PK, PD, andPK/PD studies to characterize the PK, PD, and PK/PD relationships of the drug. Results related tothe inter- and intraindividual variability in these data and the intrinsic and extrinsic factors
4 In the ICH guidance E5 Ethnic Factors in the Acceptance of Foreign Data, factors that may result in different responses to a
drug in different populations are categorized as intrinsic ethnic factors or extrinsic ethnic factors. In this guidance, these
categories are referred to as intrinsic factors and extrinsic factors, respectively.
affecting these pharmacokinetic relationships should be discussed.
This section (typically with the use of text and tables) should provide a factual presentation of alldata across studies pertinent to the following: • In vitro drug metabolism and in vitro drug-drug interaction studies and their clinical • Human PK studies, including the best estimates of standard parameters and sources of variability. The focus should be on evidence supporting dose and dose individualization in thetarget patient population and in special populations (e.g., pediatric or geriatric patients,patients with renal or hepatic impairment).
• Comparison between single and repeat-dose PK • Population PK analyses, such as results based on sparse sampling across studies that address interindividual variations in the PK or PD of the active drug substances that may be due toextrinsic or intrinsic factors • Dose-response or concentration-response relationships. This discussion should highlight evidence to support the selection of dosages and dose intervals studied in the importantclinical trials. In addition, information that supports the dosage instructions in the proposedlabeling should be discussed in Section
• Major inconsistencies in the human biomaterial, PK, or PD database • PK studies that were performed to determine whether foreign clinical data could be extrapolated to the new region (see ICH E5). The result of the studies and analysis of thesimilarity of the PK data between regions or races should be summarized in this section. Studies that use PD biomarkers (but do not evaluate clinical efficacy) can also be summarizedhere. An independent subsection can be created to summarize these kinds of data. Special Studies
This section should include studies that provide special types of data relevant to specific types ofmedicinal products.5 For immunogenicity studies and other studies in which data may correlatewith PK, PD, safety, and/or efficacy data, explanations of such correlations should be summarizedhere. Any observed or potential effects on PK, PD, safety and/or efficacy should be considered inother appropriate sections of the Clinical Summary as well, with cross-referencing to this section.
Human studies that address a specific safety issue should not be reported here, but instead shouldbe reported in Section 2.7.4, Summary of Clinical Safety.
Example 1: Immunogenicity
5 The reports of these studies should be filed in Module 5, Section
For protein products and other products to which specific immunological reactions have beenmeasured, data regarding immunogenicity should be summarized in this section. For vaccines orother products intended to induce specific immune reactions, immunogenicity data should bedescribed in the efficacy section, 2.7.3. Assays used should be described briefly and informationabout their performance (e.g., sensitivity, specificity, reliability, validity) should be summarized;the location of detailed information in the application should be cross-referenced.
Data regarding the incidence, titre, timing of onset, and duration of antibody responses should besummarized for each type of antibody assay used (e.g., IgG by ELISA, neutralization). Relationships of antibody formation to underlying disease, concomitant medication, dose, duration,regimen, and formulation should be explored and summarized. For drugs intended to be given aschronic, continuous therapy, any data on the impact of interruptions of therapy on antigenicityshould be analyzed and summarized.
It is particularly important to summarize analyses of potential clinically relevant correlates ofimmunogenicity (e.g., to determine the extent to which the presence of antibodies of a particulartype or titer appears to correlate with alterations of PK, changes in PD, loss of efficacy, loss ofadverse event profile, or development of adverse events). Particular attention should be paid toevents that might be immunologically mediated (e.g., serum sickness) and events that might resultfrom binding of cross-reactive endogenous substances by antibodies to the administered drug.
Example 2: Clinical microbiology
For antimicrobial or antiviral medicinal products, in vitro studies to characterize the spectrum ofactivity are an important part of the program of studies relevant to clinical efficacy. Clinicalefficacy studies that include characterization of the susceptibility of the clinical isolates as a partof the efficacy determination should be included in Section 2.7.3, Summary of Clinical Efficacy.
However, studies that evaluate such findings as the pattern of in vitro susceptibility of strains ofbacteria from different parts of the world (not in the context of clinical efficacy study) would beincluded here. Appendix
Tables and figures should be embedded in the text of the appropriate sections when they enhancethe readability of the document. Lengthy tables can be provided in the appendix at the end of thesection.
Table is an example of a tabular format for reporting information and results related topharmacokinetic drug-drug interaction studies. Similar tables can be prepared for PK/PD studies,dose-response studies, studies of effects on human biomaterials, and population PK studies. Thistable is not intended to be a template; it illustrates the type of information that should beconsidered by sponsors in designing their own tables. Applicants should also decide whetherinformation and results from clinical pharmacology studies are best presented in tables, text, orfigures to aid clarity. If, for example, results are best presented in text and figures, the tables canbe used simply to list the studies. In designing tables for other types of clinical pharmacology studies, such as those listed below,applicants should consider including the following types of information. These examples are forillustrative purposes only, and the sponsor should decide which information to present.
Metabolism studies using human biomaterials: Biomaterials used (e.g., microsomes,
hepatocytes), probe drugs, enzymatic pathways and percentage of contribution, andrelevant kinetic parameters (e.g., Vmax, Km) • In vitro studies of drug-drug interactions using human biomaterials:
— For studies of other drugs inhibiting the new drug, the metabolites inhibited, enzymatic pathways affected, range of inhibitor concentrations used, IC50 and Kivalues and proposed mechanism of inhibition should be included. — For studies of the new drug inhibiting other drugs, the drugs and metabolites inhibited should be included, along with the information mentioned above.
Population PK studies: Covariates studied, number and type of subjects or patients
studied, summary statistical parameters, and final estimates of mean (± standarddeviation) PK parameters SUMMARY OF CLINICAL EFFICACY
A separate Section 2.7.3 should be provided for each indication, although closely relatedindications can be considered together. When more than one Section 2.7.3 is submitted, thesections should be labeled by indication (e.g., 2.7.3 pneumonia, 2.7.3 URI). Background and Overview of Clinical Efficacy
This section should describe the program of controlled studies and other pertinent studies in theapplication that evaluated efficacy specific to the indications sought. Any results of these studiesthat are pertinent to evaluation of safety should be discussed in Section 2.7.4, Summary of ClinicalSafety.
The section should begin with a brief overview of the design of the controlled studies that wereconducted to evaluate efficacy. These studies include dose-response, comparative efficacy, long-term efficacy, and efficacy studies in population subsets. Critical features of study design shouldbe discussed (e.g., randomization, blinding, choices of control treatment, choice of patientpopulation, unusual design features such as crossover or randomized withdrawal designs, use ofrun-in periods, other methods of enrichment, study endpoints, study duration, and prespecifiedplans for analysis of the study results). Although this section is intended to focus on clinicalinvestigations, nonclinical data and clinical pharmacology data can also be referenced asappropriate to provide a comprehensive summary of human experience related to efficacy. Thissection should not include detailed information about individual studies. Summary of Results of Individual Studies
A tabular listing of all studies that provided (or were designed to provide) information relevant toproduct efficacy should generally be included (see the Section 2.7.3 Appendix), together withnarrative descriptions for important studies. The narrative descriptions should be brief (similar toan abstract for a journal article) and should describe critical design features and critical results. Similar studies can be described together, noting the individual study results and any importantdifferences among the studies. For studies that also contributed significantly to the safety analysis,study narratives should include information about the extent of exposure of study subjects to thetest drug or control agent and how safety data were collected. These narratives can be abstractedfrom the synopses of the clinical study reports (ICH E3). References or electronic links to the fullreport of each study should be included in the narratives.
Narratives of any bridging studies using clinical endpoints (i.e., certain studies intended toevaluate the ability to extrapolate certain types of foreign clinical data to the new region (see ICHE5)) should be included in this section. An analysis of the results of such studies, together withother information (e.g., PK and PD data) that addresses the ability to extrapolate the efficacy andsafety results of foreign studies, should be performed if appropriate. The conclusions of such ananalysis should be noted at the start of Section, Comparison of Efficacy Results of AllStudies, and the full report of the analysis should be provided in Module 5. Comparison and Analyses of Results Across Studies
Using text, figures, and tables as appropriate (see the Section 2.7.3 Appendix), the subsections of2.7.3.3 should summarize all available data that characterize the efficacy of the drug. Thissummary should include analyses of all data, irrespective of their support for the overallconclusion and should, therefore, discuss the extent to which the results of the relevant studies door do not reinforce each other. Any major inconsistencies in the data regarding efficacy should beaddressed, and any areas needing further exploration should be identified.
The section will generally use two kinds of analyses: comparison of results of individual studiesand analysis of data combined from various studies. Details of analyses that are too extensive tobe reported in a summary document should be presented in a separate report placed in Module 5,Section
This section should also cross-reference important evidence from Section 2.7.2, such as data thatsupport the dosage and administration section of the labeling. These data include dosage and doseinterval recommended, evidence pertinent to individualization of dosage and need formodifications of dosage for specific subgroups (e.g., pediatric or geriatric subjects, subjects withhepatic or renal impairment), and data relevant to dose-response or concentration response(PK/PD) relationships.
The demographic and other baseline characteristics of patients across all efficacy studies shouldbe described. The following information should be included.
• The characteristics of the disease (e.g., severity, duration), prior treatment in the study subjects, and study inclusion/exclusion criteria • Differences in baseline characteristics of the study populations in different studies or groups of • Any differences between populations included in critical efficacy analyses and the overall patient population that would be expected to receive the drug when it is marketed should benoted.
• Assessment of the number of patients who dropped out of the studies, time of withdrawal (a defined study day or visit during treatment or follow up period), and reasons fordiscontinuation Tabular presentations that combine and compare study populations across studies may be useful. Comparison of Efficacy Results of all Studies The results of any bridging studies using clinical endpoints (i.e., certain studies used to evaluatethe ability to extrapolate certain types of foreign clinical data to the new region (see ICH E5))should be summarized in this section. An analysis of the similarity of efficacy in subjects betweenregions, as well as any other information that may support extrapolation of the efficacy data to thenew region, should be summarized here. An independent subsection can be created to summarizethese kinds of data.
The results from all studies designed to evaluate the drug’s efficacy should be summarized andcompared, including studies with inconclusive or negative results. Important differences in studydesign (such as endpoints, control group, study duration, statistical methods, patient population,and dose) should be identified.
Comparisons of results across studies should focus on prespecified primary endpoints. However,when the primary endpoints involved different variables or time points in different efficacystudies, it can be useful to provide cross-study comparisons of important data elements that wereobtained in all studies. If results over time are important, results of studies can be displayed in afigure that illustrates the change over time in each study. Confidence intervals for treatment effects should be given to aid the interpretation of pointestimates. If differences are shown between placebo and test drugs in the change from baseline,the baseline values and the magnitude of effect in all treatment groups, including placebo andactive controls (if used), should generally be presented in the table or in text accompanying afigure. If the objective of an active control trial was to show equivalence or noninferiority, thedifference or the ratio of outcomes between treatments should be given with the confidenceinterval. The results should be evaluated by using the predefined criteria for defining equivalenceor noninferiority and the rationale for the criteria, and support for the determination that the study(studies) had assay sensitivity should be provided (see ICH E10).
Important differences in outcomes between studies with a similar design should be delineated anddiscussed. Cross-study comparisons of factors that may have contributed to differences inoutcomes should be described.
If a meta-analysis of the clinical studies is performed, it should be clear whether this analysis isconducted according to a predefined protocol or is a post hoc exercise. Any differences in trialdesigns or populations, or in efficacy measurements between trials, should be described to allowassessment of the relevance and validity of the results and conclusions (see ICH E9). A detaileddescription of the methodology and results of the meta-analysis should generally be submitted in aseparate report (Section of Module 5). Comparison of Results in Subpopulations The results of individual studies or overview analyses of efficacy in specific populations shouldbe summarized in this section. The purpose of these comparisons should be to show whether theclaimed treatment effects are observed consistently across all relevant subpopulations, especiallythose where there are special reasons for concern. The comparisons can highlight apparentvariations in efficacy that call for further investigation and discussion. The limitations of suchanalyses, however, should be recognized (ICH E9), and it is important to note that their purpose isnot to provide the basis for specific claims or to attempt to improve the evidence of efficacy insituations where the overall results are disappointing.
Given the limited sample sizes in individual studies, analyses across multiple studies should beperformed to evaluate effects of major demographic factors (age, sex, and race) and of otherpredefined or relevant intrinsic and extrinsic factors (e.g., disease severity, prior treatment,concomitant illness, concomitant drugs, alcohol, tobacco, and body weight) on efficacy. Factors ofspecial interest may arise from general concerns (e.g., the elderly) or from specific issues that arerelated to the pharmacology of the drug or that have arisen during earlier drug development.
Efficacy in the pediatric population should be routinely analyzed in applications for a proposedindication that occurs in children. Depending on the size of the data set, if extensive, detailedefficacy analyses are performed, they can be placed in Module 5, with the results of those analysesreported here. Analysis of Clinical Information Relevant to Dosing Recommendations
This section should provide an integrated summary and analysis of all data that pertain to the dose-response or blood level-response relationships of effectiveness (including dose-blood levelrelationships) and thus have contributed to dose selection and choice of dose interval. Relevantdata from nonclinical studies can be referenced, and relevant data from pharmacokinetic studies,other clinical pharmacology studies, and controlled and uncontrolled clinical studies should besummarized to illustrate these dose-response or blood level-response relationships. Forpharmacokinetic and pharmacodynamic studies from which data have been summarized in Section2.7.2.2, it may be appropriate to draw on those data in this summary while cross-referencing thesummaries in Section, without repeating those summaries.
While the interpretation of how these data support specific dosing recommendations should besupplied in the Clinical Overview, the individual study results and any cross-study analyses thatwill be used to support the dosing recommendations (including the recommended starting andmaximal doses, the method of dose titration, and any other instructions regarding individualizationof dosage) should be summarized here. Any identified deviations from relatively simple dose-response or blood level-response relationships due to nonlinearity of pharmacokinetics, delayedeffects, tolerance, or enzyme induction should be described.
Any evidence of differences in dose-response relationships that result from a patient’s age, sex,race, disease, or other factors should be described. Any evidence of different pharmacokinetic orpharmacodynamic responses should also be discussed, or discussions in Section 2.7.2 can becross-referenced. The ways in which such differences were looked for, even if no differenceswere found, should be described (e.g., specific studies in subpopulations, analysis of efficacyresults by subgroup, or blood level determinations of the test drug). Persistence of Efficacy and/or Tolerance Effects
Available information on persistence of efficacy over time should be summarized. The number ofpatients for whom long-term efficacy data are available, and the length of exposure, should beprovided. 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 efficacymay be useful.
The primary focus should be on controlled studies specifically designed to collect long-termefficacy data, and such studies should be clearly differentiated from other, less rigorous studies,such as open extension studies. This distinction also applies to specific studies designed forevaluation of tolerance and withdrawal effects. Data concerning withdrawal or rebound effectspertinent to product safety should be presented in the safety section (see Section 2.7.4).
In long-term efficacy trials, the effect of premature discontinuation of therapy or switching to othertherapies on the assessment of the results should be considered. These issues can also beimportant for short-term trials and should be addressed when discussing the results of these trials,if appropriate. Appendix
Tables and figures should be embedded in the text when they enhance the readability of thedocument. Lengthy tables can be provided in the appendix at the end of the section.
Tables should identify all studies pertinent to the evaluation of efficacy (including studies thatwere terminated or are not yet completed, studies that failed to show effectiveness for any reason,studies available only as publications, studies reported in full technical reports (ICH E3), andstudies described in abbreviated reports) and should provide the most important results of thosestudies. Note, however, that unplanned interim analyses on ongoing studies are generally notneeded or encouraged. When more than one Section 2.7.3 is provided for an application withmore than one indication, usually each section should have its own appendix with tables.
Illustrative tables for an antihypertensive drug are provided, but these examples will not berelevant to every application. In general, applications should contain tables and/or figures that aredeveloped specifically for the particular drug class and the studies that were carried out.
Table Description of Clinical Efficacy and Safety Studies Table Results of Efficacy Studies SUMMARY OF CLINICAL SAFETY
This section should be a summary of data relevant to safety in the intended patient population,integrating the results of individual clinical study reports as well as other relevant reports (e.g., theintegrated analyses of safety that are routinely submitted in some regions).
The display of safety-related data can be considered at three levels (ICH E3): • The extent of exposure (dose, duration, number of patients, type of patients) should be examined to determine the degree to which safety can be assessed from the database.
• The more common adverse events and changes in laboratory tests should be identified and classified, and their occurrence should be summarized.
• Serious adverse events (defined in ICH E2A) and other significant adverse events (defined in ICH E3) should be identified, and their occurrence should be summarized. These events shouldbe examined for frequency over time, particularly for drugs that may be used chronically.
The safety profile of the drug, described on the basis of analysis of all clinical safety data, shouldbe outlined in a detailed, clear, and objective manner, with use of tables and figures. Exposure to the Drug Overall Safety Evaluation Plan and Narratives of Safety Studies The overall safety evaluation plan should be described briefly, including special considerationsand observations concerning the nonclinical data, any relevant pharmacological class effects, andthe sources of the safety data (controlled trials, open studies). A tabular listing of all clinicalstudies that provided safety data, grouped appropriately, should generally be provided (see theSection 2.7.4 Appendix). In addition to studies that evaluated efficacy and safety and uncontrolledstudies that generated safety information, this section includes studies that consider special safetyissues. Examples include studies to compare particular adverse event rates for two therapies, toassess safety in particular demographic subsets, to evaluate withdrawal or rebound phenomena, orto evaluate particular adverse events (e.g., sedation, sexual function, effects on driving, absence ofa class adverse effect). Studies in indications for which approval is not being sought in the currentapplication and ongoing studies would also be included here if they contribute to the safetyanalysis.
Narrative descriptions of these studies should be provided here, except that narrative descriptionsfor studies that contributed both efficacy and safety data should be included in Section andcross-referenced here. The narratives should provide enough detail to allow the reviewer tounderstand the exposure of study subjects to the test drug or control agent and how safety data werecollected (including the methods used and the extent of safety monitoring of the subjects enrolled inthe individual studies). If some studies are not analyzed separately but are grouped for safetyanalysis, that should be noted, and a single narrative description can be provided. Overall Extent of Exposure A table (see example provided in the Section 2.7.4 Appendix) and appropriate text should begenerated to summarize the overall extent of drug exposure from all phases of the clinical studydevelopment program. The table should indicate the numbers of subjects exposed in studies ofdifferent types and at various doses, routes, and durations. If a large number of different dosesand/or durations of exposure were used, these can be grouped in a manner appropriate for thedrug. Thus, for any dose or range of doses, duration of exposure can be summarized by the numberof subjects exposed for specific periods of time, such as 1 day or less, 2 days to 1 week, 1 week to1 month, 1 month to 6 months, 6 months to 1 year, more than 1 year (ICH E3). In someapplications it may be important to identify diagnostic subgroups and/or groups receiving specificconcomitant therapies deemed particularly relevant to safety assessment in the intended use.
The dose levels used for each subject in this presentation could be the maximum dose received bythat subject, the dose with longest exposure, and/or the mean daily dose, as appropriate. In somecases, cumulative dose can be pertinent. Dosage can be given as the actual daily dose or on amg/kg or mg/m2 basis, as appropriate. If available, drug concentration data (e.g., concentration atthe time of an adverse event, maximum plasma concentration, area under curve) in individualsubjects may be helpful for correlation with adverse events or changes in laboratory variables.
It is assumed that all subjects who were enrolled and received at least one dose of the treatmentare included in the safety analysis; if that is not so, an explanation should be provided.
Demographic and Other Characteristics of Study Population A summary table should provide the reader with an overview of the demographic characteristics(Table of the population that was exposed to the therapeutic agent during its development.
Choice of age ranges used should take into account considerations discussed in ICH E7 and E11. If the relative exposure of demographic groups in the controlled trials differed from overallexposure, it may be useful to provide separate tables.
In addition, one or more tables should show the relevant characteristics of the study population andthe numbers of subjects with special characteristics. Such characteristics could include • Concomitant use of particular medications If these characteristics are distributed differently in controlled trials versus the overall database, itis generally be useful to present tables on both groupings.
The text accompanying the tables should mention any imbalances between the drug and placeboand/or comparator regarding any of the above demographic characteristics, particularly if theimbalances could lead to differences in safety outcomes.
If certain subjects were excluded from studies (concomitant illness, severity of illness,concomitant medications), this fact should be noted.
Separate demographic tables should be provided for every indication, although closely relatedindications can be considered together if study subject characteristics are such that risks arebelieved to be the same. Adverse Events Analysis of Adverse Events Data on the frequency of adverse events should be described in text and tables. Text shouldappear in the appropriate subsections of Section, and the tables that are not embedded inthe text should be placed in the Section 2.7.4 Appendix.
All adverse events occurring or worsening after treatment has begun ("treatment emergent signsand symptoms," those adverse events not seen at baseline and those that worsened even if presentat baseline) should be summarized in tables. Tables should contain a listing of each event, thenumber of subjects in whom the event occurred, and the frequency of occurrence in subjects treatedwith the drug under investigation, with comparator drugs, and with placebo. Such tables couldalso present results for each dose and could be modified to show adverse event rates by severity,by time from onset of therapy, or by assessment of causality.
When most of the relevant safety data are derived from a small number of studies (e.g., one or twostudies) or when very different study subject populations were enrolled in the studies that wereperformed, presentation of data by study is often appropriate. When the relevant exposure data arenot concentrated in a small number of studies, however, grouping the studies and pooling theresults to improve precision of estimates and sensitivity to differences should generally beconsidered.
While often useful, pooling of safety data across studies should be approached with cautionbecause in some cases interpretation can be difficult, and pooling can obscure real differences. Incases where differences are apparent, it is more appropriate to present the data by study. Thefollowing issues should be considered: • It is most appropriate to combine data from studies that are of similar design (e.g., similar in dose, duration, methods of determining adverse events, and population).
• If the incidence for a particular adverse event differs substantially across the individual studies in a pool, the pooled estimate is less informative.
• Any study with an unusual adverse event pattern should be presented separately.
• The appropriate extent of analysis depends on the seriousness of the adverse event and the strength of evidence of drug causation. Differences in rates of drug-related, serious events orevents leading to discontinuation or dosage change deserve more investigation, whereas ratesof other adverse events do not merit elaborate analysis.
• Examination of which subjects experience extreme laboratory value abnormalities (outliers)
can be useful in identifying subgroups of individuals who are at particular risk for certainadverse events.
Groups of studies that could be used in pooled safety analyses include the following.
• All controlled studies or subsets of controlled studies, such as all placebo-controlled studies, studies with any positive control, studies with a particular positive control, or studies ofparticular indications (and thus carried out in different populations). These groupings areconsidered the best source of information about the more common adverse events and candistinguish drug-related events from spontaneous events. Rates in control and treatment groupsshould be compared.
• All studies, excluding short-term studies in healthy subjects. This grouping is most useful for • All studies using a particular dose route or regimen, or a particular concomitant therapy • Studies in which adverse event reports are elicited by checklist or direct questioning, or It is almost always useful to carry out the first two groupings; the others chosen would vary fromdrug to drug and should be influenced by inspection of individual study results. Whatever methodsare used, it should be recognized that, as for results of single studies, any numerical rate is oftenonly a rough approximation of reality.
When a decision is made to pool data from several studies, the rationale for selecting the methodused for pooling should be described. It is common to combine the numerator events and thedenominators for the selected studies. Other methods for pooling results across studies are available (e.g., weighting data from studies on the basis of study size or inversely to theirvariance).
If substantial differences are seen between clinical trials in the rates of adverse events, thesedifferences should be noted and possible reasons for the difference should be discussed (e.g.,relevant differences in study populations, in dose administration, or in methods of collectingadverse event data).
Adverse events should be described as shown in the individual study report (ICH E3). Incombining data from many studies, it is important to use standardized terms to describe events andcollect synonymous terms under a single preferred term. This can be done with a standarddictionary, and the Medical Dictionary for Regulatory Activities (MedDRA) terminology (ICHM1) should be used. Until MedDRA can be fully implemented, other dictionaries can be used, butshould be specified. Frequencies should be presented for preferred terms and for appropriatelydefined groupings. Examination of which adverse events led to change in therapy (discontinuationof drug use, change in dose, need for added therapy) can help in assessing the clinical importanceof adverse events. These rates can be added to the adverse event rate tables or can be presented inseparate tables. Overall discontinuation rates by study can be useful, but it is also important tospecify the particular adverse events leading to discontinuation in a separate table. The preferredterms should be grouped by body system and arranged by decreasing frequency. Tabular displays of adverse event rates (see the Section 2.7.4 Appendix) should be used tocompare rates in treatment and control groups. For this analysis, it may be helpful to combine theevent severity categories and the causality categories, if they are used, leading to a simpler side-by-side comparison of treatment groups. It should be noted that while causality categories can bereported if used, the presentation of the data should include all of the adverse events that occurred(whether deemed related or unrelated to treatment). Evaluations of causality are inherentlysubjective and may exclude unexpected adverse events that are in fact treatment related. Additionally, comparisons of rates of adverse events between treatment and control groups inindividual trials should be summarized here. It is often useful to tabulate rates in selected trials(see example table, in the Section 2.7.4 Appendix).
It is usually useful to examine more closely the more common adverse events that seem to be drugrelated (e.g., those that show that a dose response and/or a clear difference between drug andplacebo rates) for relationship to relevant factors, including the following.
• demographic characteristics such as age, sex, race • other baseline features such as renal status It may also be useful to summarize the results of examination of time of onset and duration for thesedrug-related events.
Rigorous statistical evaluations of the possible relationship of specific adverse events to each ofthe above factors are often unnecessary. It may be apparent from initial display and inspection ofthe data that there is no evidence of a significant relationship to demographic or other baselinefeatures. In that case, no further analysis of these particular factors is needed. Furthermore, it isnot necessary that all such analyses be presented in this report. When the safety analyses are tooextensive to be presented in detail in this report, they may be presented in a separate report inModule 5, Section, and summarized here.
Under certain circumstances, life table or similar analyses may be more informative than reportingof crude adverse event rates.
A table in the Section 2.7.4 Appendix should list all deaths occurring while on study. The listshould also include deaths that occurred shortly after treatment termination (e.g., within 30 days oras specified in the study protocol) as well as all other deaths that occurred later but may haveresulted from a process that began during studies. Only deaths that are clearly disease related perprotocol definitions and not related to the investigational product, either in studies of conditionswith high mortality such as advanced cancer or in studies where mortality from disease is aprimary study endpoint, should be excepted from this listing. (It is assumed, however, that thesedeaths would still be reported in the individual ICH E3 study reports.) Even these deaths shouldbe examined for any unexpected patterns between study arms and further analyzed if unexplaineddifferences are observed. Deaths should be examined individually and analyzed on the basis ofrates in individual trials and appropriate pools of trials, considering both total mortality andcause-specific deaths. Potential relationships to the factors listed in Section shouldalso be considered. Although cause-specific mortality can be difficult to determine, some deathsare relatively easy to interpret. Thus deaths due to causes expected in the patient population (heartattacks and sudden death in an angina population) are individually not considered to beinformative, but even one death due to a QT interval prolongation-associated arrhythmia, aplasticanemia, or liver injury may be informative. Special caution is appropriate before an unusual deathis attributed to concomitant illness.
Summaries of all serious adverse events (other than death but including the serious adverse eventstemporally associated with or preceding the deaths) should be displayed. Serious adverse eventsthat occurred after the drug use was discontinued should be included in this section. The displayshould include major laboratory abnormalities, abnormal vital signs, and abnormal physicalobservations that are considered serious adverse events using the ICH E2A definitions. Results ofanalyses or assessments of serious adverse events across studies should be presented. Seriousevents should be examined for frequency over time, particularly for drugs that may be used chronically. Potential relationships to the factors listed in Section should also beconsidered. Other Significant Adverse Events Marked hematologic and other laboratory abnormalities (other than those meeting the definition ofserious) and any events that led to a substantial intervention (premature discontinuation of studydrug, dose reduction, or substantial additional concomitant therapy), other than those reported asserious adverse events, should be displayed.
Events that led to premature discontinuation of study drug represent an important safety concernand deserve particular attention in the analysis of drug safety for two reasons. First, even forexpected events (based on pharmacologic activity), the discontinuation or alteration of treatmentreflects the severity and perceived importance of the event to patient and physician. Second,discontinuation may represent a drug-related event not yet recognized as drug related. Adverseevents leading to treatment discontinuation should be considered possibly drug-related even if thiswas not recognized initially and even if the event was thought to represent intercurrent illness. Reasons for premature treatment discontinuations should be discussed and rates ofdiscontinuations should be compared across studies and compared with rates of discontinuationsfor placebo and/or active control treatment. In addition, the study data should be examined for anypotential relationships to the factors listed in Section Analysis of Adverse Events by Organ System or Syndrome Assessment of the causality of, and risk factors for, deaths, other serious events, and othersignificant events is often complicated by the fact that these events are uncommon. As a result,consideration of related events as a group, including less important events of potentially relatedpathophysiology, can be of critical value in understanding the safety profile. For example, therelationship to treatment of an isolated sudden death can become much clearer when considered inthe context of cases of syncope, palpitations, and asymptomatic arrhythmias.
Thus it is generally useful to summarize adverse events by organ system so that they can be
considered in the context of potentially related events including laboratory abnormalities. Such
presentations of adverse events by organ system should be placed in subsections of Section, labeled,, and titled by the organ system under
consideration. The list of organ systems to be addressed and the approach to grouping certain
events should be selected as appropriate to best present the adverse event data for the medicinal
product. If some adverse events tend to occur in syndromes (e.g., influenza-like syndrome,
cytokine release syndrome), the sponsor may choose to create some subsections of for
syndromes rather than organ systems.
The same data and summarizations should generally not be repeated in more than one subsection ofSection Instead, a summary presentation can be placed in one subsection and cross-referenced as appropriate in others.
The locations in the application of individual narratives of patient deaths, other serious adverseevents, and other significant adverse events deemed to be of special interest because of clinicalimportance (as described in ICH E3 individual study reports) should be referenced here for theconvenience of the reviewer. The narratives themselves should be a part of the individual studyreports, if there is such a report. In cases where there is no individual study report (e.g., if manyopen studies are pooled as part of a safety analysis and are not individually described), narrativescan be placed in Module 5, Section Narratives should not be included here unless anabbreviated narrative of particular events is considered critical to the summary assessment of thedrug. Clinical Laboratory Evaluations
This section should describe changes in patterns of laboratory tests with drug use. Markedlaboratory abnormalities and those that led to a substantial intervention should be reported inSection or If these data are also presented in this section, this duplicatereporting should be made clear for the reviewer. The appropriate evaluations of laboratory valueswill in part be determined by the results seen, but, in general, the analyses described below shouldbe provided. For each analysis, comparison of the treatment and control groups should be carriedout as appropriate and should be compatible with study sizes. In addition, normal laboratoryranges should be given for each analysis (ICH E3). Where possible, laboratory values should beprovided in standard international units.
A brief overview of the major changes in laboratory values across clinical studies should beprovided. Laboratory data should include hematology, clinical chemistry, urinalysis, and otherdata as appropriate. Each parameter at each time over the course of the study (e.g., at each visit)should be described at the following three levels: • The central tendency (i.e., the group mean and median values) • The range of values and the number of subjects with abnormal values or with abnormal values of a certain size (e.g., twice the upper limit of normal, five times the upper limit; choicesshould be explained). When data are pooled from centers with differences in normallaboratory ranges, the methodology used in pooling should be described. The analysis ofindividual subject changes by treatment group can be shown with a variety of approaches (e.g.,shift tables, see ICH E3 for examples). • Individual clinically important abnormalities, including those leading to discontinuations. The significance of laboratory changes and the likely relation to the treatment should be assessed(e.g., by analysis of such features as relationship to dose, relationship to drug concentration,disappearance on continued therapy, positive dechallenge, positive rechallenge, and the natureof concomitant therapy). Potential relationships to other factors listed in Section also be considered. Vital Signs, Physical Findings, and Other Observations Related to Safety
The manner of presenting cross-study observations and comparisons of vital signs (e.g., heart rate,blood pressure, temperature, respiratory rate), weight, and other data (e.g., electrocardiograms, X-rays) related to safety should be similar to that for laboratory variables. If there is evidence of adrug effect, any dose-response or drug concentration-response relationship or relationship toindividual variables (e.g., disease, demographics, concomitant therapy) should be identified andthe clinical relevance of the observation described. Particular attention should be given tochanges not evaluated as efficacy variables and to those considered to be adverse events. Particular attention should be given to studies that were designed to evaluate specific safety issues(e.g., studies of QT interval prolongation). Safety in Special Groups and Situations
This section should summarize safety data pertinent to individualizing therapy or patient
management on the basis of demographic and other factors defined as intrinsic ethnic factors in
ICH E5. These factors include age, sex, height, weight, lean body mass, genetic polymorphism,
body composition, other illness, and organ dysfunction. Safety in the pediatric population should
be routinely analyzed in applications for a proposed indication that occurs in children. Analysis of
the impact of such factors on safety outcomes should have been presented in other sections but
should be summarized here, together with pertinent PK or other information (e.g., in patients with
renal or hepatic disease). If a sufficiently large number of subjects with a given co-morbid
condition (such as hypertension, heart disease, or diabetes) was enrolled, analyses should be
carried out to assess whether the co-morbid condition affected the safety of the drug under study.
Cross-reference should be made to the tables or description of adverse events when analyses of
such subgroups have been carried out.
This section should summarize safety data pertinent to individualizing therapy or patient
management on the basis of factors defined as extrinsic ethnic factors in ICH E5. These are
factors associated with the patient environment. Examples are the medical environment, use of
other drugs (see Section, Drug Interactions), use of tobacco, use of alcohol, and food
For example, if a potential interaction with alcohol is suggested by the metabolic profile, by theresults of studies, by postmarketing experience, or by information on similar drugs, informationshould be provided here.
Studies on potential drug-drug or drug-food interactions should be summarized in the Summary ofClinical Pharmacology Studies section of the CTD (Section 2.7.2). The potential impact on safetyof such interactions should be summarized here, based on PK, PD, or clinical observations. Any observed changes in the adverse event profile, changes in blood levels thought to be associatedwith risk, or changes in drug effects associated with other therapy should be presented here. Use in Pregnancy and Lactation Any information on safety of use during pregnancy or breast-feeding that becomes available duringclinical development or from other sources should be summarized here.
All available clinical information relevant to overdose, including signs and/or symptoms,laboratory findings, and therapeutic measures and/or treatments and antidotes (if available), shouldbe summarized and discussed. Information on the efficacy of specific antidotes and dialysisshould be provided if available.
Any relevant studies and information regarding the investigation of the dependence potential of anew therapeutic agent in animals and in humans should be summarized and cross-referenced to thenonclinical summary. Particularly susceptible patient populations should be identified.
Any information or study results pertinent to rebound effects should be summarized. Events thatoccur, or increase in severity, after discontinuation of double-blind or active study medicationshould be examined to see if they are the result of withdrawal of the study medication. Particularemphasis should be given to studies designed to evaluate withdrawal and/or rebound.
Data concerning tolerance should be summarized under Section in the Summary of ClinicalEfficacy. Effects on Ability to Drive or Operate Machinery or Impairment of Mental Safety data related to any impairment in the senses or coordination or any other factor that wouldresult in diminished ability to drive a vehicle or operate machinery or that would impair mentalability should be summarized. This includes relevant adverse effects reported in safety monitoring(e.g., drowsiness) and specific studies concerning effects on ability to drive or operate machineryor impairment of mental ability. Postmarketing Data
If the drug has already been marketed, all relevant postmarketing data available to the applicant(published and unpublished, including periodic safety update reports if available) should besummarized. The periodic safety update reports can be included in Module 5. Details of the number of subjects estimated to have been exposed should be provided and categorized, asappropriate, by indication, dosage, route, treatment duration, and geographic location. Themethodology used to estimate the number of subjects exposed should be described. If estimates ofthe demographic details are available from any source, these should be provided.
A tabulation of serious events reported after the drug is marketed should be provided, includingany potentially serious drug interactions.
Any postmarketing findings in subgroups should be described. Appendix
Tabular presentations should be provided that summarize the important results from all studiespertinent to the evaluation of safety and particularly from those to support product labeling.
Tables and figures should be embedded in the text when they enhance the readability of thedocument. Lengthy tables can be provided in the appendix at the end of the section.
A few illustrative tables are provided, but a clinical summary will routinely need tables andfigures that have been developed for the particular drug, drug class, and clinical indications.
See Sections,, and of this guidance for additional discussion regardingthe content of section 4 tables.
Table Study Subject Drug Exposure by Mean Daily Dose and Duration of Exposure Table Demographic Profile of Patients in Controlled Trials Table Incidence of Adverse Events in Pooled Placebo and Active Controlled Trials Table Incidence of Adverse Events in the Largest Trials Table Patient Withdrawals by Study: Controlled Trials REFERENCES
A list of references cited in the Clinical Summary should be provided. Copies of all importantreferences should be provided in Module 5, Section 5.4. The reference list should indicate whichreferences are available in Module 5, Section 5.4. All references that have not been providedshould be available on request. SYNOPSES OF INDIVIDUAL STUDIES
ICH E3 suggests inclusion of a study synopsis with each clinical study report and provides oneexample of a format for such synopses.
This section should include the table entitled Listing of Clinical Studies, described in guidance forModule 5, followed by all individual study synopses organized in the same sequence as the studyreports in Module 5.
It is expected that one synopsis will be prepared per study for use in all regions and that the samesynopsis will be included in this section and as part of the clinical study report in Module 5. Thelength of a synopsis will usually be up to 3 pages, but a synopsis for a more complex and importantstudy may be longer (e.g., 10 pages). Within the individual synopsis, tables and figures should beused as appropriate to aid clarity.
Table Summary of Bioavailability Studies
Study Objective
Study Design
Mean Parameters (+/- SD)
Dosage Form,
Age: mean
[Product ID]
Table Summary of In Vitro Dissolution Studies
Product ID/Batch No.
Dosage Form
Collection times
Dosage Units
Mean % Dissolved (range)
Table Summary of Drug-Drug Interaction PK Studies
Study Design
# Subjects
Mean Pharmacokinetic Parameters (%CV) Substrate Drug
Mean ratio2
Protocol #
ID/Batch #
Confidence interval
leted (M/F)

2Value for substrate with interacting drug / value with placebo Table Description of Clinical Efficacy and Safety Studies
Number of
Study start
Study & Ctrl
# subjs by
Gender M/F
Primary Endpoint(s)
Study Centers
Control type

Source: http://www.medauthor.com/docs/CTD_EFFICACY.pdf


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Yorkshire and the Humber Specialised Commissionning Group Board Meeting - 24th September 2010 Decision Summary for PCT Boards 1. Policies: General Commissioning Policies for Medicines and Treatments The following four policies were approved for adoption by the SCG:- Imatinib for the adjuvant treatment of gastrointestinal stromal tumours - To be not routinely funde

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