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A Guide on the Preparation of a Common Technical Document

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GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28.

10. 2010 GUIDANCE FOR INDUSTRY ON PREPARATION OF COMMON TECHNICAL DOCUMENT FOR IMPORT / MANUFACTURE AND MARKETING APPROVAL OF NEW DRUGS FOR HUMAN USE (NEW DRUG APPLICATION – NDA) DRAFT GUIDANCE This guidance documents is for feedback purpose only Comments and suggestion on this document should be submitted within 60 days of publication to CDSCO, FDA Bhavan Kotla Road, New Delhi – 110002

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CENTRAL DRUGS STANDARD CONTROL ORGANIZATION DIRECTORATE GENERAL OF HEALTH SERVICES MINISTRY OF HEALTH & FAMILY WELFARE GOVT. OF INDIA, NOVEMBER 2010 Page 1 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 1 ABBREVIATIONS

API BA BE CD CDSCO CPP CTD FSC GMP ICH ICMJE INR iv MA NDA NRA OCR PD PK po QOS WHO Active Pharmaceutical Ingredient Bioavailability Bioequivalence Compact Disc Central Drugs Standard Control Organization Certificate of Pharmaceutical Product Common Technical Document Free Sale Certificate Good Manufacturing Practices International Conference on Harmonisation International Committee of Medical Journal Editors Indian National Rupee intravenous Market Authorization New Drug Application National Regulatory Authority Optical Character Recognition Pharmacodynamics Pharmacokinetics per oral Quality Overall Summary World Health Organization

The regulations under Drugs and Cosmetics Rules 122A, 122B and 122D and further Appendix I, IA and VI of Schedule Y, describe the information required for approval of an application to import or manufacture of new drug for marketing.

Substantial documentation and data are required in these types of submissions, resulting in large, complex applications. Till date, applicants have used many different approaches in organizing the information and the differences in organization of data in each application has made reviewing more difficult and can also lead to omission of critical data or analyses.

Such omissions can result in unnecessary delays in approvals. Thus, a common format of submission will help in overcoming these hurdles. Through the International Conference on Harmonisation (ICH) process, the Common Technical Document (CTD) guidance’s have been developed for Japan, European Union, and United States. Page 4 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 Most countries have adopted the CTD format. Hence, CDSCO has also decided to adopt CTD format for technical requirements for registration of pharmaceutical products for human use.

The same is already in use for biological products since 2009 and now this guidance document describes the format for preparation of CTD for marketing approval of pharmaceuticals for human use other than biological products (vaccines, biotechnology products, stem cell products, etc). It is apparent that this structured application with comprehensive and rational contents will help the CDSCO to review and take necessary actions in a better way and would also ease the preparation of electronic submissions, which may happen in the near future at CDSCO.

This guidance is developed by CDSCO based on The ICH Harmonised Tripartite Guideline on “Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use”. M4, Step 4 version dated January 13, 2004, and Drugs & Cosmetics Act 1940 and Rules made thereunder. Page 5 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 4 SCOPE This guideline applies to import / manufacture and marketing approval of new drugs including New chemical entity, new indication, new dosage forms, modified release form, new route of administration etc. nder the definition of new drug under Rule 122E of Drugs & Cosmetics rules as a finished pharmaceutical product. This guideline is not intended to advice on the design of studies that are required for product registration, but, indicates an appropriate format for submission of the data that have been acquired. Drugs & Cosmetics Act and Rules there under, defines the ‘content requirements’ for the specific type of submission and hence, this guidance document has to be read along with Drugs and Cosmetics Act 1940 and Rules made thereunder. Page 6 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 0. 2010 5 GENERAL CONSIDERATIONS The CTD is only a format for submission of information to CDSCO. It does not define the content. Although adherence to overall CTD structure is necessary, it should be noted that no guideline can cover all eventualities, and common sense and a clear focus on the needs of the regulatory authority assessor are the best guides to constructing an acceptable document. Therefore, applicants can modify the format at some of the subsection levels, if needed to provide the best possible presentation of the information, in order to facilitate the understanding and evaluation.

Clear and unequivocal information should be provided. Text and tables should be prepared using margins that allow the document to be printed clearly without losing any information and the left-hand margin should be sufficiently large so that information is not obscured by the method of binding. You can submit documents printed on both sides of a page, however, one should take care that the information is not obscured when the page is placed in a binder. Page 7 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010

Font sizes for text and tables should be of a style and size that are large enough to be easily readable. Times New Roman, 12-point font is recommended for descriptive text and Times New Roman, 9 to 10-point font for table contents and text. Document Pagination and segregation: o Entire submission should never be numbered consecutively by page. Page numbering should be at the document level and not at the volume or module level. o Every document should be numbered starting at page one, except for individual literature references, where the existing journal page numbering is considered sufficient. All pages of a document should include a unique header or footer that briefly identifies its subject matter. Alternatively, a similar identifier should be used on a tab that precedes the document, to facilitate finding that document within the dossier. o If a section contains more than one document, a specific table of contents for that section can be included in the tab to identify the chronology and titles of the documents contained therein. All abbreviations should be defined at the first instance they are used and listed at the end of the dossier.

References should be cited in accordance with the current edition of the uniform requirements for manuscripts submitted to biomedical journals, International Committee of Medical Journal Editors (ICMJE). Page 8 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) Submission requirements / methodology 28. 10. 2010 o Please submit ONE hard copy and THREE soft copies i. e. Compact Disc (CD) (PDF format) of the dossier. o Hard copy: Sides and front of each volume/ file /binder must be labeled with the name of the applicant company, date of submission, name of the drug(s) and the file number (Numbering of files: ‘x’ of ‘y’ files e. . if there are 10 files, file number 6 will be labeled as File No. 6 / 10). o Use of multiple volumes/ files/ binders is recommended than binding all the documents and modules in a very huge file. Preferably volumes/ files /binders should not be more than 3 inches thick and use of good quality binders is recommended. All the files should be kept together, bound by a good quality wire or thread (If there are too many volumes e. g. more than 10, then multiple grouping should be done). o CDs have to be labeled using a marker pen with the name of the applicant company, date of submission and name of the drug(s).

If there are multiple CDs for one submission dossier, then the numbering as mentioned above should be followed. Scanned copies of only signed documents like test reports, signature pages will be acceptable and rest of the document has to be in PDF format with optical character recognition (OCR). The table of content under each head should be linked to the files (s) or relevant document for easy tracking in CD’s. o Applicant should preserve a duplicate copy of the submitted dossier for any future reference and should be able to submit multiple copies, if required by CDSCO.

Page 9 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 All sentences in blue italic fonts are instructions to the applicant and the same when present in the templates has to be deleted before finalizing the documents. During cross-referencing from one module to other modules, please mention the volume, CTD module, tab identifier and page number of the other referring document/ section. Page 10 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 5. 1 FURTHER CLARIFICATIONS 1. SOURCE OF BULK DRUG(S) FOR 28. 10. 2010 MANUFACTURING

FINISHED FORMULATION Documentations required related to source of bulk drug(s) /raw material(s) when the applicant is seeking approval for manufacturing of finished formulation only. If the applicant has a manufacturing permission for bulk drugs, please provide a copy of the same. Otherwise, provide the consent letter from the approved source regarding supply of material. CLARIFICATION: In case if the applicant does not have an approval from DCGI to manufacture the Active Pharmaceutical Ingredient(s) (API), then the applicant can, Import the API Applicant has to submit all relevant nformation and documents listed in this CTD and comply with further requirements for import of API. Manufacture the API Applicant has to submit all relevant information and documents listed in this CTD and comply with further requirements for manufacture of API Obtain the API from another manufacturer which is not yet approved by DCGI In such case, the respective manufacturer of the API has to file an application separately in Form 44 along with treasury challan of requisite amount with all relevant documents. Approval of manufacture of new Page 11 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 0. 2010 drug finished formulation will be considered after approval of manufacture of the API. 2. IS CTD MANDATORY FOR ALL TYPE OF SUBMISSIONS? CTD is mandatory for all Import and/or manufacture and marketing approval of new drugs (New chemical entity, new indication, new dosage forms, new route of administration etc. ), as a finished pharmaceutical product, for first time submission and for subsequent applications until 4 years. Modified release formulations (even after 4 years of approval by CDSCO) Fixed Dose Combinations under item (a) of Appendix VI of Schedule Y of Drugs and Cosmetics Rules 1945.

However, the details and depth of documentation will vary with the type of applications. NOTE: This CTD guidance document is not applicable for the manufacture and sale of bulk drugs of a new drug approved in the country. In case of a new chemical entity, the approval of only API cannot be considered unless safety and efficacy of the finished formulation of the drug is evaluated and approved by this office. Page 12 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 6 GUIDELINES FOR PREPARATION OF CTD 6. 1 CTD: OVERVIEW

The CTD is organized into five modules (Module 1, 2, 3, 4, and 5) and a diagrammatic representation of organization of the CTD is provided in Annexure I. Module 1: General Information This module should contain documents specific to India; for example, Form 44, Treasury challan fee or the proposed label for use in India. Details to be provided are further explained in Section 6. 2 of this document. Module 2: CTD Summaries This module should begin with a general introduction to the pharmaceutical, including its pharmacologic class, mode of action, and proposed clinical use, not exceeding one page.

Module 2 should contain 7 sections in the following order: CTD table of contents CTD introduction Quality overall summary Nonclinical overview Clinical overview Nonclinical written and tabulated summaries Clinical summary The organization of these summaries is described further at Section 6. 3 of this document. Page 13 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) Module 3: Quality 28. 10. 2010 Information on Quality should be presented in the structured format as described in Section 6. 4 of this document.

Module 4: Nonclinical Study Reports The nonclinical study reports should be presented in the order described at Section 6. 5 of this document. Module 5: Clinical Study Reports The human study reports and related information should be presented in the order described at Section 6. 6 of this document. The overall organization of the CTD is presented on the following pages. Page 14 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 6. 2 MODULE 1: GENERAL INFORMATION MODULE 1: GENERAL INFORMATION 1. 1 COVERING LETTER & 28. 10. 2010 COMPREHENSIVE TABLE OF CONTENTS (MODULES 1 TO 5) 1. 1. 2. 1 1. 2. 2 ADMINISTRATIVE INFORMATION Brief introduction about the applicant company Duly filled and signed application in Form 44 and Treasury Challan (copy of treasury challan when the fee is already paid during clinical trial application) 1. 2. 3 1. 2. 3. 1 Legal and Critical Documents General, as applicable a. Copy of Clinical Trial/BE No Objection letters issued by CDSCO b. Copies of any other relevant competent authority clearances/ approvals / no objection certificates obtained or any key communication letters with authorities. 1. 2. . 2 For import and marketing of finished products a. Copy of drug sale license in Form 20B / 21B b. Copy of Free Sale Certificate (FSC) and/or Certificate of Pharmaceutical Products (CPP) issued by the Regulatory Authority of the country of origin / Free sale certificate issued by the Regulatory Authorities of Page 15 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) other major countries. 28. 10. 2010 c. Batch release certificate issued by National Regulatory Authorities d. Copy of Form 11 for imported drug product for testing purpose 1. 2. 3. For manufacture and marketing of finished products (This also includes import of raw materials and manufacture of finished formulations) a. Copy of existing manufacturing license in Form 25 / 28 / 26 b. Copy of Form-29 1. 2. 3. 4 1. 2. 3. 5 1. 2. 4 1. 2. 4. 1 Undertaking or Declaration as per Annexure II Certificate of Analysis Coordinates related to the application Name, address, telephone, fax, e-mail of applicant of drug product 1. 2. 4. 2 Name, address, telephone, fax, e-mail of manufacturer of drug substance 1. 2. 4. 3 Name, address, telephone, fax, e-mail of the responsible official 1. . 4. 4 Name, address, telephone, fax, e-mail of other manufacturer(s) involved in the production process 1. 2. 4. 5 Name, designation, address, telephone, fax, e-mail of the official responsible for releasing batches of drug product Page 16 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 1. 2. 4. 6 28. 10. 2010 Name, address, telephone, fax, e-mail of the authorized agent in India: (for imported drug products) 1. 2. 4. 7 Name, address, telephone, fax, e-mail of the manufacturing premises holding Market Authorization of the drug product (for imported drug products) . 3 1. 3. 1 GENERAL INFORMATION ON DRUG PRODUCT A brief description of the drug and the therapeutic class to which it belongs 1. 3. 2 1. 3. 3 1. 3. 4 1. 3. 5 1. 3. 6 1. 3. 7 1. 3. 8 1. 3. 9 1. 3. 10 Non-proprietary name or generic name of drug Composition (As per label claim) Dosage form Strength per dosage unit Dispensing requirements Route of administration Commercial presentation Conditions of storage or conservation Full Prescribing Information (Package insert) The prescribing the information following (package insert) shall name; comprise sections: Generic omposition; dosage form/s, indications; dose and method of administration; use in special populations (such as pregnant women, lactating women, pediatric patients, geriatric patients drug etc. ); contra-indications; warnings; effects; precautions; overdose; Page 17 of 110 interactions; undesirable and pharmacodynamic pharmacokinetic GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) properties; incompatibilities; shelf-life; 28. 10. 2010 packaging information; storage and handling instructions. 1. 3. 11 Product Labeling: Proposed draft labels and cartons have to be provided. The drafts of label and carton texts should comply with provisions of rules 96 and 97 of the Drugs and Cosmetics Rules 1945. ) a. Primary package label b. Secondary package label 1. 3. 12 Summary of the packaging procedures for Indian shipments (including box sizes, packing volumes). 1. 4 SUMMARY OF TESTING PROTOCOL(S) FOR QUALITY CONTROL TESTING together with a complete impurity profile and release specifications for the product should be submitted. 1. 5 1. 5. 1 1. 5. 2 REGULATORY STATUS IN OTHER COUNTRIES List of countries where proposed drug is Marketed List of countries where proposed drug is Approved for Marketing 1. . 3 List of countries where proposed drug is Approved as IND 1. 5. 4 List of countries where proposed drug is Withdrawn (if any, with reasons for withdrawal) 1. 5. 5 Details of any restrictions on use, in any country where it is marketed /approved 1. 6 DOMESTIC PRICE OF THE DRUG FOLLOWED IN THE Page 18 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) COUNTRIES OF ORIGIN IN INR. 1. 7 A BRIEF PROFILE OF THE 28. 10. 2010 MANUFACTURER’S RESEARCH ACTIVITY 1. 8 A BRIEF PROFILE ACTIVITY OF IN THE MANUFACTURER’S AS WELL AS BUSINESS DOMESTIC GLOBAL MARKET 1. 9 INFORMATION EXPERTS, IF ANY 1. 0 SAMPLES OF DRUG PRODUCT: Samples of drug REGARDING INVOLVEMENT OF substance and drug product (an equivalent of 50 clinical doses or double the quantity required (whichever is more) for complete testing of product with testing protocols, full impurity profile and release specifications should be forwarded to Central Drugs Laboratory, as and when required / instructed. 1. 11 PROMOTIONAL MATERIALS Page 19 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 6. 3 MODULE 2: CTD SUMMARIES MODULE 2: CTD SUMMARIES 2. 1 2. 2 TABLE OF CONTENTS OF MODULE 2 INTRODUCTION 8. 10. 2010 This should include proprietary name, non-proprietary name or common name of the drug substance, company name, dosage form(s), strength(s), route of administration, and proposed indication(s). 2. 3 QUALITY OVERALL SUMMARY Note: In general, the Quality Overall Summary (QOS) is an outline of data presented in Module 3. Please do not provide the entire information present in Module 3 corresponding sections, but, provide brief information picked from relevant sections. This QOS normally should not exceed 40 pages of text, excluding tables and figures.

The underlined text below indicates where tables, figures, or other items can be imported directly from Module 3. 2. 3. S 2. 3. S. 1 SUMMARY OF DRUG SUBSTANCE General Information (name, manufacturer) Brief information from 3. 2. S. 1 should be included. The source of bulk drug(s) /raw material(s) – If the applicant has a manufacturing permission for bulk drugs, please provide a copy of the same and further details under drug substance can be very brief. Otherwise, provide the consent letter from the approved Page 20 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) source regarding supply of material. . 3. S. 2 Manufacture (name, manufacturer) Information from 3. 2. S. 2 should be included: Information on the manufacturer; A flow diagram, as provided in 3. 2. S. 2. 2; A brief description of the, manufacturing process and the controls 28. 10. 2010 source and starting material and raw materials of biological origin used Selection and justification of critical manufacturing steps, process controls, and acceptance criteria. process validation and/or evaluation major manufacturing changes made throughout development and conclusions from the assessment used to evaluate product consistency 2. . S. 3 Characterisation (name, manufacturer) A summary of the interpretation of evidence of structure and isomerism, as described in 3. 2. S. 3. 1, should be included. When a drug substance is chiral, it should be specified whether specific stereoisomer’s or a mixture of stereoisomer’s have been used in the nonclinical and clinical studies, and information should be given as to the stereoisomer of the drug substance that is to be used in the final product intended for marketing. Page 21 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010

The QOS should also summarise the impurity levels in batches of the drug substance used in the non-clinical studies, in the clinical trials, and in typical batches manufactured by the proposed commercial process. A tabulated summary of the data can be provided. 2. 3. S. 4 Control of Drug Substance (name, manufacturer) A brief summary of justification of the specification(s), analytical included. Specification from 3. 2. S. 4. 1 should be provided. A tabulated summary of the batch analyses from 3. 2. S. 4. 4, with graphical representation where procedures, and validation should be ppropriate, should be provided. 2. 3. S. 5 Reference Standards or Materials (name, manufacturer) Information from 3. 2. S. 5 should be included. 2. 3. S. 6 Container Closure System (name, manufacturer) A brief description and discussion of the information, from 3. 2. S. 6 should be included. 2. 3. S. 7 Stability (name, manufacturer) This section should include a summary of the studies undertaken (conditions, batches, analytical procedures) and a brief discussion of the results and conclusions, the proposed storage conditions, retest date or shelf-life,

Page 22 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) where relevant. 28. 10. 2010 The post-approval stability protocol overview should be included. A tabulated summary of the stability results from 3. 2. S. 7. 3, with graphical representation where appropriate, should be provided. 2. 3. P 2. 3. P. 1 SUMMARY OF DRUG PRODUCT Description and Composition of the Drug Product (name, dosage form) Composition from 3. 2. P. 1 should be provided. 2. 3. P. 2 Pharmaceutical Development (name, dosage form) A brief discussion of the information and data from 3. 2. P. should be presented. A tabulated summary of the composition of the formulations used in clinical trials and a presentation of dissolution profiles should be provided, where relevant. 2. 3. P. 3 Manufacture (name, dosage form) A summary from 3. 2. P. 3 should include: Information on the manufacturer. A flow diagram, as provided under 3. 2. P. 3. 3. A brief description of the manufacturing process and the controls process validation and/or evaluation Page 23 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 2. 3. P. 4 Control of Excipients (name, dosage form) 8. 10. 2010 A brief summary on the quality of excipients, as described in 3. 2. P. 4, should be included. 2. 3. P. 5 Control of Drug Product (name, dosage form) A brief summary of the justification of the specification(s), a summary of the analytical procedures and validation, and characterisation of impurities should be provided. Specification(s) from 3. 2. P. 5. 1 should be provided. A tabulated summary of the batch analyses provided under 3. 2. P. 5. 4, with graphical representation where appropriate should be included. 2. 3. P. Reference Standards or Materials (name, dosage form) Information from 3. 2. P. 6 (tabulated presentation, where appropriate) should be included. 2. 3. P. 7 Container Closure System (name, dosage form) A brief description and discussion of the information in 3. 2. P. 7 should be included. 2. 3. P. 8 Stability (name, dosage form) A summary of the studies undertaken (conditions, batches, analytical procedures) and a brief discussion of the results and conclusions of the stability studies and analysis of data should be included. Conclusions with Page 24 of 110

GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 respect to storage conditions and shelf-life and, if applicable, in-use storage conditions and shelf-life should be given. A tabulated summary of the stability results from 3. 2. P. 8. 3, with graphical representation where appropriate, should be included. The post-approval stability protocol overview should be provided. 2. 3. A APPENDICES A summary of facility, equipment and excipients information described and appended under subsections of 3. 2. A should be included 2. 4 NONCLINICAL OVERVIEW

Nonclinical overview should present an integrated and critical assessment of the pharmacologic, pharmacokinetic, and toxicological evaluation of the pharmaceutical. In general, it should address the interpretation of data, the clinical relevance of findings, cross-linking with quality aspects of the pharmaceutical, and the implications of nonclinical findings for the safe use of the pharmaceutical. The implications of any differences (e. g. chirality, chemical form, and impurity profile) between the compound used in the nonclinical studies and the product to be marketed should be discussed.

If detailed references to published scientific literature are to be used in place of studies conducted by the applicant, this should be supported by an appropriate justification that reviews the design of the studies and any deviations from available guidelines. Page 25 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 The section should contain appropriate reference citations to the Tabulated Summaries. Where relevant guidelines on the conduct of studies exist, these should be taken into consideration, and any deviation from these guidelines should be discussed and justified.

Studies conducted to establish the pharmacodynamic effects, the mode of action, and potential side effects should be evaluated and consideration should be given to the significance of any issues that arise. The assessment of the pharmacokinetic, toxicokinetic, and metabolism data should address the relevance of the analytical methods used, the pharmacokinetic models, and the derived parameters. It might be appropriate to cross-refer to more detailed consideration of certain issues within the pharmacology or toxicology studies (e. g. impact of the disease states, changes in physiology, cross-species consideration of toxicokinetic data).

Inconsistencies in the data should be discussed. Inter-species comparisons of metabolism and systemic exposure comparisons in animals and humans (AUC, Cmax, and other appropriate parameters) should be discussed and the limitations and utility of the nonclinical studies for prediction of potential adverse effects in humans highlighted. The onset, severity, and duration of the toxic effects, their dosedependency and degree of reversibility (or irreversibility), and species- or gender-related differences should be evaluated and important features discussed.

The evaluation of toxicology studies should be arranged in a logical order so that all relevant data elucidating a certain effect / Page 26 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 phenomenon are brought together. Extrapolation of the data from animals to humans should be considered in relation to: animal species used numbers of animals used routes of administration employed dosages used duration of treatment or of the study Systemic exposures in the toxicology species at no observed adverse effect levels and at toxic doses, in relation to the exposures in humans at the maximum recommended human dose. he effect of the drug substance observed in nonclinical studies in relation to that expected or observed in humans If alternatives to whole-animal experiments are employed, their scientific validity should be discussed. 2. 4. 1 Introduction and GLP statement A brief introduction about the contents of this section and a comment on the GLP status of the studies submitted should be provided 2. 4. 2 2. 4. 3 2. 4. 4 2. 4. 5 2. 4. 6 Overview of the Non Clinical Testing Strategy Pharmacology Pharmacokinetics Toxicology Integrated Overview and Conclusions This section should clearly define the characteristics of

Page 27 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) human pharmaceutical as demonstrated 28. 10. 2010 by the nonclinical studies and arrive at logical, well-argued conclusions supporting the safety of the product for the intended clinical use. Taking the pharmacology, pharmacokinetics, and toxicology results into account, the implications of nonclinical findings for the safe human use of the pharmaceutical should be discussed (i. e. , as applicable to labelling). 2. 4. 7 2. 5 List of Literature References CLINICAL OVERVIEW

General Aspects The section is intended to provide a critical analysis of the clinical data in the CTD. The clinical overview should primarily present the conclusions and implications of clinical summary (section 2. 7) and individual clinical study reports (Module 5), and should not recapitulate them and cross-referencing for greater details is encouraged. This section should present the strengths and limitations of the development program and study results, analyse the benefits and risks of the medicinal product in its intended use, and describe how the study results support critical parts of the prescribing nformation. In order to achieve these objectives the clinical overview should: Describe and explain the overall approach to the clinical development of a medicinal product, including critical study design decisions. Page 28 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 Assess the quality of the design and performance of the studies. Provide a brief overview of the clinical findings, including important limitations (e. g. , lack of comparisons with an especially relevant active comparator, or absence of information on some patient populations, on pertinent endpoints, or on use in combination therapy).

Provide an evaluation of benefits and risks based upon the conclusions of the relevant clinical studies, including interpretation of how the efficacy and safety findings support the proposed dose and target indication and an evaluation of how prescribing information and other approaches will optimise benefits and manage risks. Address particular efficacy or safety issues encountered in development, and how they have been evaluated and resolved. Explore unresolved issues, explain why they should not be considered as barriers to approval, and describe plans to resolve them.

Explain the basis for important or unusual aspects of the prescribing information. The length of this section will depend on the complexity of the application. The use of graphs and concise tables in the body of the text is encouraged for briefness and to facilitate understanding. 2. 5. 1 Product Development Rationale The discussion of the rationale for the development of the medicinal product should: • Identify the pharmacological class of the medicinal Page 29 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) product. 28. 10. 2010 Describe the particular clinical/pathophysiological condition that the medicinal product is intended to treat, prevent, or diagnose (the targeted indication). • Briefly summarise the scientific background that supported investigation of the medicinal product for the indication(s) that was (were) studied. • Briefly describe the clinical development programme of the medicinal product, including ongoing and planned clinical studies and the basis for the decision to submit the application at this point in the programme. Briefly describe plans for the use of foreign clinical data. Note and explain concordance or lack of concordance with current standard research approaches regarding the design, conduct and analysis of the studies. Pertinent published literature should be referenced. Regulatory guidance and advice (at least from the region(s) where the Clinical Overview is being submitted) should be identified, with discussion of how that advice was implemented. 2. 5. 2 Overview of Biopharmaceutics The purpose of this section is to present a critical analysis of any important issues related to bioavailability that might affect efficacy and/or safety of the to-be-marketed formulation(s) (e. . , dosage form/strength proportionality, differences between the Page 30 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 to-be-marketed formulation and the formulation(s) used in clinical trials, and influence of food on exposure). 2. 5. 3. Overview of Clinical Pharmacology 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 all relevant data and explain why and how the data support the conclusions drawn.

It should emphasise unusual results and known or potential problems, or note the lack thereof. This section should address: pharmacokinetics, e. g. , 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; excretion; time-dependent changes in harmacokinetics; stereochemistry issues; clinically relevant PK interactions with other medicinal products or other substances. Pharmacodynamics, e. g. , information on mechanism of action, such as receptor binding; onset and/or offset of action; relationship of favourable and Page 31 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 unfavourable 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 edicinal products or substances; and possible genetic differences in response. Interpretation of the results and implications of immunogenicity studies, or other drug class specific PD studies summarised in Section 2. 7. 2. 4 of the Clinical Summary. 2. 5. 4 Overview of Efficacy The purpose of this section is to present a critical analysis of the clinical data pertinent to the efficacy of the medicinal product in the intended population. The analysis should consider all relevant data, whether positive or negative, and should explain why and how the data support the proposed indication and rescribing information. Those studies deemed relevant for evaluation of efficacy should be identified, and reasons that any apparently adequate and well- controlled studies are not considered relevant should be provided. Prematurely terminated studies should be noted and their impact considered. The following issues should generally be considered: Relevant features of the patient populations, including demographic features, disease stage, any other Page 32 of 110 potentially important covariates, any GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 8. 10. 2010 important patient populations excluded from critical studies, and participation of children and elderly. Differences between the studied population(s) and the population that would be expected to receive the medicinal discussed. Implications of the study design(s), including product after marketing should be selection of patients, duration of studies and choice of endpoints and control group(s). Particular attention should be given to endpoints for which there is limited experience. Use of surrogate endpoints should be justified.

Validation of any scales used should be discussed. For non-inferiority trials used to demonstrate efficacy, the evidence supporting a determination that the trial had assay sensitivity and justifying the choice of non-inferiority margin. statistical methods and any issues that could affect the interpretation of the to study the results study and (e. g. , important including modifications endpoint design, planned assessments analyses, as they were specified in the original protocol; support for any unplanned analyses; procedures for handling missing data; and orrections for multiple endpoints). Similarities and differences in results among studies, or in different patient sub-groups within Page 33 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 studies, and their effect upon 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. Support for the applicability to the new region of data generated in another region, where appropriate.

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 be considered. 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 upon, the nature and magnitude of expected clinical benefit and the basis for these expectations. 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 general population. 2. 5. 5 Overview of Safety The purpose of this section is to provide a concise Page 34 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 critical analysis of the safety data, noting how results support and justify proposed prescribing information. A critical analysis of safety should consider: 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 prolongation). 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 and study subject demographics, should be considered, and the implications of such limitations with respect to predicting the safety of the product in the arketplace should be explicitly discussed. Common and non-serious 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 be brief, focusing on events of relatively high frequency, those with an incidence higher than placebo, and those that are Page 35 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 known to occur in active controls or other members of the therapeutic class. Events that are ubstantially more or less common or problematic (considering the duration and degree of the observed events) with the test drug than with active controls 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 adverse events, including deaths, and other significant adverse events (e. g. , events leading to discontinuation should discuss or the dose results modification), and obtained for test drug versus control treatments.

Any conclusions regarding causal relationship (or lack of this) to the product should be provided. Laboratory findings reflecting actual or possible serious medical effects should be considered. Similarities and differences in results among studies, and their effect upon the interpretation of the safety data. Any differences in rates of adverse events in population subgroups, such as those defined by demographic factors, weight, concomitant illness, concomitant therapy, or polymorphic metabolism. Relation of adverse events to dose, dose regimen, and treatment duration.

Page 36 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) Long-term safety. 28. 10. 2010 Methods to prevent, mitigate, or manage adverse events. Reactions due to overdose; the potential for dependence, rebound phenomena and abuse, or lack of data on these issues. 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 appropriate. . 5. 6 Benefits and Risks Conclusions The purpose of this section is to integrate all of the conclusions reached in the previous sections about the biopharmaceutics, clinical pharmacology, efficacy and safety of the medicinal product and 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 guidelines and any important limitations of the available data should be discussed here. This assessment should address critical aspects of the proposed Prescribing Information.

This section should also consider the risks and benefits of the medicinal product as they compare to available alternative treatments or to no treatment in illnesses Page 37 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 where no treatment may be a medically acceptable option; and should clarify the expected place of the medicinal product in the armamentarium of treatments for the proposed indication. If there are risks to individuals other than those who will receive the drug, these risks should be discussed (e. . , risks of emergence of drug-resistant bacterial strains with widespread use of an antibiotic for minor illnesses). The analyses provided in previous sections should not be reiterated here. This section often can be quite abbreviated when no special concerns have arisen and 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 the most important conclusions and issues concerning each of the following points: The fficacy 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 sub-populations, e. g. , those defined by age, sex, ethnicity, organ function, disease severity, and genetic polymorphisms. Data in children and in different plans for age a groups, if applicable, Page 38 of 110 any development GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) programme in children. 28. 10. 2010

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 machinery. Examples of issues and concerns that could warrant a more detailed discussion of benefits and risks might include: the drug is for treatment of a non-fatal disease but has known or potential serious toxicity, such as a strong signal of carcinogenicity, teratogenicity, proarrhythmic potential (effect on QT interval), or suggestion of heapatotoxicity. he proposed use is based on a surrogate endpoint and there is a well-documented important toxicity. safe and/or effective use of the drug requires potentially difficult selection or management approaches that require special physician expertise or patient training. 2. 5. 7 Literature References A list of references used should be provided. Copies of all references cited in the clinical overview should be provided in Section 5. 4 of Module 5. 2. 6 NONCLINICAL WRITTEN AND TABULATED Page 39 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) SUMMARIES 8. 10. 2010 The primary purpose of the nonclinical written and tabulated summaries should be to provide a comprehensive factual synopsis of the nonclinical data. GENERAL ASPECTS: This part of guidelines is intended to assist authors in the preparation of nonclinical pharmacology, pharmacokinetics, and toxicology written & tabulated summaries in an acceptable format. However, applicants can modify the format if needed to provide the best possible presentation of the information, in order to facilitate the understanding and evaluation of the results.

Nonclinical Written Summaries Whenever appropriate, age- and gender-related effects should be discussed. Consistent use of units throughout the summaries is recommended. A table for converting units might also be useful. In the discussion and conclusion sections, information should be integrated across studies and across species, and exposure in the test animals should be related to exposure in humans given the maximum intended doses. General Presentation Issues Order of presentation of information within sections, When available, in vitro studies should precede in vivo studies.

Where multiple studies of the same type summarised within the pharmacokinetics need to be and toxicology sections, studies should be ordered by species, by route, and Page 40 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) then by duration (shortest duration first). Species should be ordered as follows: Mouse Other rodent Rabbit Dog Rat 28. 10. 2010 Hamster Non-human primate Other non-rodent mammal and Non-mammals Routes of administration should be ordered as follows : The intended route for human use Intramuscular Inhalation Intraperitoneal Oral Intravenous Subcutaneous

Topical and to end with Others. Use of Tables and Figures Although the nonclinical written summaries are envisaged to be composed mainly of text, some information contained within them might be more effectively and/or concisely communicated through the use of appropriate tables or figures. To allow authors flexibility in defining the optimal structure for the written summaries, tables and figures should preferably be included within the text. Alternatively, they could be grouped together at the end of each of the nonclinical written summaries.

Throughout the text, reference citations to the tabulated summaries should be included, in the following format: (Table X. X, Study/Report Number). Nonclinical Tabulated Summaries One tabular format can contain results from several studies. Alternatively, it may be appropriate to cite the data resulting from one study in several tabular formats. It is the responsibility of the applicant to decide on the best possible format for presentation of the data for each product. Page 41 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010

Presentation of the data in the best formats should ensure that a sufficient level of detail is available to the reviewer and should provide concise and accurate overviews of related information. 2. 6. 1 Introduction The aim of this section should be to introduce the reviewer to the pharmaceutical and to its proposed clinical use. The following key elements should be covered: Brief information concerning the pharmaceutical’s structure and pharmacologic properties. Information concerning the pharmaceutical’s proposed clinical indication, dose, and duration of use. . 6. 2 2. 6. 2. 1 Written Summary of Pharmacology Brief Summary The principal findings from the pharmacology studies should be briefly summarized. 2. 6. 2. 2 Primary Pharmacodynamics Studies on the mode of action and/or effects of a substance in relation to its desired therapeutic target are primary pharmacodynamic studies. Studies should be summarised and evaluated. Where possible, it would be helpful to relate the pharmacology of the drug to available data (in terms of selectivity, safety, potency, etc. ) on other drugs in the class. Page 42 of 110

GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 2. 6. 2. 3 Secondary Pharmacodynamics 28. 10. 2010 Studies on the mode of action and/or effects of a substance not related to its desired therapeutic target are secondary pharmacodynamic studies (these have sometimes been referred to as part on of general be pharmacology studies). Studies should summarised by organ system, where appropriate, and evaluated in this section. 2. 6. 2. 4 Safety Pharmacology Safety pharmacology studies are defined as those studies that investigate effects the of potential a undesirable on pharmacodynamic substance hysiological functions in relation to exposure in the therapeutic range and above. Studies should be summarised and evaluated in this section. In some cases, secondary pharmacodynamic studies can contribute to the safety evaluation when they predict or assess potential adverse effect(s) in humans. In such cases, these secondary pharmacodynamic studies should be considered along with safety pharmacology studies. 2. 6. 2. 5 Pharmacodynamic Drug Interactions If they have been performed, pharmacodynamic drug interaction studies should be briefly summarised in this section. 2. 6. 2. 6 Discussion and Conclusions

Page 43 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 This section provides an opportunity to discuss the pharmacologic evaluation and to consider the significance of any issues that arise. 2. 6. 2. 7 Tables and Figures Text tables and figures can be included at appropriate points throughout the summary within the text. Alternatively, tables and figures can be included at the end of the summary under this subsection. 2. 6. 3 2. 6. 4 2. 6. 4. 1 Tabulated Summary of Pharmacology Written Summary of Pharmacokinetics Brief Summary The principal findings from the pharmacokinetics tudies should be briefly summarized. This section should begin with a description of the scope of the pharmacokinetic evaluation, emphasising, for example, whether the species and strains examined were those used in the pharmacology and toxicology evaluations, and whether the formulations used were similar or identical. 2. 6. 4. 2 Methods of Analysis This section should contain a brief summary of the methods of analysis for biological samples, including the detection and quantification limits of an analytical procedure.

If possible, validation data for the analytical method and stability of biological samples should be discussed in this section. The potential impact of Page 44 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 different methods of analysis on the interpretation of the results should be discussed in the following relevant sections. 2. 6. 4. 3 Absorption The following data should be summarised in this section: Absorption (extent and rate of absorption, in vivo and in situ studies) Kinetic parameters, bioequivalence and/or bioavailability (serum /plasma /blood PK studies) 2. . 4. 4 Distribution The following data should be summarised in this section: Tissue distribution studies Protein binding and distribution in blood cells Placental transfer studies 2. 6. 4. 5 Metabolism (interspecies comparison) The following data should be summarised in this section: Chemical structures and quantities of metabolites in biological samples Possible metabolic pathways Pre-systemic metabolism (Gastro-intestinal /hepatic first-pass effects) In vitro metabolism including P450 studies Enzyme induction and inhibition Page 45 of 110

GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 2. 6. 4. 6 Excretion 28. 10. 2010 The following data should be summarised in this section: Routes and extent of excretion Excretion in milk 2. 6. 4. 7 Pharmacokinetic Drug Interactions If they have been performed, studies nonclinical (in vitro pharmacokinetic drug-interaction and/or in vivo) should be briefly summarised in this section. 2. 6. 4. 8 Other Pharmacokinetic Studies If studies have been performed in nonclinical models of disease (e. g. , renally impaired animals), they should be summarised in this section. 2. 6. 4. Discussion and Conclusions This section provides an opportunity to discuss the pharmacokinetic evaluation and to consider the significance of any issues that arise. 2. 6. 4. 10 Tables and Figures Text tables and figures can be included at appropriate points throughout the summary within the text. Alternatively, there is the option of including tables and figures at the end of the summary under this subsection. 2. 6. 5 Tabulated Summary of Pharmacokinetics Page 46 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 2. 6. 6 2. 6. 6. 1 Written Summary of Toxicology Brief Summary 28. 10. 010 The principal findings from the toxicology studies should be briefly summarized. In this section, the extent of the toxicological evaluation can be indicated by the use of a table listing of principal toxicological studies (results should not be presented in this table), for example: Study type and duration Single-dose toxicity Single-dose toxicity Repeat-dose toxicity 1 month 6 months 9 months etc. po po po Rat and dog Rat Dog Parent drug “ “ “ “ Route of administration po and iv po and iv Rat and mouse Rat and mouse Species Compound administered* Parent drug Metabolite X * This olumn required only if metabolite(s) are investigated. The scope of the toxicological evaluation should be described in relation to the proposed clinical use. 2. 6. 6. 2 Single-Dose Toxicity The single-dose data should be very briefly summarised, in order by species, by route. In some instances, it may be helpful to provide the data in the form of a table. 2. 6. 6. 3 Repeat-Dose Toxicity (including supportive toxicokinetics evaluation) Studies should be summarised in order by species, by route, and by duration, giving brief details of the methodology and highlighting important findings (e. . , Page 47 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 nature and severity of target organ toxicity, dose (exposure)/response relationships, no observed adverse effect levels, etc. ). Non-pivotal studies can be summarized in less detail (pivotal studies are the definitive GLP studies specified by ICH Guideline M3). 2. 6. 6. 4 Genotoxicity Studies should be briefly summarised in the following order: in vitro non-mammalian cell system in vitro mammalian cell system in vivo mammalian system (including supportive toxicokinetics evaluation) other systems 2. 6. 6. Carcinogenicity evaluations) A brief rationale should explain why the studies were chosen and the basis for high-dose selection. Individual studies should be summarised in the following order: Long-term studies (in order by species; including range-finding studies that cannot appropriately be included under repeat-dose toxicity or (including supportive toxicokinetics pharmacokinetics) Short- or medium-term studies (including rangefinding included studies that cannot appropriately toxicity be or under repeat-dose pharmacokinetics) Page 48 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) Other studies 2. . 6. 6 Reproductive range-finding evaluations) and Developmental and Toxicity 28. 10. 2010 (including studies supportive toxicokinetics Studies should be summarised in the following order, giving brief details of the methodology and highlighting important findings: Fertility and early embryonic development Embryo-fetal development Prenatal and postnatal development, including maternal function Studies in which the offspring (juvenile animals) are dosed and/or further evaluated, if such studies have been conducted. If modified study designs are used, the sub-headings should be modified accordingly.

Male fertility study should be summarized 2. 6. 6. 7 Local Tolerance If local tolerance studies have been performed, they should be summarised in order by species, by route, and by duration, giving brief details of the methodology and highlighting important findings. 2. 6. 6. 8 Other Toxicity Studies (if available) If other studies have been performed, they should be summarised. When appropriate, the rationale for conducting the studies should be provided. Page 49 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) Antigenicity Immunotoxicity 28. 10. 2010

Mechanistic studies (if not reported elsewhere) Dependence Studies on metabolites Studies on impurities Other studies 2. 6. 6. 9 Discussion and Conclusions This section should provide an opportunity to discuss the toxicological evaluation and the significance of any issues that arise. Tables or figures summarizing this information are recommended. 2. 6. 6. 10 Tables and Figures Text tables and figures can be included at appropriate points throughout the summary within the text. Alternatively, tables and figures can be included at the end of the summary under this subsection. 2. 6. 2. 7 Tabulated Summary of Toxicology CLINICAL SUMMARY This section is intended to provide a detailed, factual summarization of all of the clinical information in the CTD. This includes information provided in clinical study reports; information obtained from any meta-analyses or other cross-study analyses for which full reports have been included in Module 5; and post-marketing data for products that have been marketed in other regions. The comparisons and analyses of results across studies provided in this document Page 50 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) hould focus on factual observations. 28. 10. 2010 The length of the summary will vary substantially according to the information to be conveyed. 2. 7. 1 Summary of Biopharmaceutic Studies and Associated Analytical Methods 2. 7. 1. 1 Background and Overview This section should provide the reviewer with an overall view of the formulation development process, the in vitro and in vivo dosage form performance, and the general approach and rationale used in developing the bioavailability (BA), comparative BA, bioequivalence (BE), and in vitro dissolution profile database. 2. 7. 1. Summary of Results of Individual Studies A tabular listing of all biopharmaceutical studies should generally be provided, together with narrative descriptions of relevant features and outcomes of each of the individual studies that provided important in vitro or in vivo data and information relevant to BA and BE. The narrative descriptions should be brief, e. g. , similar to an abstract for a journal article, and should describe critical design features and critical results. Similar studies may be described together, noting the individual study results and any important differences among the studies.

These narratives may be abstracted from the clinical study report synopsis. References to the full report of each study should be included in the narratives. Page 51 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 2. 7. 1. 3 28. 10. 2010 Comparison and Analyses of Results Across Studies This section should provide a factual summary of all in vitro dissolution, BA, and comparative BA studies carried out with the drug substance or drug product, with particular attention to differences in results across studies. This overview should typically summarise the findings in text and tables. . 7. 1. 4 Appendix Tables and figures should be embedded in the text of the appropriate sections when they enhance the readability of the document. Lengthy tables can be provided in the appendix at the end of the Section. Tables related to bioavailability and in vitro dissolution studies may contain study ID, objectives, study design, results and location of detailed reports in the application. Applicants should decide whether information and results from these studies are best presented in tables, text or figures in order to aid clarity. 2. 7. 2 2. 7. 2. Summary of Clinical Pharmacology Studies Background and Overview This section should provide the reviewer with an overall view of the clinical pharmacology studies. These studies include clinical studies performed to evaluate human PK, and PD, and in vitro studies performed with human cells, tissues, or related materials (hereinafter referred to Page 52 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 as human biomaterials) that are pertinent to PK processes. This section should not include detailed information about individual studies. . 7. 2. 2 Summary of Results of Individual Studies A tabular listing of all clinical pharmacology studies should generally be provided, together with a narrative description of the relevant features and outcomes of each of the 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, e. g. , similar to an abstract for a journal article, and should describe critical design features and critical results.

Similar studies may be described together, noting the individual study results and any important differences among the studies. References to full report of each study should be included in the narratives. Summaries of dose-response or concentration response (PK/PD) studies with pharmacodynamic endpoints 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 2. 7. 3 or 2. 7. as appropriate and referenced, but not summarised, here. 2. 7. 2. 3 Comparison and Analyses of Results Across Studies This section should use the results of all in vitro human biomaterial studies and PK, PD and PK/PD studies to Page 53 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 characterise the PK, PD and PK/PD relationships of the drug. Results related to the inter- and intra-individual variability in these data and the intrinsic and extrinsic factors affecting these pharmacokinetic relationships should be discussed. . 7. 2. 4 Special Studies This section should include studies that provide special types of data relevant to specific types of medicinal products. For example, immunogenicity studies, susceptibility studies for a antibiotic that are not part of efficacy data 2. 7. 2. 5 Appendix Tables and figures should be embedded in the text of the appropriate sections when that enhances the readability of the document. Lengthy tables can be provided in the appendix at the end of the Section.

Applicants should also decide whether information and results from clinical pharmacology studies are best presented in tables, text or figures in order to aid clarity. If, for example, results are best presented in text and figures, the tables might simply list the studies. In designing tables, if any, for various types of other clinical pharmacology studies such as those listed below, applicants should consider including the following types of information. These examples are for illustrative purposes only and the sponsor should decide which information needs to be presented.

Page 54 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) Metabolism studies using human 28. 10. 2010 biomaterials: biomaterials used (e. g. , microsomes, hepatocytes), probe drugs, enzymatic pathways and % contribution and relevant 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 metabolite(s) inhibited, enzymatic pathways affected, range of inhibitor concentrations proposed used, IC50 of and Ki values should and be mechanism inhibition ncluded. 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: co-variates studied, number and type of subjects or patients studied, summary statistical parameters and final estimates of mean (± standard deviation) PK parameters. 2. 7. 3 Summary of Clinical Efficacy A separate Section 2. 7. 3 should be provided for each indication, although closely related indications can be considered together. When more than one Section 2. 7. is submitted, the sections should be labelled 2. 7. 3 pneumonia, 2. 7. 3 URI, etc. 2. 7. 3. 1 Background and Overview of Clinical Efficacy This section should describe the program of controlled Page 55 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 studies and other pertinent studies in the application that evaluated efficacy specific to the indication(s) sought. Any results of these studies that are pertinent to evaluation of safety should be discussed in Section 2. 7. 4, Summary of Clinical Safety. 2. 7. 3. 2 Summary of Results of Individual

Studies A tabular listing of all studies that provided (or were designed to provide) information relevant to product efficacy should generally be provided, together with narrative descriptions for important studies. The narrative descriptions should be brief, e. g. , similar to an abstract for a journal article, and should describe critical design features and critical results. Similar studies may be described together, noting the individual study results and any important differences among the studies. These narratives can be abstracted from the synopses of the clinical study reports.

References to the full report of each study should be included in the narratives. 2. 7. 3. 3 Comparison and Analyses of Results Across Studies Using text, figures, and tables as appropriate, the subsections of 2. 7. 3. 3 should summarise all available data that characterise the efficacy of the drug. This summary should include analyses of all data, irrespective of their support for the overall conclusion and should, therefore, discuss the extent to which the results of the relevant studies do or do not reinforce Page 56 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 ach other. Any major inconsistencies in the data regarding efficacy should be addressed and any areas needing further exploration should be identified. The section will generally utilise two kinds of analyses: comparison of results of individual studies, and analysis of data combined from various studies. Details of analyses that are too extensive to be reported in a summary document should be presented in a separate report, to be placed in Module 5. 2. 7. 3. 3. 1 Study Populations The demographic and other baseline characteristics of patients across all efficacy studies should be described.

Tabular presentations that combine and compare study populations across studies may be useful. 2. 7. 3. 3. 2 Comparison of Efficacy Results of all Studies The results of any bridging studies using clinical endpoints should be summarised here. The results from all studies designed to evaluate the drug’s efficacy should be summarised and compared, including studies with inconclusive or negative results. Important differences in study design such as endpoints, control group, study duration, statistical methods, patient population, and dose should be identified.

Comparisons of results across studies should focus on pre-specified primary endpoints. However, when the primary endpoints involved different variables or time Page 57 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 points in different efficacy studies, it may be useful to provide cross-study comparisons of important data elements that were obtained in all studies. If results over time are important, results of studies may be displayed in a figure that illustrates the change over time in each study.

If a meta-analysis of the clinical studies is performed, it should be clear whether this analysis is conducted according to a predefined protocol or is a post hoc exercise. Any differences in trial designs or populations or in efficacy measurements between trials should be described to allow assessment of the relevance and validity of the results and conclusions. A detailed description of the methodology and results of the metaanalysis should generally be submitted in a separate report under Module 5. 2. 7. 3. 3. Comparison of Results in Sub-populations The results of individual studies or overview analyses of efficacy in specific populations should be summarised in this section. The purpose of these comparisons should be to show whether the claimed treatment effects are observed consistently across all relevant sub- populations, especially those where there are special reasons for concern. The comparisons may highlight apparent variations in efficacy that require further investigation and discussion. The limitations of such analyses, however, should be recognised, and it is

Page 58 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 important to note that their purpose is not to provide the basis for specific claims, nor to attempt to improve the evidence of efficacy in situations where the overall results are disappointing. Given the limited sample sizes in individual studies, analyses across multiple studies should be performed to evaluate effects of major demographic factors (age, sex, and race) and of other predefined or relevant intrinsic and extrinsic factors (e. g. , disease severity, prior drugs, treatment, concomitant llness, concomitant alcohol, tobacco, and body weight) on efficacy. Factors of special interest may arise from general concerns (e. g. , the elderly) or from specific issues that are related to the pharmacology of the drug or that have arisen during earlier drug development. Efficacy in the paediatric population should be routinely analysed in applications for a proposed indication that occurs in children. Depending on the data set, if extensive, detailed efficacy analyses are performed, they can be placed in Module 5, with the results of those analyses reported here. 2. . 3. 4 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 level relationships), and thus have contributed to dose selection and choice of dose interval. Page 59 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) Relevant data from nonclinical studies 28. 10. 2010 may be referenced and relevant data from PK studies, other clinical pharmacology studies, and controlled and ncontrolled clinical studies should be summarised to illustrate these dose-response or blood level-response relationships. While the interpretation of how these data support specific dosing recommendations should be supplied in the Clinical Overview document, the individual study results and any cross-study analyses that will be used to support the dosing recommendations (including the recommended starting and maximal doses, the method of dose titration, and any other instructions regarding individualisation of dosage) should be summarised here. 2. 7. 3. Persistence of Efficacy and/or Tolerance Effects Available information on persistence of efficacy over time should be summarised. The number of patients for whom long-term efficacy data are available, and the length of exposure, should be provided. Any evidence of tolerance (loss of therapeutic effects over time) should be noted. 2. 7. 3. 6 Appendix Tables and figures should be embedded in the text of the appropriate sections when that enhances the readability of the document. Lengthy tables can be provided in the appendix at the end of the Section. Tables should identify all studies pertinent to the Page 60 of 110

GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 evaluation of efficacy (including studies that were 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, and studies described in abbreviated reports); and should provide the most important results of those studies. 2. 7. 4 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. . , the integrated analyses of safety that are routinely submitted in some regions. The display of safety-related data can be considered at three levels: 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 summarised. Serious adverse events and other significant adverse events should be identified and their occurrence should be summarised.

The safety profile of the drug, described on the basis of analysis of all clinical safety data, should be outlined in Page 61 of 110 GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 a detailed, clear, and objective manner, with use of tables and figures. 2. 7. 4. 1 2. 7. 4. 1. 1 Exposure to the Drug Overall Safety Evaluation Plan and Narratives of Safety Studies The overall safety evaluation plan should be described briefly, including special the considerations nonclinical data, and any bservations concerning relevant pharmacological class effects, and the sources of the safety data (controlled trials, open studies, etc). A tabular listing of all clinical studies that provided safety data, grouped appropriately, should generally be provided. Narrative descriptions of these studies should be provided here, except that narrative descriptions for studies that contributed both efficacy and safety data should be included in Section 2. 7. 3. 2 and crossreferenced here.

The narratives should provide enough detail to allow the reviewer to understand the exposure of study subjects to the test drug or control agent, and how safety data were collected (including the methods used and the extent of safety monitoring of the subjects enrolled in the individual studies). If some studies are not analysed separately but are grouped for safety analysis, that should be noted, and a single narrative description can be provided. 2. 7. 4. 1. 2 Overall Extent of Exposure Page 62 of 110

GUIDELINES ON COMMON TECHNICAL DOCUMENT (CTD) 28. 10. 2010 A table and appropriate text should be generated to summarise the overall extent of drug exposure from all phases of the clinical study development programme. The table should indicate the numbers of subjects exposed in studies of different types and at various doses, routes and durations. It is assumed that all subjects who were enrolled and received at least one dose of the treatment are included in the safety analysis; if that is not so, an explanation should be provided.

A summary table should provide the reader with an overview of the demographic characteristics of the population that was exposed to the therapeutic agent during its development. 2. 7. 4. 2 2. 7. 4. 2. 1 Adverse Events Analysis of Adverse Events Data on the frequency of adverse events should be described in text and tables. Text should appear in the appropriate subsections of Section 2. 7. 4. 2. 1 and the tables that are not embedded in the text should be placed in the Section 2. 7. 4. 7 Appendix. All

Cite this A Guide on the Preparation of a Common Technical Document

A Guide on the Preparation of a Common Technical Document. (2016, Oct 01). Retrieved from https://graduateway.com/a-guide-on-the-preparation-of-a-common-technical-document/

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