A Guide on the Preparation of a Common Technical Document

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Demonstration of safety and efficacy of the drug product for use in humans is essential before the drug product can be approved for import or manufacturing of new drug by the applicant by Central Drugs Standard Control Organization (CDSCO). 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. under 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. 10. 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.

o 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.g. 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 information 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.

10. 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.

2 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.

3. 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.

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.

2. 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).

1. 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 composition; 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.

5. 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 1.10 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.

28. 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.

2. 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.

3. 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 appropriate, 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.2 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).

28. 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.

6 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.

the 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 information. 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.g. , 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 pharmacokinetics; 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).

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