Industry Book of Knowledge Practical Considerations for ectd Submissions: US IND Applications in ectd format: A CMC Perspective

Industry Book of Knowledge Practical Considerations for ectd Submissions: US IND Applications in ectd format: A CMC Perspective A compilation of points to consider based on collective experiences from: Abbott, Amgen, Astellas, Amylin, AstraZeneca, B.Braun Medical, Boehringer Ingelheim, Bristol Myers Squibb, Cephalon, Eli Lilly, Glaxo-Smith Kline, Johnson & Johnson, Merck, Novartis, Pfizer, sanofi aventis, Takeda, Talecris, Wyeth

Authors: Abbott, Amgen, Astellas, Astra Zeneca, B. Braun, Boehringer-Ingelheim, Eli Lilly, epharmacmc, Glaxo-Smith Kline, Johnson & Johnson, Merck, Novartis, Pfizer, sanofi-aventis, Takeda March 24, 2010 2

Contents US INDs in ectd format: A CMC Perspective 2010 LIST OF TABLES... 4 1. ECTD IND ATTRIBUTES... 6 1.1 GUIDANCE... 6 1.2 DRUG SUBSTANCE ATTRIBUTES... 6 1.3 DRUG PRODUCT ATTRIBUTES... 6 1.4 COMPARATOR/PLACEBO ATTRIBUTES... 7 1.5 EXCIPIENT ATTRIBUTES... 10 1.6 APPENDICES ATTRIBUTES... 10 2. ORGANIZATION/LOCATION OF CMC INFORMATION IN AN ECTD IND... 11 2.1 MODULE 1... 11 2.2 MODULE 2... 11 2.3 MODULE 3... 11 3. STRATEGIES FOR ASSEMBLING AN INITIAL CMC SECTION OF AN IND IN ECTD FORMAT... 12 4. OPTIONS FOR ORGANIZATION AND LOCATION OF CMC INFORMATION FOR COMPARATORS AND PLACEBOS 16 5. LIFE CYCLE MANAGEMENT... 16 5.1 RESPONDING TO FDA QUESTIONS OR REQUESTS FOR INFORMATION... 17 5.2 IND CMC INFORMATION AMENDMENTS... 17 5.3 IND ANNUAL REPORTS... 17 5.4 MEETING REQUESTS AND BRIEFING DOCUMENTS... 18 6. FREQUENTLY ASKED QUESTIONS... 18 APPENDIX I: RELEVANT GUIDANCE... 20 ICH:... 20 FDA:... 20 FDA TECHNICAL ASSISTANCE:... 20 INDUSTRY BOOK OF KNOWLEDGE:... 20 March 24, 2010 3

List of tables Table 1 Examples of drug substance attributes... 6 Table 2 Examples of drug product attributes... 7 Table 3 Examples of comparator attributes... 8 Table 4 Examples of placebo attributes... 9 Table 5 Examples of excipient attributes... 10 Table 6 Using Module 3 full granularity for the body of CMC information... 12 Table 7 Using Module 2 single document granularity for the body of CMC information... 13 Table 8 Using Module 2 with increased granularity for the body of CMC information... 14 Table 9 Using a combination of both Modules 2 and 3 for the body of CMC information... 15 Table 10 Using Module 3 with single document granularity for the body of CMC information... 16 Table 11 Answers to frequently asked questions... 18 March 24, 2010 4

Introduction The purpose of this document is to provide helpful considerations in developing a company strategy for submitting the Chemistry, Manufacturing and Controls (CMC) IND information in ectd format for both biotech and small molecule drug products. Since there are no official guidelines for ectd INDs, this document provides options derived from broad Industry experience to help companies determine how to organize and present IND information using the principles of the ectd format. Since most companies conduct clinical trials globally, the options described provide opportunities to avoid reworking the same information into multiple different formats for clinical trial applications in other countries. This document is considered to be a living document and, as we gain more experience with ectd IND submissions, this document will be updated with any new useful information. Questions or comments may be directed to murdend@epharmacmc.com at any time. This document is not intended to be an instructional tool for ectd submissions. For that, please consult the guidances recommended in Appendix I. This document will cover the following topics: Defining useful ectd IND attributes 1 for Drug substance Drug products: products under development as well as comparators, placebos, diluents, lead-in medications, challenge agents, etc. Excipients Options for the organization and location of CMC documents in ectd INDs Options for the organization and location of comparator / placebo information Life cycle management Frequently asked questions and answers 1 Attributes = metadata March 24, 2010 5

1. ectd IND Attributes 1.1 Guidance Planning the choice of attributes is critical for managing ectd INDs throughout the product lifecycle. Attributes are assigned at the Module 3 heading levels of 3.2.S, 3.2.P, 3.2.P.4, and 3.2.A as well as Module 2 at the headings of 2.3.S, 2.3.P and 2.3.A. Once attributes are used to build an ectd submission, they cannot be changed. Therefore care should be taken to choose more general terms for the attributes, thereby allowing maximum flexibility during product development. Additionally, it should be noted that not all attribute values are required by the ICH specification, and it may make sense to omit a value for some of the optional attributes to ensure future flexibility in dossier presentation. Examples of attributes that could be considered for the CMC information in ectd INDs follow. 1.2 Drug substance attributes There are two required attributes to be assigned to the drug substance CMC information: drug substance name and manufacturer. Table 1 provides examples of attributes that would allow for the flexibility of changes during development. Table 1 Examples of drug substance attributes Drug substance attributes Substance Examples Company code INN or modified INN* Abbreviated INN** Manufacturer Sponsor company name Manufacturing site name or city location Common + Site-specific designations General reference such as all, not specified or applicant *Modified INN = INN + salt or solvate ** Abbreviated INN = INN shortened to reduce the number of characters 1.3 Drug product attributes Although no attributes are technically required for the drug product CMC information, there are three possible attributes that can be assigned to facilitate the organization of information: drug product name, dosage form and manufacturer. Table 2 provides examples of attribute selections. March 24, 2010 6

Table 2 Examples of drug product attributes Drug product attributes Product name Examples Company code INN or modified INN* Abbreviated INN** General term such as active Functional terms such as diluent, lead-in medication, challenging agent [not required, so leave blank]*** Dosage form (do not include strength) Specific dosage form designations such as tablet, capsule, liquid, film-coated tablet, injection General term such as all [not required, so leave blank]*** Manufacturer Sponsor company name Manufacturing site name or city location Common + Site-specific designations General reference such as all, not specified, or applicant [not required, so leave blank]*** *Modified INN = INN + salt or solvate ** Abbreviated INN = INN shortened to reduce the number of characters *** May be tool-dependent such that the build tool may require this information. 1.4 Comparator/Placebo attributes As will be discussed in Section 3 Organization/Location of CMC information in an ectd IND, the CMC information for comparators and placebos may reside in a variety of locations in an ectd IND and, in some cases, the assignment of attributes may not be necessary. March 24, 2010 7

Table 3 and Table 4 provide examples of possible attributes for comparator and placebo information as appropriate. March 24, 2010 8

Table 3 Examples of comparator attributes Product name Comparator attributes Examples INN Tradename General reference such as comparator * (use ectd titles for differentiation between comparators) [not required, so leave blank]** Dosage form (do not include strength) Specific dosage form designations such as tablet, capsule, liquid, film-coated tablet, injection Modification reference such as encapsulated tablet General term such as all [not required, so leave blank]** Manufacturer Sponsor name Manufacturing site name or city location General reference such as all, not specified, or applicant [not required, so leave blank]** *For consistency, when choosing a very general attribute for the name of the investigational drug product name, e.g., active, it would be appropriate to use the more general attributes of comparator ** May be tool-dependent such that the build tool may require this information. March 24, 2010 9

Table 4 Examples of placebo attributes Placebo attributes Examples Product name Placebo 1, 2, etc. Company Code of the active (use ectd titles to differentiate the placebo information from the active) General term such as placebo * (use ectd titles for differentiation between placebos) [not required, so leave blank]** Dosage form (do not include strength) Specific dosage form designations such as tablet, capsule, liquid, film-coated tablet, injection General term such as all [not required, so leave blank]** Manufacturer Sponsor name Manufacturing site name or city location General reference such as all, not specified, or applicant [not required, so leave blank]** *For consistency, when choosing a very general attribute for the name of the investigational drug product name, e.g., active, it would be appropriate to use the more general attributes of placebo. ** May be tool-dependent such that the build tool may require this information. March 24, 2010 10

1.5 Excipient attributes Based on the organization and location of the ectd IND CMC information, it may or may not be necessary to assign excipient attributes. However, as applicable, options for excipient attributes are provided in Table 5. Table 5 Examples of excipient attributes Excipient type Compendial excipients Attribute examples compendial (all compendial excipients, including those with additional testing are covered in one 3.2.P.4 section) compendial + testing (for those excipients that have additional testing performed.) Non-compendial excipients Non-compendial excipient name (each non-compendial excipient CMC information is included in a separate 3.2.P.4 section) Functional references such as coatings and binders (excipients grouped by function in separate 3.2.P.4 sections. If more than one excipient is covered in a 3.2.P.4 section, differentiation is managed by ectd titles.) Compendial excipient name when additional testing is performed Excipients of human and animal origin and novel excipients animal-human-novel common all 1.6 Appendices attributes It is not necessary to assign attributes for the appendices section. Appendices are automatically generated based on any manufacturer attribute assigned and are followed by the drug substance or drug product name and dosage form associated with the manufacturer attribute. The appendix 3.2.A.3 Excipients section is not a repeating appendix. Therefore assigning a more general attribute is recommended if more than one novel excipient is used in a formulation or if the excipient composition could change. There is minimal industry experience in this area. March 24, 2010 11

2. Organization/location of CMC information in an ectd IND The CMC section of an IND in ectd format can take many forms of organization. The first consideration is location of information in the ICH XML Backbone. With all ectd submissions, there are no validation criteria for location of information. Although Module 1 requires a fixed structure for the placement of administrative information, the placement of drug substance and drub product CMC information can follow a more flexible organizational approach, i.e., it can be located in Module 2, Module 3 or both Module 2 and 3. This flexibility in strategy should be considered in order to maximize opportunities for updating dossier content as development proceeds. 2.1 Module 1 The IND CMC-related items that now have specified locations in Module 1 of the US ectd are provided below. For ease of review of all IND applications, note the Module 1 heading for the following specific items. Please consult the FDA headings and hierarchy document as well as Module 1 Specification, as listed in Appendix I, for further detail. DMF letters of authorization Environmental Analysis Investigational Drug Labeling Cross reference to other applications Meeting Request, Background Materials and Correspondence regarding meetings Special protocol assessment request Stability study Quality Information Amendment Annual Report Summary of Manufacturing and Microbiological Changes 2.2 Module 2 A traditional Quality Overall Summary (QOS) is not required for an IND submission. An introduction or abbreviated summary of the IND CMC information may be provided in Module 2. In addition, there may also be reasons to place the body of the IND CMC information in Module 2, rather than Module 3. This decision can only be made after considering the basic principles of ectd, lifecycle management, any feedback received from the FDA, the limitations of software tools in place at your company and, of course, your company s desired business practices for authoring and publishing investigational applications. 2.3 Module 3 The principles of ectd, as they apply to Module 3 for an investigational application, need not be applied in the same manner as for marketing applications. Again, the decision for how to arrange the CMC information in Module 3 can only be made after considering the basic principles of ectd, lifecycle management, any feedback received from the FDA, the limitations of software tools in place at your company and, of course, your company s desired business practices for authoring and publishing investigational applications. March 24, 2010 12

3. Strategies for assembling an initial CMC section of an IND in ectd format Table 6 through Table 10 provide examples of CMC document location and granularity that are acceptable options for ectd INDs. As there are multiple options available, it is recommended that, for reviewer convenience, the cover letter for the ectd IND submission include an explanation of where the CMC information is located. Table 6 Using Module 3 full granularity for the body of CMC information CTD Module Item Comments Module 1 See Section 2.1 Module 1 Module 2 Module 3 Either a full QOS can be provided or only a document under 2.3 Introduction Full Module 3 Granularity that includes documents under 3.2.S., 3.2.P., 3.2.A., and 3.2.R. For example 3.2.S.1 General Properties 3.2.S.2 Structure 3.2.S.3 Nomenclature Etc. One or more documents for each CTD heading, as appropriate. Advantages Suitable for managing CMC dossiers for other regions through customized CMC document creation and for building CMC dossier content progressively over time Points to Consider Only those documents that need to be updated for an IND amendment need to be revised Can be used for all phases of development Allows consistent authoring practices for both investigational and marketing dossiers. Incremental publishing, when the tools permit, is efficient for late input (e.g., stability data) Bookmarks and headings, because of ICH restrictions on levels, can cover more subtopic in a more granular document approach rather than in a single document covering many topics. Mistakes are easily addressed without subjecting old content to re-review by the Agency. Content is minimal in early phases of development and this approach will result in multiple small documents that may be cumbersome to review (potential tool enhancement would remedy this). Depending on the attributes chosen, multiple S and/or P sections will be created and information provided in the cover letter of introduction to an amendment should identify what drug substance or drug product is currently being used in clinical trials. March 24, 2010 13

Table 7 Using Module 2 single document granularity for the body of CMC information CTD Module Item Comments Module 1 See Section 2.1 Module 1 Module 2 2.3 Introduction 2.3 Drug Substance 2.3 Drug Product 2.3 Appendices Single or multiple documents under each heading depending on the choice of attributes. Module 3 No content here Granularity is not appropriate at early stages of development. CMC sections are only summaries and thus kept in Module 2. Advantages Minimal investment in dossier management for early phase INDs Points to Consider Suitable for managing paper CMC dossiers for other regions, i.e., no compilation step needed Allows review of more information in a single document Can be used for all phases of development Keeps Module 3 clean for later use in presenting the market image/commercial formulation Can transition to a strategy providing content in module 3 at a later time in development Complete document needs to be replaced when updating the CMC information, i.e., resubmitting information that has already been reviewed March 24, 2010 14

Table 8 Using Module 2 with increased granularity for the body of CMC information CTD Module Item Comments Module 1 See Section 2.1 Module 1 Module 2 2.3 Introduction 2.3 Drug Substance 2.3.S.1 to 2.3.S.7 (7 documents here) 2.3 Drug Product 2.3.P.1 to 2.3.P.8 (8 documents here) 2.3 Appendices Module 3 No content here Granularity is not appropriate at early stages of development. CMC sections are only summaries and thus kept in Module 2. Advantages Suitable for managing CMC information over all phases of development Points to Consider Suitable for multiple author access for editing Because of the increased granularity of the module 2 documentation, only those documents that need to be updated are revised for information amendments. Can move to a strategy with providing content in module 3 when it makes sense in development More documents to manage in a document management system Can be too many small documents, cumbersome to review March 24, 2010 15

Table 9 Using a combination of both Modules 2 and 3 for the body of CMC information CTD Module Item Comments Module 1 See Section 2.1 Module 1 Module 2 Module 3 2.3 Introduction 2.3 Drug Substance 2.3 Drug Product 2.3 Appendices 2.3 Regional S.4.4 Batch Analysis S.7.3 Stability Data P.5.4 Batch Analysis P.8.3 Stability Data Single document for each heading in Module 2.3 Only these sections of data are provided in Module 3 (batch analysis and stability data). Full narrative CMC summaries are still kept in Module 2.3. Advantages Suitable for managing CMC over all sections with more frequent updates (batch analysis and stability) are smaller discrete document and are easily managed throughout development Points to Consider These data may be useful to have in Module 3 for lifecycle history, as they may be used to support phase 2A/2B formulations Watch the use of attributes in Module 3 for these limited data. Keep them general Use descriptive ectd titles rather than attributes to manage the Module 3 sections To ensure that the reviewer is aware that CMC information is in both Module 2 and Module 3, clearly reference the Module 3 documentation in the Module 2 documents and possibly use hyperlinks to connect. March 24, 2010 16

Table 10 Using Module 3 with single document granularity for the body of CMC information CTD Module Item Comments Module 1 See Section 3.1 Module 2 2.3 Introduction Only a CMC introduction is provided Module 3 3.2.S Drug Substance 3.2.P Drug Product 3.2.A Appendices Advantages Minimal investment in dossier management for early phase INDs Points to Consider Provide a single summary document for each heading. Suitable for managing CMC dossiers for other regions, i.e., no compilation step needed Allows review of more information in a single document Can be used for all phases of development ectd builder tools at your company may not allow a document to be placed directly under 3.2.S and 3.2.P Depending on the attributes chosen, multiple S and/or P sections will be created and information provided in the cover letter of introduction to an amendment should identify what drug substance or drug product is currently being used in clinical trials. Complete document needs to be replaced when updating the CMC information, i.e., resubmitting information that has already been reviewed 4. Options for organization and location of CMC information for comparators and placebos As comparators and placebos are supportive products in development, there are even more options to consider when determining where the corresponding CMC information for these products can reside when using ectd format. In addition to using one of the same options as provided for your investigational drug product in Section 3, comparator and placebo information can also be provided as a single document in Module 1.11.1 Quality information amendment or under Regional Information. 5. Life cycle management Once the IND is submitted in ectd format, all subsequent submissions must be made in ectd format and this will require an understanding of the ectd operators: append, delete, new and replace. Please refer to the Industry Book of Knowledge: Practical Considerations for ectd Submissions: A CMC Perspective for a basic understanding of the ectd paradigm for a discussion on how these operators apply to CMC information. Depending on the strategy for the organization of the body of CMC information, some companies visibly highlight the changed CMC information in the revised documents. This decision should be March 24, 2010 17

carefully considered as it will have impact when the CMC documentation is intended for use in more than one investigational trial dossier For ectd INDs, life cycle management will include the following submission types: Responses to FDA questions or requests for information IND CMC information amendments IND annual reports Meeting requests and briefing documents 5.1 Responding to FDA questions or requests for information Many companies are using the Module 1, Section 1.11.1 Quality Information Amendment location for the responses to FDA questions and requests for information. The operator used for subsequent responses is new as these are non-related documents. Any necessary revisions to the body of CMC information, based on the response, will be managed according to the chosen strategy of the organization of the CMC information. For example, if the company strategy was to use full Module 3 granularity, the appropriate document in Module 3 would be replaced with a new document. If the company strategy was to use Module 2, the appropriate document there would be replaced with a new document. Cross references, with or without hyperlinking can be made from the response document to the changed CMC information. 5.2 IND CMC information amendments Generally, an introduction describing the content of the CMC information amendment is provided and it is usually located in Module 2, Section 2.3 Introduction. However Module 1, Cover Letter or Module 1, Section 1.11.1 Quality Information Amendment have also been successfully used. Companies use the operators new or replace for subsequent IND CMC information amendment introductions. The necessary revisions to the body of CMC information will be managed according to the chosen strategy of the organization of the CMC information. For example, if the company strategy was to use full Module 3 granularity, the appropriate document in Module 3 would be replaced with a new document. If the company strategy was to use Module 2, the appropriate document there would be replaced with a new document. Cross references, with or without hyperlinking can be made from Introduction to the changed CMC information. 5.3 IND Annual Reports Module 1, Sections 1.13.5 Summary of Manufacturing Changes and 1.13.6 Summary of Microbiological Changes are the defined locations for the ectd IND Annual Reports. Each year, the annual report documents will have the operator new. Depending on your company s strategy for including new CMC information in an annual report, revisions to the body of CMC information will be managed according to the chosen strategy of the organization of the CMC information. March 24, 2010 18

For example, if the company strategy was to use full Module 3 granularity, the appropriate document in Module 3 would be replaced with a new document. If the company strategy was to use Module 2, the appropriate document there would be replaced with a new document. Cross references, with or without hyperlinking can be made from the Module 1, Sections 1.13.5 Summary of Manufacturing Changes and 1.13.6 Summary of Microbiological Changes documents to the changed CMC information. 5.4 Meeting requests and briefing documents Module 1, Section 1.6 Meetings is the location for FDA meeting requests, meeting background information and correspondence related to the meetings. It is technically possible to use the pre- IND meeting information as the initial sequence (0000) of the ectd IND. However, if the ectd IND is the initial sequence, some companies will resubmit the pre-ind meeting information to capture it as part of the ectd IND history. 6. Frequently asked questions Table 11 Answers to frequently asked questions Question 1 If a company uses a less granular approach for the organization of CMC information early in development, is it necessary to increase the granularity as development progresses? 2 If a company uses Module 2 for the primary location of their CMC information early in development, when should the company move the CMC information to Module 3? 3 Is there any company experience with cross referencing an ectd IND in an NDA application? 4 How important are the Sponsor s tools for generating, storing and compiling CMC information as well as generating ectd submissions in determining a company strategy for ectd INDs? 5 Where are companies providing their BSE/TSE information in ectd INDs? Answer To date, companies have been successful in either maintaining or increasing the granularity of their CMC information. The decision to move the location of CMC information from Module 2 to Module 3 should be based life cycle considerations of the document and on company strategy for managing CMC documentation. There is company experience in cross-referring to other US INDs and NDAs (this can be done in Module 1.4.4 with a textual cross-reference), but few companies have experience using a technical cross-reference. However it is acknowledged that this must be done per pdf document (and not, for example, per 3.2.S section) and hence has limited attraction The sponsor s tools can have impact on the company s strategy for the organization of CMC information. For example, although the ICH ectd Specification Guidance allows for a document to be included under the heading of 3.2.S and 3.2.P (see Table 10); this is not technically feasible with some tools. It is important to know what restrictions your tools have. Either with the applicable drug substance or drug product section (e.g., 3.2.P.2 and/or 3.2.P.4.5) or in the A.2 Adventitious agents safety evaluation section. March 24, 2010 19

Question 6 How is the information for radio-labeled for drug substances / drug products being handled in ectd INDs? Options: Answer As a separate S or P section Managed through descriptive titles when attribute choices were general 3.2 R Regional Information 7 How are companies efficiently maintaining global CMC information documentation? All described strategies for the organization of CMC information permits easy re-use of documents 8 How are companies converting paper INDs to ectd INDs? Either at the time of the IND Annual Report or at will 9 How are companies managing in-licensed products that are already in ectd format? Once an IND is submitted in ectd format, all subsequent submissions must be in ectd format regardless of the IND holder. Recognizing that different companies can have different strategies for managing CMC information in ectd INDs, it is important to give careful and early consideration for how you will manage your first CMC Information amendment for this in-licensed product. 10 How are companies managing the CMC information for clinical trial supplies that are no longer used; is this information typically deleted? Deleting such information can be a company strategy but he FDA does not expect this to be done. Deleting CMC information does require careful consideration. March 24, 2010 20

APPENDIX I: Relevant Guidance ICH: M2 WG: http://estri.ich.org/ectd/ectd_specification_v3_2_2.pdf FDA: Providing Regulatory Submissions in Electronic Format Human Pharmaceutical Product Applications and Related Submissions Using the ectd Specifications http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/uc m072349.pdf FDA ectd Table of Contents Headings and Hierarchy [PDF] (updated 7/7/2005) ectd Backbone Files Specification for Module 1 [PDF] (updated 12/13/2006) FDA Technical Assistance: For more general information regarding the preparation of submissions in electronic format, please contact the Electronic Submissions Coordinator at esub@fda.hhs.gov. Industry Book of Knowledge: Practical Considerations for ectd Submissions: A CMC Perspective for a basic understanding of the ectd paradigm http://www.iriss-forum.org/?page_id=154 March 24, 2010 21