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IND Submissions: A Primer

Barnett Educational Services
March 3, 2009
SKU: BNT2127076

Abstract Table of Contents Related Reports

IND Submissions: A Primer provides a “hands-on” approach that teaches regulatory professionals - novice and veteran alike - to work with the regulations, guidance documents, content templates, contributing authors, and style guides necessary to write an IND. The book’s writing tips show regulatory professionals how to produce a range of U.S. drug and biologics submissions that comply with the requirements and are also clear to read. Included with the book is a CD filled with electronic examples.

IND Submissions: A Primer is the only comprehensive IND manual of its kind. This 600-page, spiral-bound, hardcover book is easy to use, providing step-by-step instructions on how to plan, write, and submit regulatory documents. Each chapter (62 in total) is divided by easy-to-read tabs. It is the ideal resource for new professionals entering the field, a useful training guide, and a valuable reference for the experienced professional.

Specific topics include:

Regulations and guidance document references
Overview and background of why the submission is required
Structure of the submission itself
Details on who should contribute to the submission
Where to pull, re-use, or start as a basis for information needed in a submission
Tips and lessons learned from the author's experience
Different perspectives on how a submission can be approached
Applicable FDA Form 1571 information for each submission
Paper publishing tips
Electronic CTD publishing sections for each submission, where applicable
Real life examples taken from the press and approved NDAs when available
Electronic examples and content templates to utilize so that an RA professional can begin immediately working on a submission

The book’s author, Meredith Brown-Tuttle, RAC, is a regulatory consultant whose background incorporates all aspects of drug, device, and biologics development including clinical research, data management, medical writing, and regulatory affairs. She served for six years on the Board of Editors for the Regulatory Affairs Professional Society’s journal, “Focus,” and has published numerous articles, edited books and book chapters, and presented at professional meetings on a variety of clinical research and regulatory topics. Ms. Brown-Tuttle also teaches about regulatory submissions, intelligence, strategy, and agency interactions for the Regulatory Affairs Certificate program at UC Santa Cruz.

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Chapter 1: Style Guides; Guidance Documents; What is a Style Guide?; Why do you Need a Style Guide?; Is a Style Guide Required?; Requirements from the Guidance Documents; Recommendations from the AMA & other sources; Headings; What will your headings look like?; Headers and Footers; What do you include in the header and/or footer?; List of Figures and Tables; Table and Figure Headings; Table and Figure Footers; Figure Style; Table Style; Header and Footer Numbering; Acronyms, Abbreviations and Definitions; Indentation; Lists; Text; Citation Reference; Title Page; Confidentiality Statement; Punctuation and Grammar; Numbering; Date Format; Superscript and Subscript; Breaks; Trademark; Bookmarks; Hyperlinks; GLP or GCP Statement; Proofreader’s Marks; What to do with Documents Received from Contributors?; How do you Create a Style Guide?; Tip; Training Users; Including Style Guide Elements as a Style Sheet; Color Copies; Tips; Electronic Examples; Reproduction prohibited 00:iii
Chapter 2: Creating and Use of Content Templates; Steps for Content Template Use; Why Use a Content Template?; Tips; Electronic Examples
Chapter 3: Submission Planning; Outlining the Submission; Submission Contributions; Submission Checklist & Creating the Timeline; Defining Timelines Using the; Submission Timing; Submission “Kick-off” Meeting; Submission “Kick-off” Memo; Submission Management; What to do with Corrections, Edits and Contributions from Previous Drafts; Monthly Planning Meetings and Tracking; Submission Scheduling; Bundling Items for Submission Every 30 Days; Submission Content Re-use; Tips; Electronic Examples
Chapter 4: Writing, Organization and Editing Tips; Writing Goals; Submission Pitfalls; Inverted Pyramid Writing Style; Areas of Contributions; Who Writes Submissions?; Contributions from Other Departments; Sections Written by Regulatory Personnel; Editing Process: What to do with all the Editorial Changes?; Individual Edits; Group Editing Sessions; Corrections, Edits and Contributions from Previous Drafts; Submission Content Re-use; Developing Key Messages
Chapter 5: Forms; Regulations; FDA Form 1571; Filling Out FDA Form; Cross-Referencing Multiple INDs; FDA Form 1571—Serial Number Errors; How Many Boxes can you Check in Item; FDA Form; FDA Form 3500A; Re-use Tips; Pagination; Reproduction prohibited 00:v; Print Single- or Double-Sided?; Form Expiration Dates; Original, Original, Who has the Original?; Tips; Electronic Examples; References
Chapter 6: Submission Basics; Regulations; What is a Submission?; Locking Down Sections; The Cover Letter; Information Previously Submitted; IND Submission Numbering; Tracking Submission Numbers; How does a Sponsor Address Duplicate Submission Numbers?; Number of Copies Needed; Desk Copies; Need for Agency Response; Where to Send the Submission; What Happens to a Submission When it Reaches FDA?; Shipping the Submission; Tracking Submission Shipment; Tips
Chapter 7: Assuring Quality in a Submission; Regulations; Supporting Documentation; QA of Submission Against Source or Supporting Documentation; Documenting the QA; How is Electronic Submission QA Different?; Electronic Checksum; Submission QA; Formatting; Pages; Page Orientation; Copy Quality; Length; Pagination; Tabs & Slip Sheets; Volume Size; Cover Letter; FDA Form; Binder Label; Bookmarks/Hyperlinks; Checksum; Tips; Electronic Examples
Chapter 8: Paper Publishing; Regulations & Guidance Documents; Publishing Tools/Technologies; Publishing Process: Hybrid; Binder Covers; Where to Find Binder Covers; Binder Specifications; IND Binder Cover Colors; FDA Perspective on Binders Usage and Color; Labels; Pagination; How to Handle Blank Pages; Copies for Submission; Tabs; Slip Sheets; Volumization; Scanners; Copiers; FDA Form; Assembling the Submissions; Shipping; Packing Carton Specifications; Tips; Electronic Examples; References
Chapter 9: Electronic Publishing; Regulations; Guidance Documents; MAPPs; Specifications; Electronic Publishing; What are Electronic Publishing Advantages?; Electronic Publishing Disadvantages; How do Electronic Submissions Relate to 21 CFR Part 11?; What is a Submission?; Publishing Process; Publishing Tools/Technologies; Tools Needed for Electronic Submissions; Challenges to Implementing an Electronic Publishing System; Scanners; Electronic CTD (eCTD); eCTD Basics Overview; XML; Metadata; XML Backbone; Style Guide; Directory Structure; Folder and File Naming Conventions; Reproduction prohibited 00:vii; Document Formats for eCTS; What File Formats Should I Use for Electronic Datasets?; Granularity; How Granularity Affects Content Templates; (TOC); Hyperlinks and Bookmarks; Pagination; PDF Overview; Security; Checksum; Lifecycle Management; Archive; Electronic Submissions Procedures; Media Requirements for Submission; Media Label Requirements; FDA Form; FDA Form; Quality Assurance; How do you Start the Electronic Publishing Process with the Agency?; Additional Elements to Include in the Cover Letter; If Submitting Electronically, are Paper Copies also Needed?; Document Information for Previous Submissions; Do you Resubmit Information Already Submitted in Paper?; Referencing Previously Submitted Information; Receipt Date For Electronic Submissions; eCTD Submission Waivers; Technical Problems or Questions; Electronic Submission Gateway; Involvement of IT; Commitments; Tips; Electronic Examples; References; Table 1: Glossary of Electronic Terms; Table 2: FDA ESG Monthly Submission Statistics
Chapter 10: Tracking Submissions, Agency Communication and Commitments; Regulations & Guidance Documents; Index History - Background; How to Organize an Index History; Outstanding Items and Questions Log; Index History Software Available; Agency Contact and Documentation; Sharing Files with Other Departments; Conclusion; Tips; Electronic Examples; Table 1: Index History Example—Word Processing Table; Table 2: Information to Track in a Premarketing Application Index History; Table 3: How to Create an OI or OQ List
Chapter 11: Filing Considerations; Regulations; Paper Archives; How to File; Where to File; What to File; Submission Copies; Electronic Archives; Electronic Submissions in Process; Electronic Record of Paper Submissions; How Long to Keep Records; How to Deal with Expanding Paper Files and Insufficient Space; Paper Filing System Options; File Folder and Binder Selection; File Folder Color Coding; Tips; Table 1: File Storage Options
Chapter 12: Managing References; Regulations; Guidance; What Needs to be Cited; Foreign References; FDA Recommended Style; How are Citations Located?; Citation Search Engines; What is PubMed; Process for Triaging Incoming References; Bibliographic Software; Pagination; Tabs & Slip Sheets; eCTD Format; Electronic Examples; Tips
Chapter 13: The Common Technical Document Format; Guidance Documents; Electronic CTD (eCTD); Hybrid CTD; CTD Guidance Documents Defined; What is a Module?; Sections of the CTD; What is an Overview?; What is a Summary?; Module 1 - Contents; Module 2 - Contents; 2.1 -; 2.2 - CTD Introduction; 2.3 - Overall Quality Summary; 2.4 - Nonclinical Overview; 2.5 - Clinical Overview; Reproduction prohibited 00:ix; 2.6 - Nonclinical Written and Tabulated Summary; 2.7 - Clinical Summary; Module 3 - Quality; 3.1 -; 3.2 - Body of Data; 3.3 - Literature References; Module 4 - Nonclinical Study Reports; 4.1 -; 4.2 - Study Reports and Related Information; 4.3 - Literature References; Module 5 - Clinical Study Reports; 5.1 -; 5.2 - Tabular Listing of all Clinical Studies; 5.3 - Clinical Study Reports; 5.4 - Literature References; Can you Add New Numbers into the CTD Format if Needed?; Does the CTD Replace the NDA and BLA?; Does the FDA Accept NDA’s and BLA’s in a non-CTD Format?; Where to Put the ISS and ISE?; How do you Deal With Multiple Quality Sections for Combination Products or Multiple Indications?; Transferring IND Information into the CTD Format; Once you Use the CTD Format, do you Always Need to Use it?; When can you Switch to the CTD Format?; Other Types of Submissions Using the CTD Format; How is Pagination Different in the CTD Format?; Electronic Examples
Chapter 14: Electronic Document Management Systems; Regulations; Guidance Documents; What is an EDMS?; Attributes of an Efficient Filing System; Why would a Company Use an EDMS System?; How does an EDMS Organize Documents?; How do you Implement an EDMS?; Converting from Paper to Electronic; FDA Definitions; EDMS and Electronic Publishing; Who “Owns” the EDMS?; Tips; Table 1. EDMS Components; Table 2. EDMS Critical Questions
Chapter 15: FDA Meeting Types; Regulations; Guidance Documents; Informal Meetings; Tips; Table 1. Meeting Types; Table 2. Meetings—By Phase of Investigation; Table 3. Clinical Investigations Phases
Chapter 16: Meeting Request; Regulations; Guidance Documents; Question and Issue Development; When to Request a Meeting; How to Request a Meeting; Submission; What to Expect from the Agency after the Request is Submitted; Meeting Request Components; Product Name and Application Number; Chemical name and structure; Proposed indication(s); Type of meeting being requested; Brief statement of the meeting’s purpose; List of the meeting’s specific expected objectives/outcomes; Preliminary proposed agenda; Draft list of specific questions, grouped by discipline; List of agency staff participants sponsor requests for the proposed meeting; Approximate date on which information package will be sent to the agency; Suggested meeting dates and times (i.e., morning or afternoon); Requesting an in-person meeting or teleconference; Cover Letter: Meeting Request; Length; Pagination; FDA Form; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; eCTD Format; Commitments; Waiting Period; Tips; Electronic Examples; Table 1. Types of Issues and Questions; Table 2. Meeting Request Components; Table 3. Draft Meeting Agenda
Chapter 17: Meeting Information Package; Regulations; Guidance Documents; Information Packages; Format for Meeting Packages; Submission; Agenda; Questions/Issues to be Addressed; Meeting Package Due Date; How Many Review Copies to Send; Length; Pagination; Cover Letter; FDA Form; Reproduction prohibited 00:xi; FDA Form; Quality Assurance; Paper Publishing; Tabs & Slip Sheets; eCTD Format; Commitments; Tips; FDA Perspective; Electronic Examples; References; Exercise; Table 1. Information Package—Submission Contents; Table 2. Information Package—Sample for an End-of-Phase 2 Meeting; Table 3. Meeting Types
Chapter 18: Meeting Follow-Up and Planning; Regulations; Guidance Documents; Setting the Date; Meeting Package Due Date; Meeting Rehearsal; Conducting the Meeting; External Experts; In Person or Over the Phone?; Pre-Meeting Minutes Availability; Canceling the Meeting; Length of Meeting; FDA Perspective; Tips; Electronic Examples
Chapter 19: Meeting Minutes; Regulations; Guidance Documents; Agency Perspective; Timing of Agency Meeting Minutes; Sponsor Perspective; Reaching Team Consensus on Meeting Minutes; Timing of Sponsor Meeting Minute Submission; Before the Meeting: Requesting the Agency’s Pre-Meeting Minutes; Whose Meeting Minutes are Official?; Disagreement between Sponsor and Agency Meeting Minutes; Length; Pagination; Format; Cover Letter: Sponsor Meeting Minutes; Cover Letter: Letter for Clarification; FDA Form; FDA Form; Assembling the Submissions; Tabs & Slip Sheets; Paper Publishing; eCTD Format; Commitments; FDA Perspective; Waiting Period; Tips; Electronic Examples; References
Chapter 20: Responding to an Agency Request for Additional Information; Regulations; Getting Team Input; Timeline for Response; Format; Length; Pagination; FDA Form; FDA Form; Other Items to Send with Response; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; eCTD Format; Commitments; Waiting Period; Tips; Electronic Examples
Chapter 21: Dispute Resolution; Regulations; Guidance Documents; Initial Steps to Resolve a Dispute, Chain of Command; Other Kinds of Disputes; Using Consultants; Special Advisory Committee; When to Use Dispute Resolution; Ombudsman; Dispute Resolution Cover Letter; Where to Send Formal Dispute Resolution Requests; Dispute Resolution Submission; What Happens to Requests for Dispute Resolution?; Agency Response; Agency Timeline for Response—PDUFA Products; Agency Timeline for Response—Non-PDUFA Products; Meeting Minutes; Publishing Information; Real World Example; Tips; Electronic Examples; References; Figure 1: Chain of Command for Dispute Resolution
Chapter 22: Types of INDs; Regulations; Commercial IND; Investigator or Research IND; Emergency Use IND; Treatment IND; Screening or Exploratory IND; Table 1. CDER Original INDs Received:Calendar Years 1986-
Chapter 23: Emergency, Compassionate or Single Use INDs; Regulations; When do you Use the Compassionate/Emergency/Single Use IND?; Emergency Use IND; Single Use IND; Compassionate Use IND; How do you Apply for the Compassionate/Emergency/Single Use IND?; Physician Request for an IND for Emergency, Compassionate or Single Use, Submission Contents; What should the Sponsor Submit to Complete the IND File for the Physician?; What does the Sponsor Need to do for the Physician IND?; What does the Physician Need to Provide to the Sponsor?; Publishing; Commitments; Waiting Period; Tips; Other Perspectives; References
Chapter 24: Treatment Use IND; Regulations; Guidance Documents; When to Apply for a Treatment IND?; Treatment IND Submitted by A Sponsor; A Treatment Protocol is to be Supported by the Following; Treatment IND Submitted by a Physician Investigator; ClinicalTrials.gov; Charging for Investigational Drug; When do Sponsors Usually Request to Charge?; FDA Form 1571 - Special Box for Both Treatment IND and Charging for an Investigational Drug?; Tips; Electronic Examples; References
Chapter 25: Exploratory or Screening INDs; Regulations; Guidance Documents; MAPPs; What is an Exploratory IND?; Why Submit an Exploratory IND Instead of a Traditional Commercial IND?; How is an Exploratory IND Different from a Traditional IND?; How do you Apply for the Exploratory IND?; Clinical Section; What Clinical Information should be Included in an Exploratory IND?; Types of Studies; Chemistry, Manufacturing and Control Section; Pharmacology & Toxicology Section; Follow-up INDs; IND Withdrawal; What are FDA Reviewers Looking For?
Chapter 26: The IND Team and How to Start the IND; IND Rules; IND Application; Who Makes Up the Team; IND Strategy Development Team; The IND Strategy; How to Start the IND; Managing the Timeline; Electronic Examples
Chapter 27: IND Basics and Items 1 and 2; Regulations; Guidance Documents; MAPPs; Why Submit an IND?; The IND application must contain information in three broad areas; How are Drug and Biologic INDs Different?; Drugs; Biologics; Confidentiality of IND Submission; Building the IND; Cover Letter; Item 1.0—FDA Form; Item 2.0— (TOC); IND in a CTD Format; Why Submit in the CTD Format?; If you submit in the CTD format, will you have to continue to submit in the CTD format?; Numbering of the IND Amendments; IND Number; How Drug and Biologic IND Numbers are Different; How Drug and Biologic IND Numbers have Changed; Where to Send the Initial IND?; Length; Pagination; Quality Assurance; Does Each Section have its Own Volume?; Should Sections Break Across Volumes?; FDA Receipt of the IND; IND Effective Date; Why is this Date Important?; Reproduction prohibited 00:xv; What do FDA Reviewers Want?; Medical Review; Chemistry Review; Pharmacology/Toxicology Review; Safety Review; Is an IND Approved?; IND Submission Outcome; What typical deficiencies are found?; eCTD Format; Assembling the Submissions; Tabs & Slip Sheets; Paper Publishing; Commitments; Waiting Period; Tips; Other Perspectives; Electronic Examples; IND Exercise; Table 1. IND in a CTD Format; Figure 1: FDA Internal IND Review Process
Chapter 28: Clinical IND Items 3, 4, 5 and 6; Regulations; Guidance Documents; What is a Clinical Investigation?; What is an Investigator?; What is a Human Subject?; What is an Adequate and Well-Controlled Clinical Trial?; Waiver of Requirements for an Adequate and Well-Controlled Clinical Trial; General Requirements for Use of an Investigational New Drug in a Clinical Investigation; When does an IND go into Effect?; When can Drug be Shipped?; Is an IND Required with a Phase I Protocol?; Submitting Multiple INDs for the Same Compound; Item 3.0—Introductory Statement and General Investigational Plan; Section 3.0 Tips—Introductory Statement; Section 3.0—General Investigational Plan; Section 3.0 Tips—General Investigational Plan; Item 4.0—Reserved; Item 5.0—Investigator’s Brochure; Section 5.0—Tips; Section 5.0—Publishing; Item 6.0—Phase 1 Clinical Protocol(s); Additional Items to Send with the Protocol: Informed Consent Form (ICF); What are the Elements of Informed Consent?; Required; Recommended; Additional Items to Send with the Protocol: Case Report Forms; Section 6.0—Tips; Section 6.0—Publishing; How are Biologics Different?; What is the Difference Between Phase I and Phase II Clinical Trial Protocols?; Length; Pagination; Electronic Examples; Table 1. Types of Clinical Trial Designs
Chapter 29: Item 7: Chemistry, Manufacturing and Controls; Regulations; Guidance Documents; MAPPs; Phase; How Do GMPs Fit?; 7.0—Introduction; 7.A—Drug Substance; Drug Substance: Tips; 7.B—Drug Product; Drug Product: Tips; 7.C—Placebo; Placebo: Tips; 7.D—Clinical Labeling; Clinical Labeling: Tip; 7.E—Environmental Assessment; 7.F—Combination Products: The Device “CMC” Section; 7.G—References; When to Start Writing this Section; What are the Minimum Requirements for an IND?; Managing the Timeline; How Biologics Submission would Differ; Tracking of Lots from all Studies; Agency Concerns, Reasons for a Clinical Hold based on the CMC Section; Length; Pagination; Tips; Table 1. Glossary of CMC Terms
Chapter 30: Item 8: Nonclinical IND; Regulations; Guidance Documents; MAPPs; Introduction; Why are Animal Studies Required by Regulatory Agencies?; Typical Nonclinical Safety Studies; Study Strategy; What Types of Studies are Needed to Support the Filing of the IND?; Choice of Animal Model; What is an Integrated Summary?; What is an Integrated Summary? (continued); Section 8—Pharmacology; Section 8—Toxicology; Section 8.D—Qualifications of the Individual(s) who Evaluated the Animal Safety Data; 8.E—Location of Records; Reproduction prohibited 00:xvii; 8.F—GLP Compliance Statement; 8.G—Bibliography/Supportive Literature; Order of Studies; Order of Animals; Route of Administration Order; Dosing Order; Managing the Timeline; Pediatric Population; How a Biologics Submission would Differ; Should Final Study Reports be Included with the Initial IND?; Length; Pagination; Study Report Format; Tips; Electronic Examples; References; Table 1. Nonclinical Study Overview and Considerations; Table 2. Overview of Typical Nonclinical Studies Needed for IND*; Table 3. Glossary of Nonclinical Terms
Chapter 31: IND: Items 9, 10, 11 and Potentially 12; Regulations; Guidance Documents; Item 9.0—Previous Human Experience with the Drug; What Will Section Look Like?; 9.0—Previous Human Experience with the Drug; 9.A—Drug Previously Investigated or Marketed in the U.S. or Foreign Country; 9.B—Drug Combination Previously Investigated or Marketed; 9.C—Drug Withdrawn from Marketing; If this section is not applicable, what do you write?; Item 10.0—Additional Information; What Will This Section Look Like?; 10.0—Additional Information; 10.A—Drug Dependence and Abuse Potential; 10.B—Radioactive Drugs; 10.C—Pediatric Studies; 10. D—Other Information; If this section is not applicable, what do you write?; Item 11.0 - Relevant Information; What Will This Section Look Like?; 11.0—Relevant Information; 11.A—Information Previously Submitted; 11.B—Material in a Foreign Language; If this section is not applicable, what do you write?; Item 12.0—References; What Will This Section Look Like?; 12.0—References; 12.1—Bibliography; 12.2—Copies of Pertinent Literature; Tabs & Slip Sheets; Electronic Examples
Chapter 32: Letters of Cross Reference or Authorization (LOA); Regulations; Guidance Documents; What is a Cross-Reference or Letter of Authorization (LOA)?; Why Request an LOA?; CMC Section of IND or NDA; Drawbacks to LOAs and Consequences to IND Holders for Deficiencies; When do you Use or Need a LOA?; Agent or Consultant LOAs; What Type of Information Needs to be Included in a LOA from a Vendor?; Referencing Another IND; Referencing a DMF; Emergency/Single/Compassionate Use IND Cross-Reference; Who gets Copies of the Letter?; Copy to Applicant, Sponsor or Other Holder; What to do with Original?; Managing the Timeline; Submitting DMF/IND Cross-Reference Cover Letter Format—from a Vendor; Submitting DMF/IND Cross Reference Cover Letter Format - on Behalf of Company, for a Vendor; Length; Pagination; FDA Form; Assembling the Submissions; Paper Publishing; Other Items to Send With the LOA; eCTD Format; Electronic Examples
Chapter 33: IND Amendments; Regulations; Guidance Documents
Chapter 34: New Protocols, Protocol Amendments, Protocol Concept Sheets and Synopses; Regulations; Guidance Documents; Typical Types of Protocol Amendments; Protocol by Phase of Investigation; Managing the Timeline; When to Send In?; When Can a Clinical Trial Begin?; Include the Model Informed Consent Form?; Amendment Process; What Triggers an Amendment; Length; Pagination; Format; Cover Letter: Initial Protocol; Cover Letter: Protocol Amendment; Cover Letter: Protocol Synopsis; FDA Form; FDA Form; Reproduction prohibited 00:xix; Quality Assurance; Items to Submit with the Protocol; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; eCTD Format; Commitments; Waiting Period; Tips; Other Perspectives; Electronic Examples
Chapter 35: Transfer of Obligations; Regulations; Sponsor Responsibilities; What Responsibilities are Usually Transferred to a CRO?; When to Submit?; Submission Length; Pagination; Format; Cover Letter; FDA Form; FDA Form; eCTD Format; Assembling the Submissions; When to Update; Tips; Other Perspectives; Electronic Examples; Table 1. Transfer of Obligations (Example)
Chapter 36: Investigator’s Brochure Update; Regulations; Guidance Documents; When to Update; What Triggers an Update; Who gets the Update?; Managing the Timeline; Length; Pagination; Format; Cover Letter; FDA Form; FDA Form; Quality Assurance; Items to Send with the IB; Assembling the Submission; Paper Publishing; Tabs & Slip Sheets; eCTD Format; Electronic Examples; Tips
Chapter 37: IND Safety Reports; Regulations; Guidance Documents; What is an Adverse Event; What is a Serious Adverse Event; ICH E2A Definition of an Adverse Drug Reaction (ADR) or Serious Adverse Event (SAE); ICH E2A Definition of an Unexpected Adverse Drug Reaction; 21 CFR §312.32 Definition of an Unexpected Adverse Drug Experience; 21 CFR §312.32 Defines Serious Adverse Events; How are SAEs Reported?; Notification Timeframe; Reporting Timeframes—7 Day Report; Reporting Timeframes—15 Day Report; Reporting Timeframes—Follow-Up Information; SAE Numbering; Reporting Sources; Report Format; Narrative Format—Minimum Requirements; Narrative Format—Preferred Contents; Completing FDA Form 3500A; Submitting an SAE; Questions About Safety Reports or Completing Forms; Managing the Timeline; Tracking SAEs; Multiple INDs; How Biologics are Different; Who Else Needs to be Notified?; Length; Pagination; Cover Letter: Initial IND Safety Report—FDA Form 3500A; Cover Letter: Initial IND Safety Report—Narrative; Cover Letter: IND Safety Report for Follow-Up, FDA Form 3500A; Cover Letter: IND Safety Report for Follow-Up, Narrative; FDA Form; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; eCTD Format; Commitments; Waiting Period; Tips; Electronic Examples; Table 1. Reporting Matrix; What is MedDRA?
Chapter 38: Investigator’s Submission; Regulations; Table of Investigators; Managing the Timeline; FDA Form 1572 Updates; Reproduction prohibited 00:xxi; How Biologics Submissions Differ; Curriculum Vitae’s (CV); Cover Letter; Other Items to Send with Submission; Length; Pagination; Assembling the Submission; FDA Form; FDA Form; Paper Publishing; Tabs & Slip Sheets; eCTD Format; Commitments; Waiting Period; Tips; FDA Perspectives; Other Perspective; Electronic Examples; Table 1. Sample Table of Investigator
Chapter 39: Fast Track Designation; Regulations; Guidance Documents; Why would a Sponsor Apply for Fast Track?; Criteria that must be Met for Application; What is a Serious Condition?; What is Life-Threatening?; What is Severely Debilitating?; What is an Unmet Medical Need?; What to do when a Therapy Currently Exists?; Managing the Timeline; Timing During Development; Sections of Application; 1.0—Summary of the Request; 2.0—Indication or Disease Overview; 3.0—Disease is a Serious Life-Threatening Condition; 4.0—Disease is an Unmet Medical Need; 5.0—How Drug X Has Potential to Fill Unmet Medical Need; 6.0—Conclusion; 7.0—Bibliography/Supportive Literature; 8.0—Appendices; Outcomes; Designation Letter; Nondesignation Letter; Nondesignation Appeal and Resubmission; Revocation of Fast Track Designation; Continuous Marketing Application Pilot Programs Defined; Length; Pagination; Submission Header; Cover Letter; Cover Letter: Resubmission (if necessary); FDA Form; FDA Form; Assembling the Submission; Paper Publishing; Tabs & Slip Sheets; Other Items to Send with Request; eCTD Format; Commitments; Waiting Period; Tips; FDA Perspectives; Electronic Examples; Fast Track Applications to Date; Number of Fast Track Applications Received; Fast Track Products Approved Since; References
Chapter 40: Clinical Study Reports; Regulations; Guidance Documents; Format; Managing the Timeline; Length; Pagination; Cover Letter; FDA Form; FDA Form; Quality Assurance; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; Other Items to Send with the CSR; CTD Format; Commitments; Tips; Other Perspectives; FDA Perspectives; Electronic Examples
Chapter 41: Pediatric & Geriatric Waiver/Deferral; Regulations; Pediatric Guidance Documents; Geriatric Guidance Documents; Pediatric Age Groups Defined; Geriatric Age Groups Defined; What is a Waiver?; What is a Deferral?; What is Meaningful Therapeutic Benefit?; Full Waiver; Partial Waiver; Reproduction prohibited 00:xxiii; Why will a Waiver be Granted?; Deferral; How will Waiver/Deferral Request and Response be Acknowledged by FDA?; Can a Waiver/Deferral Agreement be Revoked?; Sections of Pediatric Waiver and Partial Waiver Application; 1.0—Introduction; 2.0—Age Group(s) Included in Waiver Request; 3.0—Statutory Information; 4.0—Bibliography/Supportive Literature; How Does the Partial Waiver Differ from the Full Waiver?; Sections of a Pediatric Deferral Application; 1.0—Introduction; 2.0—Indication; 3.0—Age Group(s) Included in Waiver Request; 4.0—Reasons for Not Including All Pediatric Patients; 5.0 —Reasons for Deferring Pediatric Studies; 6.0—Pediatric Plans Submitted to the Agency; 7.0—Bibliography/Supportive Literature; 8.0—Appendices; Geriatric Patients in Safety Database; Geriatric Waiver; Sections of Geriatric Waiver and/or Deferral; FDA Response—Waiver; FDA Response—Deferral; Timing of Waiver Request; Alternative: Submit with the NDA; Consequences of Not Applying for a Waiver During the IND or NDA Phase; Consequences of Not Responding to a Request for Pediatric Trials or Additional Information; Length; Pagination; Submission Header; Cover Letter: Pediatric Full Waiver (if a Stand Alone Submission); Cover Letter: Pediatric Partial Waiver (if a Stand Alone Submission); Cover Letter: Pediatric Deferral (if a Stand Alone Submission); Cover Letter: Geriatric Waiver (if a Stand Alone Submission); FDA Form; FDA Form; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; Other Items to Send with Waiver; eCTD Format; Commitments; Waiting Period; Other Perspectives; Electronic Examples
Chapter 42: Responding to Clinical Holds; Regulations; Guidance Documents; Complete Clinical Hold; Partial Clinical Hold; Discussion of Deficiency; How does a Clinical Hold Affect a Trial?; How is a Sponsor Notified of a Clinical Hold?; Reasons for a Clinical Hold; Phase; Phase 2 or; Sponsor Response to a Clinical Hold; Agency Timeline for Response; Agency Actual Response Time; If Clinical Hold Issues are not Resolved, what are the Next Steps?; When a Clinical Hold is Lifted; How is a Sponsor Notified when a Clinical Hold is Lifted?; If Clinical Hold is Never Lifted?; Managing the Timeline; Length; Pagination; Cover Letter/Format for Clinical Hold Response; Sending in an Amendment to the Clinical Hold Response; FDA Form; FDA Form; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; Other Items to Send with a Clinical Hold Response; eCTD Format; Commitments; Waiting Period; Tips; Electronic Examples; References; Table 1. Overview of Responses to Clinical Holds; Table 2. 2006 Responses to Clinical Holds (CBER/CDER)
Chapter 43: Special Protocol Assessment - Clinical Protocols; Regulations; Guidance Documents; What is a Special Protocol Assessment (SPA)?; How does the SPA Process Work?; SPA Overview; Advisory Committee Review; SPA Request Outcome; Review; Denial; Managing the Timeline; Agency Timeline for Review and Response; Protocol Amendments During the Review Period; Protocol Amendments After the Review Period; Length; Pagination; Format; Background Summary; Cover Letter: Special Protocol Assessment Request; FDA Form; FDA Form; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; Other Items to Send with Protocol; eCTD Format; Commitments; Waiting Period; Tips; Electronic Examples; References; Table 1. Special Protocol Assessments, Number Received Per Year; Table 2. Special Protocol Assessments (CBER/CDER)
Chapter 44: Statistical Analysis Plan; Regulations; Guidance Documents; Managing the Timeline; Length; Pagination; Format; Cover Letter: SAP; FDA Form; FDA Form; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; eCTD; Commitments; Waiting Period; Tips; Electronic Examples
Chapter 45: Clinicaltrials.gov and FDA Form 3674; Regulations; Guidance Documents; What Trials and Information must be Posted in the Databank?; Foreign Trial Site Information; Managing the Timeline/When to Submit Information; What Information do you Post on Clinicaltrials.gov?; How do you Post on Clinicaltrials.gov?; How do you Manage Protocol Amendments?; How Often should the Information be Updated?; How Long will Information Remain on ClinicalTrials.gov?; Treatment INDs and Expanded Access Programs; Format; Is the Sponsor’s IND Number Disclosed on the Site?; FDA Form; What Submissions don’t have to have a FDA Form 3674?; Do you have to Comply?; Noncompliance Enforcement & Fines; Paper Publishing; eCTD Format; Commitments; Waiting Period; Tips; Other Perspectives; Electronic Examples; References
Chapter 46: Changes in the Chemistry, Manufacturing and Controls Section; Regulations; Guidance Documents; MAPPs; What can Change Between the Initial IND and Phase 3?; When to Submit?; What are Requirements?; Phase 2/3 Introduction; Phase 2—Drug Substance; 7.A—Drug Substance; Phase 2—Drug Product; 7.B—Drug Product; Phase 3—Drug Substance; 7.A—Drug Substance; Phase 3—Drug Product; 7.B—Drug Product; Tracking of Lots from all Studies; Length; Pagination; Format; Tips
Chapter 47: Comparability Protocols - Chemistry, Manufacturing and Controls Information; Regulations; Guidance Documents; What is a Comparability Protocol?; Why Use a Comparability Protocol?; What is the Agency Looking for?; What Must the Sponsor Prove?; Evaluation of a Manufacturing Change and Adverse Effects; When Nonclinical and Clinical Lots are Different; Conducting Additional Nonclinical or Clinical Trials to Verify Comparability; What Kind of Nonclinical or Clinical Trials Might be Needed to Establish Safety and Efficacy of the; Changed Product?; Nonclinical; Clinical; How Many Changes are Allowed?; Comparability Protocol Proposal Outcome; Why is a Comparability Protocol Important?; How a Biologics Submission would Differ; Reproduction prohibited 00:xxvii; Managing the Timeline; What if Study Results do not Meet the Criteria Specified in the Approved Comparability Protocol?; How is an Approved Comparability Protocol Modified?; What Information is Typically Included in the Comparability Protocol?; Format - Proposed Protocol; Format: Protocol with Study Results; Length; Pagination; Cover Letter: Initial Protocol; Cover Letter: Protocol Results; FDA Form; Other Items to Send with Protocol; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; eCTD Format; Waiting Period; Tips; Other Perspectives; Electronic Examples; Table 1. Glossary
Chapter 48: Special Protocol Assessment— Stability; Regulations; Guidance Documents; What is a Special Protocol Assessment (SPA)?; How Does the SPA Process Work?; SPA Overview; Managing the Timeline; Agency Timeline for Review and Response; SPA Request Outcome; Review; Denial; Protocol Amendments During the Review Period; Protocol Amendments After the Review Period; Length; Pagination; Format; Background Summary; Cover Letter: Special Protocol Assessment Request; FDA Form; Assembling the Submissions; Paper Publishing; Other Items to Send with Protocol; Tabs & Slip Sheets; eCTD Format; Commitments; Waiting Period; Tips; Electronic Examples; References
Chapter 49: Nonclinical Study Reports & Amendments; Regulations; Guidance Documents; When does the 120 Day Clock Start?; Managing the Timeline; Length; Pagination; Format; Cover Letter: Study Submission; FDA Form; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; Other Items to Send with the Study Report; eCTD Format; Commitments; Tips; Electronic Examples
Chapter 50: Nonclinical Study Waivers; Regulations; How is a Waiver Granted?; Managing the Timeline; Submission Format; How would a Biologics Submission Differ?; Length; Pagination; Cover Letter: Nonclinical Waiver (if a Stand Alone Submission); FDA Form; Assembling the Submission (if a Stand Alone Submission); Paper Publishing; Tabs & Slip Sheets; Other Items to Send with Waiver; eCTD Format; Waiting Period; Electronic Examples
Chapter 51: Special Protocol Assessment— Carcinogenicity; Regulations; Guidance Documents; What is a Special Protocol Assessment (SPA)?; How does the SPA Process Work?; How is the Carcinogenicity SPA Process Different?; SPA Overview; Carcinogenicity Assessment Committee (CAC); Managing the Timeline; Agency Timeline for Review and Response; SPA Request Outcome; Review; Reproduction prohibited 00:xxix; Denial; How Big is a SPA Request?; Pagination; Format; Background Summary; Cover Letter: Special Protocol Assessment Request - Notification; Cover Letter: Request for Special Protocol Assessment; FDA Form; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; Other Items to Send with SPA Request; eCTD Format; Commitments; Waiting Period; Tips; Electronic Examples; References
Chapter 52: IND Annual Report; Regulations; Guidance; Due Date; IND Effective Date; Reporting Period; Data Cut-off Date; Clean vs. Dirty Data; Coordinating the AR Team; Managing the Timeline; Sections of the Annual Report; 1.0 - Individual Study Information; 2.0 - Clinical Summary; 2.A - Adverse Events; 2.B - IND Safety Reports; 2.C - Deaths; 2.D - Drop Outs Due to Adverse Events; 2.E - Action of the Drug or Biologic; 3.0 - Nonclinical Study Update; 4.0 - Chemistry Manufacturing and Control Changes; 4.A - Summary; 4.B - Stability; 5.0 - General Investigational Plan; 6.0 - Investigator’s Brochure; 7.0 - Phase I Protocol Modifications; 8.0 - Foreign Marketing Developments; 9.0 - Outstanding Business; How are Biologics Annual Reports Different?; Section 2.F: Confirmation that Clinical Oversight and Monitoring are being Conducted in Accordance with; the March 6, 2000 Gene Therapy Response Letter; Section 4.C: Changes in Manufacturing Procedures; Section 4.D: QA and QC Audit Summary; Managing Multiple IND Annual Reports; Do you Combine Multiple Sections on the Same Page?; Length; Pagination; Cover Letter; FDA Form; FDA Form; Other Items to Send with Annual Report; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; eCTD Format; Commitments; FDA Perspective; Tips; Electronic Examples
Chapter 53: Orphan Drug Annual Report; Regulations; Guidance; Orphan Drug Annual Reporting Regulations; Due Date; Coordinating the IND and Orphan Annual Reports; How does the Orphan Drug Annual Report Differ from the IND Annual Report?; Managing the Timeline; Length; Pagination; Cover Letter: Annual Report Using IND Annual Report; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; Electronic Publishing; Commitments; Tips; Electronic Examples
Chapter 54: The CMC Annual Report 54:433; Regulations54:433; Managing the Timeline54:434; Length54:434; Pagination54:434; Format54:434; Cover Letter54:434; FDA Form 157154:435; Assembling the Submissions54:435; Paper Publishing54:435; Tabs & Slip Sheets54:435; eCTD Format 54:435; Electronic Examples54:435
Chapter 55: Orphan Drug Designation; Regulations; Guidance Documents; Forms; Office of Orphan Products Development; Why Apply for Designation?; Qualifications for Orphan Drug Designation; When Request Designation; Sections of Applications; 1.0—Statement of Orphan-Drug Designation Request; 2.0—Information on Sponsor’s Contact Person or Resident Agent; 3.0—Description of Rare Disease or Condition; 4.0—Description of the Drug and Rationale for Use; 5.0—Clinical Superiority Explanation, if Applicable; 6.0—Medical Plausible Subset; 7.0—Summary of Drug’s Regulatory Status and Marketing History; 8.0—Prevalence of Drug’s Target Population or Cost Recovery, if Applicable; 9.0—Statement of Real Party of Interest; 10—Other, if Applicable; Copies of Literature Citations; Population Prevalence; Scientific Rationale; Cross Reference to IND Information; Pediatric Subset Request; Application Challenges; Managing the Timeline; Orphan Grants; How Much Grant Money is Available?; How are Awards made?; Who may Apply?; How are Applications Reviewed?; List of Orphan Designations and Approvals; How to Track and File Maintenance Information; Length; Pagination; Format; Cover Letter; FDA Form; FDA Form; Assembling the Submissions; Tabs & Slip Sheets; Paper Publishing; Electronic Submissions; Where to Send; Commitments; Waiting Period; Outcome; Maintenance/Amendments to the Application; Revocation of Orphan Designation; Other Perspectives; Tips; Electronic Examples; References
Chapter 56: Developing the Package Insert; Regulations; Guidance Documents; What is a Label?; What is Labeling?; What is a Package Insert?; Sections of the Package Insert; Item; Regulation; Annotation; Why does the PI Need to be Annotated?; Highlights Section; When is the Highlight’s Section Required?; Full Prescribing Information: Contents; Boxed Warning; Agency Format Requirements; How to Assemble the First Draft of the Package Insert; Managing the Timeline; Length; Pagination; Submission to Agency; Electronic Examples
Chapter 57: Target Product Profile; Regulations; Guidance Documents; Additional Reasons to Use the TPP; Why Submit a TPP?; Can the TPP be Submitted without a Meeting Package?; TPP Advantages; TPP Use with a Meeting Package; Target Product Profile Format; Target; Annotations; Comments; Sections it Covers; How to Use the Tool?; How to Assemble the Initial TPP?; Managing the Timeline; Length; Pagination; Cover Letter: TPP Submission without a Meeting Request; FDA Form; FDA Form; Assembling the Submissions; Paper Publishing; Reproduction prohibited 00:xxxiii; eCTD Format; Tips; Electronic Examples
Chapter 58: USAN and INN Name Development; Laws and Regulations; Why is a USAN Name Important?; How do you Create a USAN Name?; What Research on the Chosen Name should be Done Before Submission?; Where do you Find the Application?; What are the Costs Associated with a USAN?; What Information will you Need for the Application?; What Happens After the Application is Submitted?; What Information will be Received Back from USAN after the Initial Application is Filed?; Does USAN Accept all Proposed Names?; USAN Facilitation of an INN Expert Group Review; When is the Nonproprietary Name Official?; Does the USAN Confirmation Letter Need to be Sent to the Agency?; Timeline; USP; INN Overview; Length; Waiting Period; Tips; Electronic Examples; References; Table 1. Decoding the “Name” Usage
Chapter 59: Trade or Proprietary Name Development; Regulations; Guidance; How Many Names can a Drug have?; How does a Company Develop a Trade Name?; What Research should a Sponsor Conduct Before Submitting a Trade Name to the Agency for Review?; What does FDA Look for in the Review of a Trade Name?; The Trade Name Assessment Process; A Proposed Trade Name may be Rejected Under any of the following Scenarios; When Submit a Trade Name Evaluation?; Same Drug, Different Indication, Different Trade Name?; Why do Companies Develop a Trade Name and Use it During the Development Process?; When can a Sponsor Start Using the Trade Name on Documents?; Documenting the Use of a Trivial or Trade Name Throughout the Drug’s Development; Review Timeline; Alternative Trade Name Submission Method; Appeal; Pilot Program; Length; Pagination; Cover Letter; FDA Form; FDA Form; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; Other Items to Send with Submission; eCTD Format; Tips; Other Perspectives; Electronic Examples; References; Table 1. Decoding the “Name” Usage
Chapter 60: Change in Company Name, Address, Contact Person, Medical Monitor or Ownership; Regulations; Managing the Timeline; Who Needs to be Notified?; What Needs to be Changed or Updated?; Company Bought; Change in Agency Contact Person; Change in Medical Monitor; Length; Pagination; Letter: Name Change; Letter: Change in Ownership (from Company Being Acquired); Letter: Change in Ownership (by Acquiring Company); Letter: Change in Address; Letter: Change in Contact Person; Letter: Change in Medical Monitor; FDA Form; FDA Form; Assembling the Submissions; Paper Publishing; Tabs & Slip Sheets; Other Items to Send with Submission; eCTD Format; Electronic Examples
Chapter 61: Inactivating, Withdrawing, Terminating, Discontinuing or Reinstating an IND; Regulations; Inactivating an IND; Withdrawal of an IND; Termination of an IND; How does Notification of Termination Happen?; Reinstatement Request; How do you Reinstate an IND?; Clinical Investigations Under an IND on Inactive Status may only Resume; Length; Pagination; Format; Cover Letter: Inactivate; Cover Letter: Withdrawal; Cover Letter: Reinstatement; Reproduction prohibited 00:xxxv; FDA Form; FDA Form; Assembling the Submissions; If it is a Reinstatement Submission; Tabs & Slip Sheets; Paper Publishing; eCTD Format; Waiting Period; Tips; Electronic Examples
Chapter 62: Drug and Biologics Master Files; Regulations; Guidance Documents; What is a Drug Master File?; Who would Apply for a DMF?; Types of Drug Master Files; What happened to Type I DMFs?; Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel; Type II: Drug Substance, Drug Substance Intermediate, and Material Used in their Preparation, or Drug Product; Drug Substance Intermediates, Drug Substances and Material Used in their Preparation; Drug Product; Type III: Packaging Material; Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in their Preparation; Type V: FDA Accepted Reference Information; Environmental Assessment; Stability; How to Submit Information not in a Specific DMF Type?; Agency Receipt of DMF; DMF Acknowledgement Letter; Agency Review of DMFs; How does a DMF Review Differ from an IND Review?; For IND Applications, typically; While for DMFs; Who Must File a DMF?; DMF Holder Obligations; Updating the DMF; Who to Notify of Updates?; DMF Amendments; Annual Update; Transfer of Ownership; Do you Refer to your IND or DMF?; Public Disclosure of DMF Information; Where to Send a DMF?; CDER; CBER; Major Reorganization of a Drug Master File; Length; Pagination; IND or CTD Format; Format; Why do you Need an LOA?; Who Else Needs a Copy of the LOA?; List of People Authorized to Reference DMF; DMF Closure; Inactivation of DMF; Reactivating a DMF; Cover Letter: DMF Submission; Cover Letter: DMF Amendments; Cover Letter: Letter of Authorization; FDA Form; Assembling the Submissions; Paper Publishing; Binder Specifications; eCTD Format; Tabs & Slip Sheets; Commitments; Waiting Period; Tips; Electronic Examples; References; Table 1. DMF Glossary; About Cambridge Healthtech Institute; Cambridge Healthtech Institute Conferences; The Pharmaceutical Strategy Series; Barnett International; Insight Pharma Reports; CHI’s Marketing Services; Cambridge Meeting Planners; Cambridge Healthtech Associates; Cambridge Healthtech Media Group; Bio-IT World; eNewsletters; Lead Generation Programs; Contact Us

IND Submissions: A Primer

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