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March Breakfast. Pre-IND and IND Development: Lessons Learned BIOCOM’s CRO Workshop 28 July 2010 Sybille Sauter, Ph.D., RAC Cato Research ssauter@cato.com. www.biocom.org. March Breakfast. Workshop Schedule. www.biocom.org. March Breakfast. Agenda. Pre-IND meetings

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slide1

March Breakfast

Pre-IND and IND Development: Lessons LearnedBIOCOM’s CRO Workshop28 July 2010Sybille Sauter, Ph.D., RACCato Researchssauter@cato.com

www.biocom.org

slide2

March Breakfast

Workshop Schedule

www.biocom.org

slide3

March Breakfast

Agenda

  • Pre-IND meetings
  • Investigational New Drug (IND) applications
  • Looking at Europe (CTA, scientific advice, protocol assistance)
  • Panel Discussion, Q&A

www.biocom.org

slide4

March Breakfast

Drug Development Process

NDA/BLA

IND

Pre-IND Phase

Marketing Application Phase

Post Marketing Phase

IND Review Phase

Development

Preclinical

IND

Review

CLINICAL TRIALS

Ph I Ph II Ph III

ND/BLA

Review

Post

Marketing

Pre IND

Meeting

Pre IND

Meeting

End of Ph 2

Meeting

Pre-NDA/BLA

Meeting

Safety

Meetings

End of Ph 3

Meeting

Post NDA/BLA

Meeting

IND review - 30 Days

www.biocom.org

slide5

March Breakfast

Pre-IND Meetings

www.biocom.org

slide6

March Breakfast

Pre-IND Meeting Facts

  • Not required but highly recommended
  • FDA grants 1 pre-IND meeting per application
  • Usually held 6-12 months before IND submission
  • FDA provides clear guidance for pre-IND meeting process and associated documents
    • Guidance for Industry: “Formal Meetings Between the FDA and Sponsors or Applicants”, 2009
    • SOPP 8101.1: Scheduling and Conduct of Regulatory Review Meetings with Sponsors and Applicants (CBER)
    • Guidance for Industry: “IND Meetings for Human Drugs and Biologics, CMC Information”, 2001
  • Trend: FDA grants less pre-IND meetings!

www.biocom.org

slide7

March Breakfast

FDA: PDUFA Meeting Workload

www.biocom.org

slide8

Cons

  • Requires time and resources

March Breakfast

Why Have a pre-IND Meeting?

Pros

  • Introduces your product/company to FDA
  • Minimizes risk for clinical hold
  • Solidifies regulatory and development path for CMC, nonclinical and clinical aspects before finalizing the IND

www.biocom.org

slide9

March Breakfast

Meetings Are Not Appropriate when…

  • Timing is off (premature, too late for full benefit)
  • Key people are not available to meet
  • Important information is missing

www.biocom.org

slide10

March Breakfast

Pre-IND Meetings May Not be Necessary if…

  • Not a first-in-class product, accepted clinical trial designs and well established endpoints
  • High level of familiarity with FDA Division, repeated IND filings for similar indications for several years

www.biocom.org

slide11

March Breakfast

Pre-IND Meetings Are Recommended if….

  • Questions are not answered by regulations and guidances
  • Novel indication
  • Sponsor new to drug development
  • Pharmacologic or toxicologic signals of concerns
  • New molecular entity
  • Unique molecular entity or studies
  • Sponsor wishes to discuss methods to enhance development (i.e., orphan or fast track designation, accelerated approval)
  • Drug intended to treat a serious and life-threatening illness

www.biocom.org

slide12

Clinical

Dev Time

NDA

Review Time

IND: Clinical

Hold Rate

(Vaccines)

100

100

50

80

80

40

60

60

30

Months

Months

Percentage

40

40

20

20

20

10

No mtg

Mtg

0

0

0

March Breakfast

Do pre-IND Meetings Really Make a Difference?

Source: DL Miller, JJ Ross. Vaccine INDs: review of clinical holds. Vaccine, 23(9), pp1099–1101, 2005.

DiMasi and Manocchia, DIA Journal 1997

www.biocom.org

slide13

March Breakfast

Maximize the Benefit of your Pre-IND Meeting

  • Establish a good relationship with your FDA project manager
  • Do not have a meeting until you are ready
  • Spend most of your time discussing your questions (avoid background presentation)
  • Receive feedback for all aspects of your IND
    • CMC, nonclinical, clinical, regulatory

www.biocom.org

slide14

March Breakfast

Pre-IND Meeting: Type B Meeting

Source: Guidance for Industry: “Formal Meetings Between the FDA and Sponsors or Applicants”, May 2009

www.biocom.org

slide15

March Breakfast

Pre-IND Meeting: Overall Timeframe

  • Assumptions
  • All information for pre-IND package available
  • FDA grants pre-IND mtg request
  • Pre-IND mtg scheduled within 60 days following request

Step 2

Step 4

Step 1

Step 5

Hold Pre-IND

mtg

Submit pre-IND

package

Submit mtg

minutes

Request

pre-IND mtg

Step 3

Draft

questions

Meeting

preparation

FDA review

response

Mtg

minutes

Generate pre-IND package

Months

1 2 3 4 5

www.biocom.org

slide16

March Breakfast

If Your Don’t Hear from FDA by Day 21 after Sending the Request…

CENTER FOR DRUG EVALUATION AND RESEARCH

PRE-IND Consultation Contacts

Source:http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/Overview/UCM166356.pdf

www.biocom.org

slide17

March Breakfast

Pre-IND Questions: Remember…

  • Sponsor is expected to have the drug development thought through with data/science supporting the rationales for proposal
  • Do not ask FDA what to do next!
    • instead, make a proposal and ask whether FDA concurs
  • Make sure that answers to your questions are not already available in the guidances
  • Only ask questions that FDA can answer, be specific, avoid open-ended questions
  • Number of questions: varies (~ 4-8)

www.biocom.org

slide18

March Breakfast

Not so Helpful Questions

  • Will a designated FDA preclinical reviewer work with the sponsor to provide feedback on the optimal design of the proposed preclinical study?
  • How appropriate is study design A and is there a preference regarding specific endpoints?
  • In regards to shipping and handling, what are the minimum and maximum periods of cold storage stability that FDA would find acceptable for the assembled biologic/device?
  • Is <infectious agent> testing of the source animals required, and if yes, what actions should be taken in the event of a positive finding?
  • What limits must be established for decrease in platelets and hematocrit during the treatment procedure?

www.biocom.org

slide19

March Breakfast

Helpful Questions: Examples

  • Does the Division agree with the proposed starting dose and dose escalation scheme for the Phase 1/2 study in <study population>?
  • Does the Division agree that the current nonclinical safety studies conducted with <drug> in rats and dogs are sufficient to support the proposed Phase 1 study in <study population>?
  • Does the Division agree with <Sponsor’s> assessment of the NOAEL (no observable adverse effect level) and derivation of the initial safe starting dose?
  • Does the Division agree that the analytical test procedures used to manufacture and characterize the master cell bank are adequate to support manufacture of the active ingredient ?
  • Does the Division agree that the proposed release specifications, analytical tests, and acceptance criteria for drug substance and initial clinical drug product are sufficient to begin Phase 1 studies?

www.biocom.org

slide20

March Breakfast

Common Shortcomings Identified by FDA

  • Inadequate CMC information
  • Insufficient pre-clinical support
  • Unacceptable clinical trial design
  • Lack of information on selection of dosage

www.biocom.org

slide21

Pre-IND Phase

IND Review Phase

Marketing Application Phase

Post Marketing Phase

Pre Pre IND

Meeting

(Informal)

March Breakfast

Pre-pre-IND Meetings

Development

Preclinical

IND

Review

CLINICAL TRIALS

Ph I Ph II Ph III

BLA

Review

Post

Marketing

Pre IND

Meeting

End of Ph 2

Meeting

Pre-BLA

Meeting

Safety

Meetings

End of Ph 3

Meeting

Post BLA

Meeting

IND review - 30 Days

Source: Celia Witten, Ph.D., M.D.,Office Director, Office of Cellular, Tissue, and Gene Therapies (OCTGT), CBER/FDA, ISSCR/CIRM/ISCT Workshop, June 15, 2010

www.biocom.org

slide22

March Breakfast

Pre-pre-IND Meetings

  • Limited to products reviewed by CBER’s Office of Cellular, Tissue, and Gene Therapies (OCTGT)
  • Sponsor can get informal general advice from CBER pharmacology/toxicology reviewers
  • Intended to be a focused, scientific dialogue based on preliminary work
  • Pre-pre IND package: max 25 pages
    • Description of intended product
    • Outline of proposed clinical trial
    • Summary of preclinical data
    • Specific questions concerning the pharmacology/toxicology aspect
  • Additional information
    • http://www.gtrp.org/Home/Documents/Information/VectorDev.doc

www.biocom.org

slide23

March Breakfast

Recombinant Advisory Committee (RAC) Meetings

  • Conduct public review and discussion of science, safety and ethics for products containing recombinant DNA (gene transfer protocols)
  • May request in-depth review and public discussion (20-30%)
  • Protocols discussed at quarterly meetings
  • RAC recommendation provided to the PI, Institutional Review Board, Institutional Biosafety Committee, FDA
  • RAC minutes posted on Office of Biotechnology Activities website

www.biocom.org

slide24

March Breakfast

Pre-IND Meetings: Case Study 1

  • Background
    • Pre-pre-IND meeting to discuss complex gene therapy product with two types of nucleotides plus liposome
    • Target population: end-stage cancer patients
    • Had a pre-IND meeting and asked whether initial trial in target population could be a repeated dose study
  • Pre-IND Meeting outcome
    • FDA said YES!
  • Consequence
    • Fast-forwarded drug development plan
    • Sponsor needed more product, funds, and time for multiple dose GLP toxicology and clinical studies

www.biocom.org

slide25

March Breakfast

Lessons Learned: Pre-IND Meeting

  • Determine whether you need a pre-IND meeting
  • Request meeting only when you are ready
  • Submit a high-quality pre-IND briefing package
  • Ask specific and clear questions that can be answered
  • Take great care in evaluating FDA’s preliminary responses
  • Be well prepared for the pre-IND meeting, anticipate questions, identify back-up positions
  • State your case confidently
  • Know your regulations and guidances

www.biocom.org

slide26

March Breakfast

IND Submissions

www.biocom.org

slide27

March Breakfast

The IND – It’s a Process

  • Project management
    • Internally: scientists, senior management
    • Externally: vendors, consultants, inventors
    • Agree on milestones, objectives, timelines, resource allocation, responsibilities
  • Medical writing (style guide, document templates)
  • CMC, nonclinical, clinical experts
  • Regulatory experts (strategy, operations/submissions)

www.biocom.org

slide28

March Breakfast

www.biocom.org

slide29

March Breakfast

Effective Management Tools

Time

Kickoff Meetings

Table of contents

Communication plan

Target product profile

Global program timeline

Rolling submission management

Cost

Quality

www.biocom.org

slide30

March Breakfast

Integrated Table of Contents

www.biocom.org

slide31

March Breakfast

Key IND Requirements

  • First-in-human (FIH) study protocol
  • Rationale for intended use (in vitro and in vivo pharmacology)
  • Toxicology data supporting the starting dose and duration of the FIH study
  • Assurance of quality of drug substance/product used in toxicology studies and in the FIH study

www.biocom.org

slide32

March Breakfast

Inexperienced Sponsors Tend to…

  • Have difficulty finding the right balance for the most efficient drug development route
    • Do more than is necessary
    • Don’t perform all the studies necessary
  • Conduct activities in series rather than in parallel
  • Solicit advice from multiple parties
    • Contradicting advice can be confusing

www.biocom.org

slide33

March Breakfast

IND Submissions – Facts to Consider

  • Resources to understand FDA’s thinking
    • FDA approval packages of similar drugs/indications
    • Advisory Committee Meetings
  • Recent changes at FDA
    • 38% of FDA’s drug review staff have < 2 years experience
    • Emphasis on safety impacts decision making (appears more conservative)
  • Electronic submissions in the common technical document format (eCTD) are encouraged by FDA

www.biocom.org

slide34

March Breakfast

eCTD Submissions – Background

  • eCTD implemented in 2005 by FDA
  • Applies to INDs, NDAs, ANDAs, BLAs, DMFs and associated submissions
  • United States
    • 01 Jan ‘08: electronic submissions must be in eCTD format (not mandatory but industry standard)
  • Europe
    • 01 Jan ‘10: electronic submissions must be in eCTD format (centralized procedure, EMA)

www.biocom.org

slide35

Submission Media of Original INDs

3,500

3,000

2,500

2,000

Number of Submissions

1,500

1,000

500

0

2005 2006 2007 2008 2009

Paper or mixed

Gateway or electronic

March Breakfast

Electronic Submissions – an FDA Perspective

  • 12.5% of original INDs in electronic format
  • 56.2% of original NDAs in electronic format

Source: DIA EDM Meeting, 2010, Theresa Mullin

www.biocom.org

slide36

March Breakfast

Recommended: CTD Format and Electronic

Not partof the CTD

Regionaladministrative information

Module 1

Non-clinical overview

Module 2

Clinical overview

The CTD

Quality overallsummary

Non-clinical summary

Clinical study

Non-clinical study reports

Module 4

Clinical study reports

Module 5

Quality

Module 3

CTD: common technical document

www.biocom.org

slide37

Module 1

(Regional Information)

Module 2

(Summaries)

Module 3

(Quality)

Module 4

(Nonclinical Reports/Safety)

Module 5

(Clinical Reports/Efficacy)

March Breakfast

Traditional IND (US) Format

CTD Format

1. Form FDA 1571

2. Table of Contents*

3. Introductory Statement

4. General Investigational Plan

5. Investigator’s Brochure

6. Clinical Study Protocol

7. Chemistry, Manufacturing, and Controls Data

8. Pharmacology/Toxicology Data

9. Previous Human Experience

10.Additional Information

a. pre-IND correspondence

b. Literature References

c. Investigational Drug Labeling

www.biocom.org

slide38

March Breakfast

Two Most Common Questions for Creation of IND in eCTD Format

  • Timelines?

- yes, an eCTD application can be faster than a paper submission

2. Authoring best practices?

www.biocom.org

slide39

March Breakfast

IND Submission – Overall Timeframe

  • Assumptions
  • Nonclinical studies with audited final reports ~ 3-4 months, all other information available
  • FDA clears IND after 1st round of review

FDA Decision

Site initiation visit/CTM

Identify/evaluate clinical site and PI

Protocol to IRB

Submit IND

pre-IND mtg

FDA

review

Generate and compile IND

Nonclin toxicology

final report

1 2 3 4 5 6 7 months

www.biocom.org

slide40

March Breakfast

Best eCTD Authoring Practices – Your Main Goal is …

  • Effective communication!

www.biocom.org

slide41

March Breakfast

Best Authoring Practices

  • Adhere to CTD hierarchy
  • Use appropriate level of granularity
  • Generate comprehensive study tagging files
  • Make clear references to study reports
  • Use smart hyperlinking practices
  • Use meaningful file names

www.biocom.org

slide42

March Breakfast

Advice from FDA: 5 Most Common Technical Errors with eCTD Submissions

  • Always send Module 1 with any eCTD submission
  • Check your numbers
  • Don’t submit “extra” files
  • Don’t use “bad” characters in file or folder names (space, / \ : ? “< > |)
  • Learn to use the Electronic Submissions Gateway

www.biocom.org

slide43

March Breakfast

Advice from FDA: 5 Ways to Make Your eCTD Submission Reviewer-friendly

  • Use the fillable PDF version of all forms
  • Avoid the use of scanned documents
  • Make your documents easy to navigate
  • Don’t go crazy with granularity
  • Ask “If I were a reviewer..”

www.biocom.org

slide44

March Breakfast

IND Submission: Case Study 1

  • Inhaled drug for pulmonary disease
  • Toxicology studies: 2 animals had died at a dose 1000-fold higher than biologically active dose, iv
  • IND put on hold due to toxicology findings (spleen abnormalities?)
  • Resolution
    • Spleen from all animals in toxicology studies examined by independent pathologist (compared with historical controls)
    • IND cleared following submission of pathology report
    • No additional toxicology study necessary

www.biocom.org

slide45

March Breakfast

IND Submission: Case Study 2

  • Topical combination product for wound healing
  • On Day 29 after IND submission, FDA announced in a t-con that the IND will be put on hold due to concerns with the clinical protocol (safety assessments)
  • Resolution
    • FDA accepted a letter of commitment letter from the sponsor to make all suggested protocol changes
    • IND was not put on hold
    • Protocol changes filed as amendment later

www.biocom.org

slide46

March Breakfast

Lessons Learned: IND Submission

  • Take pre-IND input from FDA seriously
  • IND should be driven by science and data
  • Avoid incomplete data
  • Determine NOEL/NOAEL in toxicology studies
  • Ensure that impurity profile of the drug substance is the same in the material for toxicology studies and the first clinical study
  • Develop a clear positive benefit/risk argument
  • High quality submission
  • Understand regulatory guidances and requirements

www.biocom.org

slide47

March Breakfast

Looking at Europe…

www.biocom.org

slide48

March Breakfast

Scientific Advice and Protocol Assistance - Differences

Scientific Advice (SA)

  • SA given on all medicinal products for human use on questions concerning quality (CMC), non-clinical, clinical and risk management aspects, irrespective of whether or not the product is a centralized procedure candidate
  • Subject to a fee

Protocol Assistance (PA)

  • PA given for orphan products on the same above questions; orphan products reviewed via the centralized procedure
  • Eligible for fee reductions for all fees payable

www.biocom.org

slide49

March Breakfast

Scientific Advice and Protocol Assistance – Common Features

  • SA/PA with individual agencies in Europe or with the European Medicines Agency (EMA)
  • SA/PA can be requested several times during initial product development but also during the post authorization phase
  • Procedure typically 3 months:
    • Request SA/PA via letter of intent
    • Send briefing package with questions and company’s position at least 5 days prior to the internal EMA meeting
    • Written report provided on Day 40 (without) or 70 (with discussion meeting) after review start

www.biocom.org

slide50

March Breakfast

Scientific Advice and Protocol Assistance – Common Features (cont’d)

  • Advice/Assistance is non-binding
  • PA and SA are not made public

Source: EMEA-H-4260-01-Rev. 6 http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004089.pdf

www.biocom.org

slide51

March Breakfast

Clinical Trial Application (CTA)

  • Comparable to US INDs but
    • Clinical trials in the EU conducted according to each individual Member State’s laws and regulations
    • Needs to be submitted for each clinical study
  • Required before the start of a clinical study
    • Favorable opinion from the Ethics Committee
    • Favorable opinion from the Competent Authority of the respective Member State

www.biocom.org

slide52

March Breakfast

Clinical Trial Application (cont’d)

  • Core documents for Competent Authorities
    • Cover letter, EudraCT number and protocol number
    • Confirmation of receipt of the EudraCT number
    • CTA form
    • Clinical protocol
    • Investigator’s brochure
    • Investigational Medicinal Product Dossier (quality/CMC)

www.biocom.org

slide53

March Breakfast

Questions and Answers

Sybille Sauter, PhD., RAC

Cato Research

ssauter@cato.com

www.biocom.org

slide54

March Breakfast

Cato Research Links

Cato Research Website

www.cato.com

Cato Research Blog

www.ask-cato.com

Follow Cato Research on Twitter

twitter.com/catoresearch

www.biocom.org

slide55

March Breakfast

Additional Information:Steps 1-5 of pre-IND Meeting

www.biocom.org

slide56

March Breakfast

Pre-IND Meeting: Format

  • Face-to-face
    • First interaction with FDA, discussion of complicated issues
    • Advantage: “put a face to the voice”, body language, potential for side discussions
    • Disadvantage: costs, no “off-line” sponsor discussions
  • Teleconference
    • More routine, uncomplicated pre-IND meetings

www.biocom.org

slide57

March Breakfast

Step 1: Pre-IND Meeting Request Letter

  • Purpose: get FDA agree to meet!
  • Address: send letter to appropriate Division director
    • List of key officials:

CDER:http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ContactCDER/UCM070722.pdf;

CBER: http://www.fda.gov/aboutfda/centersoffices/cber/ucm123224.htm

    • HHS address directory:

http://directory.psc.gov/employee.htm

  • Length: ~3-5 pages

www.biocom.org

slide58

March Breakfast

Step 1: Pre-IND Request Letter (cont’d)

  • Content
    • Product and chemical name and structure
    • Proposed indication
    • Type (Type B) and format (t-con, face-to-face) of meeting
    • Purpose and objectives of meeting
      • Include brief background of underlying issues
      • Can include brief summary of completed/planned studies and trial design
    • Proposed agenda
    • List of questions by discipline
      • include brief explanation of context and purpose of the questions
    • List of proposed attendees from sponsor and FDA
    • Suggested dates/times for the meeting

Source: Guidance for Industry: “Formal Meetings Between the FDA and Sponsors or Applicants”, May 2009

www.biocom.org

slide59

March Breakfast

Step 2: Pre-IND Briefing Package

  • Purpose: FDA to verify acceptability of data for IND by providing the following..
    • Historical background on drug development concept
    • Information on the active ingredient and initial and future preclinical, clinical, and CMC development strategy in support of NDA
    • Clear and concise summary of overall development plan
    • FDA has opportunity to comment
  • Address
    • Send to Division director, attn: FDA project manager
  • Number of copies
    • Varies by Division (discuss #copies/electronic version with project manager)
  • Length
    • Depends on available information (~ 50 pages)

Source: Guidance for Industry: “Formal Meetings Between the FDA and Sponsors or Applicants”, May 2009

www.biocom.org

slide60

March Breakfast

Step 2: Pre-IND Briefing Package (cont’d)

  • Content
    • Product name and PIND number
    • Chemical name and structure
    • Proposed indication
    • Type of meeting being requested
    • Brief statement of purpose and objectives
    • Proposed agenda
    • Data to support discussion organized by discipline and question
      • Clinical study synopsis
      • In vitro and in vivo toxicology results
      • Rationale for safe clinical starting dose
      • Manufacturing scheme for API and formulation for clinical study
      • Brief assay description
      • Full description of the development plan
    • List of sponsor attendees, affiliations, and titles
    • Suggested dates and times
    • Proposed format of the meeting

www.biocom.org

slide61

March Breakfast

Step 3: Meeting Preparation

  • Begin with the end in mind: what is your goal for this meeting?
  • What is your first and second line back-up position?
  • Make a list of potential FDA questions and how you will respond
  • Rehearsal
  • Prepare a short presentation and back-up slides with data for anticipated questions

www.biocom.org

slide62

March Breakfast

Step 3: Meeting Preparation (cont’d)

  • Who do you bring? (essential experts: CMC, nonclinical, clinical, regulatory)
  • Identify moderator to lead the discussion
  • Identify key responders and note-takers
  • Submit foreign visitor data request form (fax, email) to the FDA regulatory project manager at least 11 business days before the FDA meeting
  • Evaluate FDA’s preliminary responses to your questions and adjust your strategy if needed

www.biocom.org

slide63

March Breakfast

Step 4: Pre-IND Meeting

  • Introduction
  • Skip the presentation – use the time for discussion
  • Seek clarification on FDA responses if necessary
  • Ask specific, well-phrased questions, prioritize your questions
  • Stay focused on the agenda
  • Don’t hide concerns – share them and propose solutions
  • DO NOT: show new data, change existing information

www.biocom.org

slide64

March Breakfast

Step 4: Pre-IND Meeting (cont’d)

  • Good communication skills
    • Listen, never assume – be clear
    • “Help me understand…”
    • “Thank you, we will take that into consideration…”
  • End of meeting
    • Moderator will repeat salient points, agreements, action items
    • Thank FDA for guidance

www.biocom.org

slide65

March Breakfast

Step 5: After the Meeting

  • Do not discuss meeting on FDA premises
  • Debrief meeting, review meeting notes
  • Generate and send your draft meeting minutes and any additional information requested to FDA within 2 weeks
  • FDA may consider sponsor’s minutes during preparation of official minutes (in “Word”)
  • FDA provides official meeting minutes within 30 days
  • Major differences indicate need for further discussion

www.biocom.org

slide66

March Breakfast

Additional Information:Best Authoring Practices

www.biocom.org

slide67

March Breakfast

CTD Hierarchy

  • Electronic submissions require adherence to CTD hierarchy
  • Placement of documents lower than the CTD headings is discouraged
  • Map submission document to a CTD section early in the planning process

www.biocom.org

slide68

March Breakfast

CTD Mapping Strategies: Granularity

  • In contrast to standard paper format, for the eCTD format the entire document changes
    • Consider using high degree of granularity from the beginning to plan for changes/updates/additions to document
    • Most significant for Module 3: CMC/Quality
    • Maintain highest level of granularity for Module 3, e.g. 3.2.S.X.X., 3.2.P.X.X
    • Increased granularity allows for frequent and fast updates and revisions

www.biocom.org

slide69

March Breakfast

CTD Mapping Strategies: Report Placement

  • Sometimes reports could go in more than one CTD section
  • Example: Bioanalytical report for metabolite ID in dog, mouse, and human plasma
    • 4.2.2.1 Analytical Methods and Validation Reports

OR

    • 5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies

www.biocom.org

slide70

March Breakfast

Referencing Study Reports

  • A common problem is a reference to study reports by CTD section only rather than by study number/name
  • FDA reviewers typically focus on study number, not CTD section

www.biocom.org

slide71

March Breakfast

Referencing Study Reports (cont’d)

  • Unclear

In vitro studies showed that CureAll does not inhibit CYP450 (Section 4.2.2.4.1). Further in vitro studies showed that CureAll appears to be a substrate for CYP226, with a t½ of 36 min (Section 4.2.2.4.2 and 4.2.2.4.3).

  • Better

As shown by Study ABC-001, CureAll does not inhibit CYP450. Further in vitro studies showed that CureAll appears to be substrates for CYP226, with a t½ of 36 min (Study OPQ-002 and Study XYZ-003).

  • Or

As shown by Study ABC-001 (Section 4.2.2.4), CureAll does not inhibit CYP450. ….

www.biocom.org

slide72

March Breakfast

When and What to Hyperlink?

  • References to tables, figures, sections, study reports, appendices, etc. that are NOT on the same page
  • Avoid repeated hyperlinking to the same location within one page
  • Embed links to narratives within the body of text
    • “Narratives for subjects who died during the first 48 weeks are presented in the 48-Week CSR, Section 14.3_3.”
  • Hyperlink to sources listed at the bottom of your table

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March Breakfast

Smart Hyperlinking Practices

  • Unclear

Tables 1-3 indicate the significant SAEs reported for each clinical study

  • Clear

All significant SAEs reported for each clinical study are indicated in Table 1, Table 2, and Table 3

  • List of Investigators
    • Submit individual files by investigator rather than one main hyperlinked list
    • The main list is quickly outdated as new investigators are added to the study

www.biocom.org

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March Breakfast

Consistent Naming Conventions

  • Examples found for references to cover letters within one application
    • Cover Letter
    • Cover Letter – December 12, 2008
    • CL
    • 1.2 Cover Letters
    • Cover Letter 8/15/2009

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