# Presentation: 765699

## The Biological Pre-IND Meeting

- Karen D. Weiss, M.D.
- Director, Office of Drug Evaluation VI
- Center for Drug Evaluation and Research

## Purpose of pre-IND meeting

- Address critical issues for filing an IND
- Does not guarantee the IND will sail through (no guarantee there will not be a clinical hold once the IND is submitted)
- Some pre-IND meetings are more than what they seem –
- Product extensively studied overseas
- Need to ensure right expertise

## To have or not to have...

- [the pre-IND meeting] that is the question.  Whether tis nobler in the mind to suffer the slings and arrows of submitting an IND without a pre-IND meeting or to take arms against a sea of ....
- 	From Hamlet Act III/Scene I – with ‘slight’ paraphrasing

## When in doubt

- Err on side of having
- May not need to be face to face meeting
- Encourage teleconferencing
- FDA responses to questions provided (to sponsor) ahead of meeting
- Frequency/consistency of this approach?
- Utility?
- May result in sponsor canceling mtg.  –  utility?

## Timing of pre-IND meeting

- Too early
- changes in standards, practices from time of meeting to IIND
- May not have sufficient information to make the meeting productive
- Too late
- Not sufficient time to incorporate FDA advice

## pre-IND meetings - facts

- Defined (PDUFA II) as a Type B meeting
- Agency must hold within 60 days of request
- Date determined within 14 days of request
- Meeting packet due 30 days in advance of the  meeting, FDA may cancel if deficient
- Include TOC, agenda, attendees, questions to the agency
- Meeting summary 30 days after the meeting
- Disagreements – should follow up, resolve, informal and formal dispute resolution
- OTRR held ~ 120 pre-IND meetings /year
- (average of 3 years - FY ’00 -’02)

## Contents of the Pre-IND Meeting Packet

- Size ranges – one very thin volume to several volumes
- Limited time to review - be selective, but choose wisely
- Critical needs:
- Development plan
- Mechanism of action, ultimate use
- Product information
- Some pre-clinical data
- Proposed clinical study

## Types of CMC issues

- Graded nature of CMC information – appropriate for level of development
- General outline of the manufacturing procedure
- Characterization of master and working cell banks
- Viral clearance
- Stability
- Sufficient for the duration of the pre-clinical, proposed clinical studies
- Potency assay

## CMC cont’d

- Source, country of origin of animal derived materials
- Release specifications
- Tests for quality, identity, purity, potency
- Differences (if any) from pre-clinical vs clinical
- Formulation issues
- Aggregates
- Immunogenicity
- Assays for, Potential consequences of
- Comparability
-  – physiochem characterization, side by side analyses

## GMPS

- Elements of cGMP’s need to be in place for manufacture of clinical materials in Phase 1:
- Personnel training
- Written procedures, & documentation that allow for reproducibility, and traceability
- “Quality Unit” oversight
- Validation/ qualification of critical safety-related processes (e.g., Virus Attenuation/ Toxin inactivation)
- Multiproduct manufacturing considerations
- Appropriate facilities, change control procedures
- Laboratory controls
- cGMPs develop, progress with process and product development

## Pre-clinical issues 

- Goal of the pharm/tox program - support the safety of the proposed clinical study
- The “Three R’s” -
- pharmacology = RATIONALE
- toxicology = RECOMMENDATIONS
- demonstration of safety = REGULATORY EXPECTATIONS

## Pre-Clinical cont’d

- Pharmacology
- desired biologic effect
- Toxicology
- Rationale for starting dose, dose escalation, safety
- Relate the product and findings from that used pre-clin to that for proposed clinical study
- What to monitor in clinic, how to select patients
- Toxico-kinetics - drug distribution (ADME)

## Pre-Clinical Issues

- Relevance of the animal species
- Use of NHPs
- Immunogenicity issues
- Species specificity- antibody development in animals may limit ability to chronically dose animals
- Potential adverse effects
- allergic, serum-sickness reactions
- altered pharmacokinetics
- sub therapeutic levels
- Cross reactivity to a normal, essential protein

## Pre-clinical issues 

- Format:
- Completed studies - summary data
- Full tabulation for the actual IND
- Overview of proposed/ongoing studies
- Highlight and address significant findings – e.g., animal deaths
- Address GLP issue
- Need for special evaluations – histopath, recovery (retain samples)
- Need for long term studies – repro- tox,
- 	carcinogenicity, mutagenicity

## Sources of Toxicology Data

** **
**GLP compliant toxicity studies conducted by a contract laboratory**
**well-controlled studies conducted in house**
**published data in peer-reviewed journals**
**cross-reference to other similar products in previously submitted MF/IND**

## GLPs

- “Pivotal” toxicology studies
- Development under “Animal Rule”
- Long term tox, carc, repro tox, mutagenicity
- Not necessarily for proof of concept pharmacology studies
- In certain evolving areas, approaches not standardized for GLP

## Clinical Issues 

- Design features:
- Often proposed phase 1 single dose/dose rising cohort study
- Need for control arm -
- Dose/Route/Observation period betw doses
- Eligibility criteria
- Healthy volunteers vs target population
- Monitoring, safety assessments, stopping rules
- Immunogenicity assessments, banked serum
- Compliance with GCPs

## Pre-pre-IND Process

- Informal scientific discussions between FDA and sponsor
- Telecon, scientific meetings/workshops, outreach presentations
- Often no or minimal pre-read materials submitted by sponsor
- _Targeted _discussion of specific issue of interest
- Allows for information exchange – a “two-way” street
- Often used for toxicology programs

## Guidance Documents

- Content and Format of INDs for phase 1 Studies of Drugs, including Well-characterized, Therapeutic Biotechnology-derived products Nov 1995
- Guidance for Industry Formal Meetings with Sponsors for PDUFA Products Feb 2000
- Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use Feb 1997
- ICH S6, M3, S5a, S2b