# Presentation: 543583

## IND Case Studies

**Karen D. Jones**
- Chief, Project Management Staff
- Division of Biologic Oncology Products
- Office of Oncology Drug Products
- Office of New Drugs
- Center for Drug Evaluation and Research
- FDA

## Case 1: IND for a Recombinant Therapeutic Protein; 2nd Line Use in Oncology Setting

- Product is novel
- Planned study is Phase 2, multi-center
- Sponsor requests Pre-IND meeting
- FDA grants meeting request
- FDA reviews Pre-IND meeting briefing package

## Case 1:  FDA Pre-IND Review – Preclinical Issues Identified 

- Final study reports for nonclinical pharmacology and toxicology studies should be submitted in the IND
- Ongoing nonclinical chronic toxicology studies
- Complete histopathology, toxicokinetic and immunogenicity evaluations of all animals required
- Assay methodologies to detect immunogenicity required
- Sponsor agreed to provide requested information

## Case 1: FDA Pre-IND Review –Clinical Issues Identified 

- Proposed Phase 2 trial is actually a dose escalation Phase 1 trial coupled to a dose ranging Phase 2 trial
- Phase 2 portion of the trial may not proceed until risk of a specific toxicity is assessed in patients treated at the highest dose level in Phase 1
- FDA recommends partition of the trial into separate Phase 1 and Phase 2 trials
- The proposed trial does not require patients to have received existing approved therapy prior to investigational therapy
- The proposed trial does not include an appropriate comparator arm
- The proposed trial does not include appropriate stopping rules
- Sponsor agreed to address FDA concerns

## Case 1: FDA Pre-IND Review –CMC (Quality) Advice

- The IND should include the following:
- Certificates of Analysis for each lot to be used in the clinical trial
- Release specifications for drug substance and drug product
- Shelf-life and storage conditions for the product
- Stability protocols, assays and data
- Description of bioassay
- Plans for immunogenicity testing
- Sponsor agreed to provide the requested information

## Case 1: Pre-IND Meeting 

- FDA provides a written response to sponsor’s meeting questions and additional advice 24-48 hours in advance of the meeting (all identified issues are relayed)
- Sponsor seeks clarification at meeting of FDA written responses and additional comments
- Agreements are reached and documented in meeting minutes issued to sponsor within 30 days of meeting

## Case 1: Initial IND 30 Day Review Cycle 

- Potential Clinical Hold Issues identified
- DLT definition not adequate
- Stopping rules not adequate
- Additional eligibility criterion required
- No preclinical hold issues identified
- No CMC hold issues identified, but additional information will be requested

## Case 1: FDA Action/Resolution 

- Teleconferences held to notify sponsor of issues identified
- Agreement reached on protocol revisions
- Sponsor submits written agreement via fax
- FDA issues a “Study May Proceed” fax
- IND proceeds
- Advice/Information Request letter issues

## Case 1: Conclusion

- Early and Successful Communication Results in Successful INDs

## Case 2a: IND for a Radiolabeled Chimeric Monoclonal Antibody Product Administered Intracranially for an Oncology Indication

- Initial Problem:
- Submitted as a new protocol under sponsor’s existing IND for a different product (new radiolabel, antibody fragment)
- Sponsor did not contact FDA prior to submission
- Resolution: Teleconference and establishment of new IND
- Different investigational products require separate INDs
- Request for new FDA Form 1571

## Case 2a: Initial 30 Day Review Cycle: Issues Identified 

- Animal-derived component involved in mfr. of product not tested for viral contaminants
- No preclinical or clinical study data to support starting dose
- IND lacked a plan for collection & analysis of dosimetry data
- IND lacked a sufficient description of treatment plan

## Case 2a: Issues Identified (Cont.)

- Eligibility criteria not acceptable
- DLT definitions not acceptable
- Unacceptable plan for patient follow-up to resolution of toxicity
- Undocumented approach to rescue treatment for life-threatening infections
- Study protocol lacked details of chemotherapy regimen to be used immediately following investigational drug

## Case 2a: FDA Action

- Teleconferences held to receive clarification and to request information
- Sponsor unable to submit required information within initial 30 day review cycle
- IND placed on clinical hold
- Significant and Unreasonable Risk 21 CFR 312.42(b)(i)
- Notification via telephone followed by FDA Clinical Hold letter

## Case 2a: Resolution

- Sponsor’s Complete Response received 6 months later & reviewed
- New 30 day review clock
- Requested data provided
- Teleconference: agreement by sponsor to submit revised protocol (confirmation of agreement via email)
- Clinical Hold removed: Data and commitments provided sufficient to address safety concerns

## Case 2a: Conclusion 

- Lack of initial communication by sponsor (including no pre-IND meeting) resulted in insufficient time to resolve hold issues during the initial 30 day review cycle

## Case 2b: Same IND as Case 2a: New Issues

- Serious adverse events (SAEs) reported to sponsor’s cross-referenced INDs
- Sponsor’s publication data not consistent with SAEs reported to INDs
- Protocols inconsistently identified in annual and safety reports
- Previous commitment to submit revised protocol not met

## Case 2b: FDA Action

- IND placed on Clinical Hold
- Significant and unreasonable risk 21 CFR 312.42(b)(i)
- Insufficient information to assess safety 21 CFR 312.42(b)(iv)
- FDA requested information via teleconference and letter:
- Copy of all protocols, protocol amendments, informed consent documents, IRB correspondence and patient information
- Biodistribution images and reports for all patients
- Clinical monitoring program
- Revised protocol

## Case 2b: Resolution; New Problem

- Sponsor’s Complete Response (CR) received 6 months later & reviewed
- New 30 day review clock
- Requested data provided
- CR satisfactorily addresses original hold issues identified in FDA correspondence
- New clinical hold issues identified based on information submitted

## Case 2b: FDA Action 

- Clinical hold maintained
- Sponsor notified via teleconference
- FDA issues Continue Clinical Hold letter

## Case 2b: Sponsor Response/Resolution

- Sponsor elects not to respond to clinical hold on this IND
- Sponsor withdraws IND after several years
- Sponsor does address clinical holds on cross-referenced INDs

## Case 2b: Conclusion 

- INDs that are poorly organized and contain conflicting information result in information requests from FDA and may result in clinical holds if insufficient information is present to assess safety
- Failure to keep a commitment to submit a protocol that is acceptable to FDA will result in a clinical hold
- Cross-references are more than a formality

## Questions? 

- FDA/CDER/OND/OODP/DBOP Contact Information:
- Main Line: 301-796-2320
- Fax: 301-796-9849
- Initial Contact-CPMS
- Email: karen.jones@fda.hhs.gov
- IND Specific Contact
- Assigned Regulatory Project Manager