1. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH Working with FDA: Biological Products and Clinical Development 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

2. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

3. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

4. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

5. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

6. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

7. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

8. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

9. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones Case 1: Conclusion  Early and Successful Communication Results in Successful INDs

10. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

11. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

12. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

13. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

14. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

15. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

16. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

17. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

18. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

19. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones Case 2b: FDA Action  Clinical hold maintained Sponsor notified via teleconference FDA issues Continue Clinical Hold letter

20. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

21. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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

22. Working with FDA: Biological Products and Clinical DevelopmentKaren Jones 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