14 Jones Case Studies Reviewed

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICESNATIONAL INSTITUTES OF HEALTH

Working with FDA:Biological Products and Clinical Development

IND Case Studies

Karen D. JonesChief, Project Management StaffDivision of Biologic Oncology ProductsOffice of Oncology Drug ProductsOffice of New DrugsCenter for Drug Evaluation and ResearchFDA

Working with FDA: Biological Products and Clinical Development Karen 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


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: [email protected]

IND Specific Contact• Assigned Regulatory Project Manager

Documents

14 Jones Case Studies Reviewed