IND Case Studies

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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

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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

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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

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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

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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

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Case 1 Pre-IND Meeting

• FDA provides a written response to sponsors
  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

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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

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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

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Case 1 Conclusion

• Early and Successful Communication Results in
  Successful INDs

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

• Initial Problem
• Submitted as a new protocol under sponsors
  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

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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

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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

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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

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Case 2a Resolution

• Sponsors 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

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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

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Case 2b Same IND as Case 2a New Issues

• Serious adverse events (SAEs) reported to
  sponsors cross-referenced INDs
• Sponsors 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

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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

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Case 2b Resolution New Problem

• Sponsors 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

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Case 2b FDA Action

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

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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

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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

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Questions?

• FDA/CDER/OND/OODP/DBOP Contact Information
• Main Line 301-796-2320
• Fax [phone]
• Initial Contact-CPMS
• Email karen.jones_at_fda.hhs.gov
• IND Specific Contact
• Assigned Regulatory Project Manager