Paula M' Jacobs, Ph'D'

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Nuts and BoltsYou Too Can Prepare an IND
DCTD Phase 0 Workshop

• Paula M. Jacobs, Ph.D.
• SAIC Frederick
• Cancer Imaging Program/DCTD/NCI/NIH
• September 5, 2006
• Phase 0 Trials in Oncologic Drug Development

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Overview of Early Development

• Synthesize a number of new imaging drugs
• Evaluate them in pre-clinical settings
• Pick the best ones to test in humans
• Learn to prepare them consistently
• Perform in vivo pharmacology and toxicology in
  appropriate animal models
• Chose initial dose for human studies least risk
• Assemble the data and submit to FDA or to your
  RDRC
• Obtain IRB approval
• Test in human subjects

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Approach to Regulatory Requirements

• Regulations are the same for
• Labeled therapeutic agents
• Functional imaging agents
• General imaging agents
• Development strategy may differ with goal
• Basic information about a therapeutic
• Basic information about a tumor
• Imaging for evaluating response to therapy

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Investigational Clinical Trials

• The sponsor must apply for permission to study
  drugs in humans
• From FDA for IND traditional or exploratory
• From the Radioactive Drugs Research Committee
  (RDRC) at your institution
• From an IRB for either
• Sponsor
• Individual physician
• Institution
• Industry

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RDRC vs. IND

• RDRC for basic research only
• E.g., kinetics, distribution, dosimetry
• NOT safety or efficacy
• Pediatric studies restricted
• Only small doses and few patients
• Drug must have been in humans before
• IND not restricted to basic research
• Can study safety and efficacy (i.e., clinical
  trials)
• Can do basic research
• Pediatric studies less restricted

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Types of IND

• Three types of traditional INDs
• An investigator initiated IND
• Emergency use IND (E-IND)
• Treatment IND
• And a new type
• Exploratory (phase 0, x-IND)

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Whats the difference?

• Traditional
• Single agent
• Plans for Phase 1, 2, 3 trials and NDA
• Extensive pre-clinical data needed to begin
• Dose escalation, therapeutic evaluation
• Exploratory
• Multiple agents under one IND, go/no go
• Microdose, first in man studies
• No therapeutic intent
• Biodistribution, pharmacokinetics, safety
• Less pre-clinical data required
• Resubmit as Traditional IND if successful

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Where to get information

• FDA Guidance on the IND process with multiple
  links to other documentation
• http//www.fda.gov/cder/regulatory/applications/in
  d_page_1.htm
• Comprehensive FDA Guidance Page
• http//www.fda.gov/cder/guidance/guidance.htm
• An how-to guide from the Biological Development
  Program at NCI-Frederick with multiple links
• http//wwwbdp.ncifcrf.gov/pdf/GuidetoRegSubs.pdf
• Schedule a pre-IND meeting

Talk to the FDA!
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Nuts and Bolts of an IND

• What data are needed
• What supporting information is needed
• How is the application put together
• What happens when it is submitted

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Information Required in INDs

• Pharmacology/toxicology in animals
• Dosimetry for radiopharmaceuticals
• CMC Chemistry, Manufacturing and Controls
• Some of these data may be referenced from
  existing INDs or the literature
• Clinical Information

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Clinical Protocols and Investigator Information

• Detailed protocol for clinical study
• Qualifications of clinical investigators
• Commitments
• To obtain informed consent
• To obtain review of the study by an institutional
  review board (IRB)
• To adhere to the investigational new drug
  regulations

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IND Application

• 1. Form 1571 (Application)
• 2. Table of Contents of Application
• 3. Introductory Statement
• 4. General Investigational Plan
• 5. Investigators Brochure (multi-site)
• 6. Protocol
• Study Protocol
• Investigator Data Form 1572, CV

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IND Application

• 7. Chemistry, Manufacturing, and Control
  Data
• 8. Pharmacology and Toxicology Data
• 9. Previous Human Experience
• 10. Additional Information.
• Dosimetry
• Letter from IND or DMF-holder allowing cross-
  reference to their files
• Site/NCI Data and Safety Monitoring Plan
• Cited literature

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Practical Issues

• Make it easy for multiple reviewers to find and
  understand the information repeat information
  in different sections
• Include all sections, even if empty
• Comprehensive Table of Contents and TOC for any
  section more than a few pages
• Consecutive page numbers for entire IND (can be
  numbered by section )
• Include copies of all cited literature
• Dont assume the reviewers will be expert in your
  subject area

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What happens next?

• Submit 5-15 copies (ask FDA Division)
• Wait 30 calendar days before beginning the first
  study on IND
• The document goes to several reviewers
• FDA reviews the IND first and foremost for risk
  to subjects NOT for scientific interest
• FDA may request changes
• Safety related in protocol
• Purity/safety related in CMC
• FDA will call/fax with questions

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Begin your investigational study in human subjects

• Thanks for your atttention

jacobsp_at_mail.nih.gov
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The Next Speaker isDr. Anthony Shields