The Radioactive Drug Research Committee Approval Process for Tracer Use

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The Radioactive Drug Research Committee Approval
Process for Tracer Use

• Anthony F. Shields, M.D., Ph.D.
• Karmanos Cancer Institute
• Wayne State University
• Detroit, Michigan

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RDRC

• Basic research for the purpose of advancing
  scientific knowledge
• The research is intended to obtain basic
  information regarding the metabolism of
  radioactive drugs including kinetics,
  distribution, dosimetry, and localization
• OR
• Obtain basic information regarding human
  physiology, pathophysiology, and biochemistry of
  radioactive drugs.
• The research in NOT intended to determine the
  safety and efficacy of a radioactive drug in
  human subjects as a therapy, diagnostic or
  preventive medical product.
• The research is NOT intended for the immediate
  therapeutic, diagnostic or preventive benefit.

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RDRC

• Title 21 Code of Federal Regulations (CFR) 361.1
• Conditions for RDRC Research
• Basic Science Research not intended for
  immediate therapeutic,diagnostic, or similar
  purposes or to determine the safety and
  effectiveness of the drug
• No pharmacologic effect
• Radiation dose limits
• FDA approves committee members
• RDRC Responsibilities
• Reviews and approve each research protocol per
  regulations, with IRB concurrence
• Submit variety of regulatory reports to FDA

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RDRC

• 74 Active RDRCs as of June, 2006.
• RDRC protocols average 10 subjects each.
• RDRC PET protocols average 8 patients
• IND PET protocols average 62 patients
• RDRC research (as of 2003)
• 77 PET tracer development
• 5 gamma tracer development
• 18 beta (in vitro bioassay)
• Types of RDRC research (2003)
• Neuroreceptor 45
• Cancer 15
• Diabetes 12
• Cardiac 9
• Other 22 (Exercise, pain, obesity,
  acupuncture, prostheses, GI, pulmonary, auditory,
  bone physiology, etc.)

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Purpose of Research

• RDRC
• The research is intended to obtain basic
  information regarding
• Metabolism of the radioactively labeled drug
• kinetics
• distribution
• dosimetry
• localization
• Human physiology, pathophysiology, biochemistry
• The research is not intended for immediate
  therapeutic, diagnostic, or similar purposes, or
  to determine the safety and effectiveness of the
  drug in humans for such purposes (i.e., to carry
  out a clinical trial)

• IND
• Intent of the research is not restricted
• Can include
• Research involving therapeutic, diagnostic, or
  preventive benefit to the subject
• Study of safety and efficacy (clinical trial)
• Basic research that does not meet the
  requirements of 361.1
• Basic research that meets requirements of 361.1

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Review, Approval, and Oversight

• RDRC and IND Both Need
• Institutional Review Board (IRB)
• 21 CFR 56
• Responsibilities include
• Review of initial research and subsequent changes
• Authority to approve, require modification in, or
  disapprove research activities.
• Authority to suspend or terminate approval of
  research
• Approval must be obtained prior to implementation
• Continuing review of ongoing research
• Criteria for approval
• Minimization of risks to subjects risks are
  reasonable in relation to anticipated benefits
• Equitable selection of subjects
• Compliance with the informed consent requirements
  of 21 CFR 50, including subpart D if some
  subjects are children
• Adequate provision for monitoring data to ensure
  safety of subjects
• Protection of rights and welfare of vulnerable
  subjects
• Adequate provisions to protect privacy and
  confidentiality

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Review, Approval, and Oversight (cont.)

• RDRC
• Radioactive Drug Research Committee
• Approved, monitored by FDA
• Responsible for ensuring that the requirements of
  361.1 are met
• Qualified study investigators
• Proper licensure for radioactive materials
• Appropriate selection and consent of research
  subjects
• Appropriate quality of radioactive drug
  administered
• Sound research protocol design
• Reporting of adverse events
• Approval by IRB
• Labeling

• IND
• FDA
• Reviews
• Protocols, protocol changes
• Study investigators
• CMC, Pharm/tox, PK
• Information amendments
• Primary objectives of review
• To assure the safety and rights of subjects
• To assess the scientific quality of the clinical
  investigations
• Ability of sponsor to proceed
• First 30 days
• Ongoing studies

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Review, Approval, and Oversight (cont.)

• RDRC
• Annual report
• Study Summary
• Membership Summary
• Special Summary
• Adverse events
• If requested
• Minutes
• Full protocols
• FDA monitors the activities
• of the approved RDRCs
• Notification of deficiencies
• On-site inspections

Reporting to FDA Monitoring by FDA FDA enforcement actions
IND Annual report New protocols Protocol
changes New investigators Information
amendment Adverse events FDA monitors the
research On-site inspections Full or partial
clinical hold, termination of IND
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Dosing
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Study Subjects
RDRC IND
Informed Consent (21 CFR 50) Number of subjects Required, incl. Subpart D Sufficient but no greater than necessary for the purpose of the study Should reflect that the study is intended to obtain basic research information (usually lt30) Required, incl. Subpart D No limit
Subjects lt 18 years of age Permitted only in special situations described in 361.1(d)(5) Permitted
Women of child bearing potential Must state in writing that she is not pregnant, or be confirmed as not pregnant Permitted
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Adverse Event (AE) Reporting

• RDRC
• Investigator must immediately report to RDRC all
  AEs associated with use of the radioactive drug
  in the research study
• Serious- FDA recommends 2 business days
• All others- FDA recommends 5 business days
• RDRC must immediately report to FDA all adverse
  events probably attributable to use of the
  radioactive drug in the research study
• Serious- FDA recommends 7 business days
• All others- FDA recommends 15 business days

• IND
• Sponsor must review all info relevant to the
  safety of the drug from any source, foreign or
  domestic
• clinical trials
• literature
• animal studies
• commercial marketing
• unpublished papers
• reports from foreign regulatory authorities
• Safety reports
• Serious/unexpected within 15 days of receipt
• Unexpected fatal or life-threatening within 7
  days of receipt
• Annual reports

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Information Needed for RDRC

• With any tracer one needs to know
• Toxicity data
• Can be obtained on tracer from
• previous unlabeled drug studies
• knowledge that it is a natural compound in the
  body
• knowledge that it is a metabolite of a drug that
  has been given to patients
• Dosimetry
• From animal studies
• Studies of related compounds
• Purity and specific activity of with the tracer.
• Sterility

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Personal RDRC ExamplesStudies of Labeled
Thymidine and Analogs

• 11C-Thymidine
• 11C-Thymidine had been used at other centers in
  patients (dosimetry).
• Unlabeled drug had previously used in cancer
  patients at high doses (toxicity data).
• Natural body and blood constituent (toxicity
  data).
• 11C-Thymine
• Natural body and blood constituent (toxicity
  data).
• Unlabeled thymidine is metabolized to thymine, so
  we used thymidine toxicity data.
• Used 11C-thymidine dosimetry data, since
  thymidine converted to thymine and cleared more
  rapidly.
• We did not need direct toxicity or dosimetry data
  with thymine.

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Personal RDRC ExamplesStudies of Labeled
Thymidine Analogs

• 18F-FLT (3'-deoxy-3'-fluorothymidine)
• Unlabeled FLT had previously been in AIDS
  patients at high doses (it was too toxic).
• Dosimetry from dog studies.
• 18F-FMAU (1-(2-deoxy-2'-fluoro-ß-D-arabinofuranos
  yl)thymine)
• Unlabeled FMAU had previously been in AIDS
  patients at high doses (it was too toxic).
• Dosimetry from dog studies.
• 18F-FAU (1-(2-deoxy-2'-fluoro-ß-D-arabinofuranosy
  l)uracil).
• FAU had NEVER been injected into patients.
  Toxicity data used from FIAU which is metabolized
  to FAU.
• Dosimetry from dog studies.

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Conclusions

• The RDRC mechanism complements the IND process
  for pilot studies of radioactive tracers.
• It generally allows for testing up to about 30
  patients on a given study.
• One needs toxicity and dosimetry data, but this
  can sometimes be inferred from data and natural
  compounds, unlabeled drugs, and metabolites.
• Radiochemical purity and specific activity are
  needed.
• Since RDRC committees are run by individuals at
  different institutions, the rulings can sometimes
  vary.
• Proposals to allow testing of very small
  quantities of tracer without toxicity data would
  help to speed imaging development.