IRB Member Education Update June 2004

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IRB Member Education UpdateJune 2004

• -Applicability of 21CFR
• -Adverse Event Reporting under 21CFR

John Farley, MD, MPH Center for Clinical Trials
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Case 1a

• The IRB is reviewing an investigator-initiated
  pilot study to evaluate the potential efficacy of
  cidofovir in the treatment of post kidney
  transplant patients with previously diagnosed
  polyoma virus nephropathy. Cidofovir is a
  marketed drug which is approved for the treatment
  of cytomegalovirus.
• Is Title 21 of the Code of Federal Regulations
  (21CFR) relevant to the review of this study?

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Scope of 21CFR

• Applies to all clinical investigations regulated
  by the Food and Drug Administration (FDA) under
  the Federal, Food, Drug, and Cosmetic Act as well
  as clinical investigations that support
  applications for research or marketing permits
  for products regulated by the FDA.

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Requirements for Submitting Investigational New
Drug Application (IND) to the FDA

• If the sponsor intends to conduct a clinical
  investigation with an investigational new drug
  subject to licensing provisions of the Federal
  Food, Drug, and Cosmetic Act or Public Health
  Service Act.
• Sponsor may not begin a clinical investigation
  until a required IND is in effect.
• Separate IND is required for exemption from
  informed consent under 21CFR50.24 (emergency
  research).
• (21CFR312.20)

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Exemption from IND Reqs

• The clinical investigation of a drug product
  lawfully marketed in the U.S. is exempt from the
  reqs if all of the following apply
• Not intended to be reported to the FDA as a
  well-controlled study in support of new
  indication or change in labeling
• Lawfully marketed as a prescription drug product
  and not intended to support a significant change
  in advertising.
• Route of administration, dosage level, or patient
  population does not significantly increase the
  risks (or decrease acceptability of the risks).
• (21CFR312.2a)

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IND Application Procedures

• IND goes into effect 30 days after receipt by the
  FDA unless the FDA notifies the sponsor of a
  clinical hold. (312.40)
• At any time during the investigation, the FDA may
  request more data or communicate about
  deficiencies in the IND (312.41). A clinical hold
  may be issued at any time (312.42).
• The sponsor is the person or entity holding the
  IND not necessarily the same as the entity
  paying for the study.

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Case 1b

• As the IRB is discussing their concerns with the
  investigator re the possible need for an IND,
  Gilead Pharmaceuticals Inc. agrees to sponsor the
  study and Gilead files an IND application with
  the FDA which goes into effect.
• Because an IND is in place, what minimum safety
  monitoring and reporting activity can the IRB
  assume will be ongoing for this study?

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Regulatory Sources for Safety Monitoring and
Reporting of Studies Conducted Under 21CFR

• International Conference on Harmonization
  (international standards) (ICH) major sections
  published in the Federal Register representing
  FDA current thinking)
• Section E2A, Guideline on Clinical Safety Data
  Management published Federal Register March 1,
  1995
• Section E6, Good Clinical Practice Consolidated
  Guideline published Federal Register May 9, 1997
• The provisions of ICH E2A were largely encoded in
  21CFR312.32 entitled IND Safety Reports.

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Definitions of Adverse Experiences (also known as
SAEs) Associated With the Use of a Drug

• Life-threatening adverse drug experience places
  the patient at immediate risk of death
• Serious adverse drug experience
• Results in death
• Life-threatening
• Requires or prolongs hospitalization
• Results in persistent/significant
  disability/incapacity
• Congenital anomaly/birth defect
• OR action on the part of a physician is necessary
  to avert any of the above
• Unexpected adverse drug experience the
  specificity of severity of the adverse experience
  is not consistent with the Investigator Brochure
  or risk information described elsewhere in the
  IND application
• (21CFR 312.32)

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Reporting of Adverse Events

• Reporting for SAEs is expedited.
• The sponsor must report to FDA within 7 days
  (death, life-threatening) or 15 days (other SAE).
  
• 21CFR312.32( c) uses the serious and unexpected
  adverse experience term when referencing sponsor
  obligations for safety reporting to the FDA.
• Industry standard is for site investigators to
  notify the sponsor with 48 hours and notify their
  own IRB promptly.
• Sponsors notify other investigators promptly
  per ICH. These notifications are intended as
  amendments to the Investigators Brochure.
• (ICH Guideline Clinical Safety Data Management,
  Federal Register, March 1, 1995 21CFR312.32)

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FDA Safety Monitoring

• IND Safety Reports FDA may place a clinical
  hold on an IND at any time based on IND Safety
  Reports.
• Annual Reports The sponsor (holder of the IND)
  is required to submit an annual report to the FDA
  which includes a summary of all IND safety
  reports and all deaths of study subjects during
  the prior year.

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Disclaimer

• Facts of Case 1 altered for teaching purposes.