Regulatory Issues in Research from IND to NDA

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Regulatory Issues in Research from IND to NDA

• Steven Lemery, MD

Disclaimer This talk is a work of Dr. Lemery
and should not be construed as official FDA views
or official FDA advice.
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FDA hierarchy
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Division Hierarchy
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Who Approves Drugs?

• Commissioner?
• Popular vote?
• Consensus of the few?
• Medical Officer Decision?
• Other?
• The Secretary (of HHS) shall approve an
  application for a drug unless the Secretary
  finds

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Medical Officer Duties

• INDs
• NDAs/BLAs
• Industry meetings
• Advisory committee preparation
• Post-marketing activities

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Bases for FDA decisions

• Statutes binding
• Regulations binding
• Guidance
• Court decisions
• Precedent
• Policy
• Advisory committee advice

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FDA Drug Law

• 1906 Pure Food and Drug Act Labeling
• 1938 Food Drug and Cosmetic Act Safety
• 1962 Kefauver-Harris Amendments to FDC Safety
  and Effectiveness

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1962 Kefauver-Harris Amendments to FDC

• Substantial evidenceadequate and well controlled
  trials
• Review by experts (FDA)
• Authority to regulate the investigation of drugs

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FDA Drug Law

• 1970 Pharmaceutical Manufacturers of America
  versus Richardson
• 1973 Weinberg versus Hynson, Wescott, and
  Dunning
• 1979 United States versus Rutherford

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FDA Law

• 1992 Subpart H regulations
• 1997 FDAMA
• 2007 FDAAA

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IND to NDA

• IND

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IND definition

• Notice of Claimed Investigation Exemption for a
  New Drug

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Interactive Question 1
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When is an IND required?21 CFR 312.2

• Questions to ask
• Are you using a drug in humans?
• Is the drug FDA approved?

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When is an IND required?21 CFR 312.2

• Exemption criteria for studies involving FDA
  approved drugs (refer to guidance document)
• Will not change labeling
• Not support new advertising
• Does not significantly increase risk
• Complies with IRB and IC regs
• Complies with 21 CFR 312.7

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Interactive Question 2
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FDA IND Reviews

• Clinical
• Statistical
• Pharmacology/Toxicology
• Clinical Pharmacology
• Chemistry/Manufacturing/Controls (CMC)
• Regulatory Project Manager

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Required components of an IND

• Does information pertaining to manufacturing,
  toxicology, and pharmacology need to be submitted
  for all new INDs?
• 21 CFR 312.23

http//www.fda.gov/cber/ind/ind.htm for
information on specific requirements and forms
to submit when submitting an IND
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FDA actions regarding INDs

• Allow study to proceed
• Place IND on full clinical hold
• Place IND on partial clinical hold

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Clinical Holds21 CFR 312.42

• Unreasonable risk
• Unqualified investigator
• Misleading, erroneous, or incomplete investigator
  brochure
• Exclusion of men or women (life threatening
  disease)
• Insufficient information to assess risk

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Interactive Question 3
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Clinical Holds Phase 2 or 3

• A study is clearly deficient in design to meet
  its stated objectives

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The process does not stop with the initial IND
submission!

• Sponsor and Investigator Obligations

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Sponsor Obligations 21 CFR 312.50 to 312.59

• Select qualified investigators
• Adequately control study drug
• Provide investigators information
• Ensure the study is conducted according to the
  protocol (Good Clinical Practice)
• Ensure investigators and FDA are informed of
  certain adverse events
• Maintain adequate records

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Investigator Obligations21 CFR 312.60-312.69

• Comply with the protocol
• Protect rights, safety, and welfare of subjects
• Obtain IC and IRB approval
• Maintain records
• Submit required reports

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Safety Reports 21 CFR 312.32Sponsor shall notify
FDA and all investigators of the following

• Serious and unexpected AE (15 days)
• Unexpected fatal or life-threatening event (7
  days)
• Findings in animals that suggests a significant
  risk
• Any relevant follow-up information

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Other INDs

• Expanded Access

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Other INDs

• Open label protocol
• Treatment use
• Group C treatment IND
• Emergency use IND

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NDA/BLA
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Common Endpoints for Cancer Drugs

• Overall Survival
• Progression Free Survival
• Disease Free Survival (adjuvant)
• ORR

http//www.fda.gov/cder/guidance/7478fnl.pdf
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Interactive Question 4
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Accelerated Approval(Approval under Subpart H)

• Adequate and well controlled
• Effect is on a surrogate
• Surrogate is reasonably likely to predict
  clinical benefit
• Applicant must study the drug further

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Pre-Marketing Safety Assessment

• Purposes
• Level of evidence for label inclusion

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Post-Marketing Safety

• 15 day alert reports for serious and unexpected
  events
• Periodic Safety Reports at quarterly intervals
  after approval of an application then annually
• FDAAA

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Interactive Question 5
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Why the High Failure Rate in Trials to
Demonstrate Effectiveness and Safety?

• Incomplete Understanding of Biology of Disease.
• Suboptimal Investigations Prior to Pivotal
  Trials.
• Non-Prospective Biomarker Development.
• Inadequate FDA Interaction During Development.
• Lack of Sufficient Drug Development Capital.

From Joe Gootenberg (2008 Duke-AACR meeting)
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Questions