FDA MEDICAL REVIEW of the IND

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FDA MEDICAL REVIEW of the IND

• Robert Kane, MD
• Medical Officer, DODP, CDER

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Review Activities - 1

• Meetings and Review of commercial/research
  protocols
• Pre-IND
• IND (phase 1)
• Phase 2 and 3, SPAs
• Pre-NDA
• NDA
• Post Marketing (phase 4)

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IND Review Process

• Prescribed by Law and Regs
• Content and Format of IND (guidances)
• http//www.fda.gov/cder/guidance/index.htm
• http//www.fda.gov/cder/guidance/clin2.pdf
• CFR 312

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Phase 1 IND Review

• Initial dose and schedule selection
• Safety IRB, Consent, monitoring
• Patient population selected
• Process for determining MTD and RP2D

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Phase 1 Clinical Protocol

• Regulatory requirements
• (21 C.F.R. 312.23(a)(6))
• Statement of objectives and purpose
• Investigator information
• Patient inclusion/exclusion criteria
• Study design
• Dosage and administration
• Data collection what and when
• Adverse event procedures

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Sponsor and Investigator Obligations

• Obligations of sponsors and investigators
• Sponsor obligations (21 C.F.R. 312.50)
• Management of IND
• Safety reports
• Transportation/shipment of drug
• Collection of unused drug
• Records maintenance and retention
• Investigators obligations (21 C.F.R. 312.60)
• Assure IRB review and informed consent
• Adherence to protocol
• Adverse event reporting
• Trial supervision
• Records maintenance and retention

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IND Safety Reports 21 C.F.R. 312.32

• Reasonable possibility that the experience may
  have been caused by the drug
• Disability
• Life-threatening adverse drug experience
• SAE
• Unexpected AE

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Subpart E Drugs Intended to Treat
Life-threatening and Severely- debilitating
Illnesses 21 C.F.R. 312.81)

• Diseases or conditions where the likelihood of
  death is high unless the course of the disease is
  interrupted
• diseases or conditions that cause major
  irreversible morbidity
• Sponsors are encouraged to consult with FDA on
  the applicability of these procedures to specific
  products.
• Created Fast Track and Priority Review

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IND Exemptions

• Drug product is marketed in the US
• Investigation is not intended to support a new
  indication or labeling change
• No change in advertising
• Administration - route or dose level or patient
  population or other factor that significantly
  increases the risks of use?

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Clinical Hold of Studies not Designed to be
Adequate and Well-controlled21 C.F.R. 312.42

• Safety/Investigator Qualification
• Reasonable evidence that this trial (that is not
  adequate and well-controlled) is impeding
  enrollment to a study that is
• Insufficient quantities of drug to conduct a
  well-controlled trial as well
• One or more other adequate and well-controlled
  investigations strongly suggest lack of efficacy

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Overview of Therapeutic Development
Standard
Accelerated
Pre-IND.
IND Filing
NDA Filing
NDA Filing
Pre-clinical
4
1
2
3
Comprehensive multidisciplinary review often with
Advisory Committee discussion
Safety and Phase 4 monitoring
Monitor safety, review new protocols, annual
reports, approve exceptions
Consultation
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NDA
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Basis for New Drug Approval - NDA

• Demonstration of efficacy with acceptable safety
  in adequate and well-controlled studies CFR
  314 NDA Regulations
• Ability to generate product labeling that
• Defines an appropriate patient population for
  treatment with the drug
• Provides adequate information to enable safe and
  effective use prescribing of the drug
• Analogous rules for Biologics - BLA

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Adequate and Well-controlledClinical
Investigations

• Required by FDA Regulations
• Defined in CFR 314.126 (NDA regs)
• Clear statement of objectives
• Methods of assessment are well-defined and
  reliable
• Clearly-described analysis plan
• Valid comparison with control to allow a
  quantitative assessment of drug effect
• Adequate measures to minimize bias

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Types of Approval

• Regular approval Clinical benefit
• Accelerated approval Surrogate endpoint (PDUFA
  1992)
• Endpoint reasonably likely to predict-
• Serious or Life Threatening disease
• Better than existing therapy (if any)
• See Johnson, Williams, Pazdur JCO 2003211404-11.

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Regular Approval Requires Efficacy Endpoints of
Clinical Benefit

• Longer Survival (quantity)
• Easy to measure
• Better Survival (quality)
• Hard to measure
• Effective and Safe in context -
• (Risk / Benefit)

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Quantitative Assessment of Drug Effect

• Adequate sample size/power
• Magnitude of statistically persuasive treatment
  effect (effect size)
• Internal consistency between centers and between
  subgroups
• Consistency of secondary endpoints
• Independent substantiation of results

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Time in Development - Days