HIV1 Resistance Testing in Drug Development

1
HIV-1 Resistance Testing in Drug Development

• Antiviral Drugs Advisory Committee Meeting
• November 2-3, 1999

2
Introduction

• Implications of HIV drug resistance
• Patient management perspective
• Drug development perspective
• Meeting Goals
• Origin of meeting
• Session objectives
• Acknowledgments

3
Implications of HIV Drug Resistance (1)

• Clinical Management Perspective
• Critical factor affecting safe and effective use
  of therapeutics for HIV
• One of the important causes of treatment failure
• Limits options for alternative regimens
• Exposes patients to risk of drug-induced toxicity
  without potential benefit
• Public health problem of transmission of
  resistant virus raises additional issues

4
Implications of HIV Drug Resistance (2)

• Drug Development Perspective
• Complicates interpretation of trial results
• Limited understanding of why patients respond or
  fail combination therapy in clinical trials
• Limits ability to test new drugs in patient
  population with greatest need (heavily
  pretreated)
• Limits ability to provide advice on the optimal
  use of a new drug in labeling

5
What are some current limitations?

• Diverse methodologies in genotypic and phenotypic
  testing uncertain correlation
• No approved assays
• No uniform requirements for resistance
  characterization in drug development or
  post-marketing
• Lack of consensus regarding clinical utility and
  interpretation of testing
• Incomplete understanding of relationship with
  cofactors

6
HIV Resistance Testing in Drug Development
Meeting Goals

• Define what is known and what needs further study
• Reliability of assays, interpretation of results,
  and strength for predicting treatment outcome
• Discuss approaches for defining resistance
  (mutational algorithms, breakpoints) now, and in
  the future
• Discuss standardized methods for analyzing data
• Obtain guidance on use of resistance testing in
  drug development
• Discuss what future initiatives should be
  undertaken to encourage progress

7
Development of Meeting

• Charge from Advisory Committee Chair
• Identification of some common goals with
  industry-sponsored HIV Resistance Collaborative
  Group
• Broader solicitation of relevant information and
  perspective
• Iterative approach to developing agenda (issue
  identification was a goal in itself!)

8
HIV Resistance Collaborative GroupRepresentation

• Pharmaceutical companies
• Diagnostic companies
• ACTG virology/statistics/clinical trials
• Academicians
• European Health Authorities
• FDA (CDER, CBER, CDRH)
• Community

9
Federal Register Announcement

• Notification of meeting
• Request for
• Data on the relationship of HIV mutation
  development and changes in susceptibility
• Prospective or retrospective data on relationship
  between genotype or phenotype and clinical
  outcome
• Proposals for resistance testing in clinical
  trials
• Proposals for product labeling claims

10
Meeting Format

• Scientific workshop
• Not product specific
• No voting issues
• Modular
• Each session has specific objectives and points
  for committee discussion
• Invited presentations selected to provide
  relevant background for discussion
• Common theme for each session recommendations
  for progress

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Objectives - Session 1Resistance Technology

• General principles, and exploration of
  performance characteristics of currently
  available genotypic phenotypic assays
• Limitations
• Quality control issues
• Correlation between genotype and phenotype
• Role of assays in drug development
• Update on proposed approach to assay regulation
  (CBER)

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Objectives - Session 2Clinical Validation

• Explore predictive value of baseline genotype or
  phenotype and treatment outcome
• Prospective trials
• Retrospective analyses using a common analysis
  plan
• Discuss approaches for categorizing and analyzing
  resistance patterns
• Identify additional clinical research to further
  define clinical utility

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Objectives - Session 3Practical Considerations

• Identify patient populations for whom resistance
  testing in drug development is most useful
• Explore other factors to consider when resistance
  testing is incorporated into clinical trials

14
Objectives - Session 4Potential Roles in Drug
Development

• Obtain guidance on in vitro and clinical data
  necessary to characterize resistance and
  cross-resistance potential
• Obtain guidance on post-marketing evaluation of
  resistance
• Feedback on potential scenarios for use of
  resistance testing to support regulatory claims

15
Acknowledgments

• HIV Resistance Collaborative Group
• Invited Speakers
• Douglas Richman
• Phillipe Clevenbergh
• John Baxter
• John Mellors
• Victor DeGruttola
• Michael Para
• Mounir Ait-Khaled
• Veronica Miller
• Susan Little
• Richard DAquila

• FDA
• Jeff Murray
• Girish Aras
• Narayana Battula
• Debra Birnkrant
• Gary Chikami
• Andrew Dayton (CBER)
• Walla Dempsey
• Tom Hammerstrom
• Lauren Iacono-Connors
• Richard Klein
• Katherine Laessig
• Jonathan Ma
• Lalji Mishra
• Joanne Rhoads
• Rhonda Stover
• Kim Struble
• Joseph Toerner