Hiv 1 resistance testing in drug development
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HIV-1 Resistance Testing in Drug Development. Antiviral Drugs Advisory Committee Meeting November 2-3, 1999. Introduction. Implications of HIV drug resistance Patient management perspective Drug development perspective Meeting Goals Origin of meeting Session objectives Acknowledgments.

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Hiv 1 resistance testing in drug development

HIV-1 Resistance Testing in Drug Development

Antiviral Drugs Advisory Committee Meeting

November 2-3, 1999


Introduction

Introduction

  • Implications of HIV drug resistance

    • Patient management perspective

    • Drug development perspective

  • Meeting Goals

  • Origin of meeting

  • Session objectives

  • Acknowledgments


Implications of hiv drug resistance 1

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


Implications of hiv drug resistance 2

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


What are some current limitations

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


Hiv resistance testing in drug development meeting goals

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


Development of meeting

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!)


Hiv resistance collaborative group representation

HIV Resistance Collaborative GroupRepresentation

  • Pharmaceutical companies

  • Diagnostic companies

  • ACTG virology/statistics/clinical trials

  • Academicians

  • European Health Authorities

  • FDA (CDER, CBER, CDRH)

  • Community


Federal register announcement

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


Meeting format

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


Objectives session 1 resistance technology

Objectives - Session 1:Resistance 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)


Objectives session 2 clinical validation

Objectives - Session 2:Clinical 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


Objectives session 3 practical considerations

Objectives - Session 3:Practical 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


Objectives session 4 potential roles in drug development

Objectives - Session 4:Potential 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


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 D’Aquila

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

Acknowledgments


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