Clinical Trial Design for Heavily Treatment-Experienced Patients

1
Clinical Trial Design for Heavily
Treatment-Experienced Patients

• Meeting of the Antiviral Drugs Advisory Committee
• January 11, 2001

2
Introduction

• Statement of the issues
• Meeting objectives
• Defining the patient population
• How we reached this point
• Where we need to go
• FDAs role focus
• Public comment
• Agenda
• Acknowledgements

3
Issues

• Utility of initial regimens is time-limited.
• Insufficient treatment options for heavily
  treatment-experienced patients.
• Very few antiretroviral labels have information
  on dosing, safety or efficacy in
  treatment-experienced patients.
• Development of new agents and labeling is a
  public health priority.

4
Todays Objectives

• Facilitate and promote development of new
  therapies for patients most in need of treatment
  options
• Foster collaboration between companies
• Obtain recommendations for incorporation into
  Guidances (HIV RNA, Resistance Testing and
  Alternative Dosing)

5
Defining the Heavily Treatment-Experienced
Population

• For purpose of discussion
• Loss or lack of virologic response to at least 2
  HAART regimens
• Experience with at least one member of each class
• Why this definition?
• Designing comparative trials is problematic

6
How We Reached This Point

• Historically, FDA has recommended that ARVs be
  studied in broad patient population and has
  provided for flexibility in endpoint, however ...
• Registrational studies largely conducted in naïve
  or NRTI-experienced population
• Evolving treatment since trial initiation
• New drug may not be expected to be effective due
  to cross-resistance
• Challenges of trial design and data
  interpretation in experienced population

7
Trial Design Challenges

• Heterogeneity of population
• Identification of acceptable comparators
• Defining endpoint that is clinically-relevant and
  achievable
• Consideration for additional dose finding
• Complicated safety assessments

8
Where We Need to Go

• Development of new agents with acceptable
  tolerability and established efficacy in
  experienced patients.
• Development of novel clinical trial design
  approaches

9
FDAs Role

• Ongoing discussions with Community and Industry
• 1999 letter to Sponsors re use of gt1
  investigational agent
• Labeling and other regulatory incentives
• Accelerated approval, priority review
• Consensus about need for FDA-sponsored working
  meeting on this topic

10
FDAs Focus

• Registrational vs strategy trials
• Registrational adequate and well-controlled,
  pivotal trials
• Strategy exploratory studies to assess efficacy
  of a regimen
• Distinction difference in ability to evaluate
  contribution of a given drug
• Also interested in other trials that will provide
  prescribing information for labeling

11
Request for Public Input October 2000 Letter and
FRN

• Proposals for trial design role of specific
  designs
• Comments on patient population stratification
• Appropriate control arms role of resistance
  testing
• Outcome measures
• Pediatric considerations

12
Morning AgendaTrial Design Issues

• Therapeutic Challenges - A Clinical Perspective
  Douglas Ward
• Trial Design Options for Adults Martin Schechter
• Trial Design Options for Pediatrics
  Coleen Cunningham
• Trial Design Options from a Patient Perspective
  Carlton Hogan
• Summary of Public Responses and Regulatory
  Perspective Katherine Laessig
• Questions and Discussion

13
Afternoon AgendaEndpoint Issues

• Open Public Hearing
• Continued Discussion of Morning Questions
• Response Rates in Heavily Pretreated Patients
  Roy Gulick
• Statistical Considerations for Endpoints
  Victor DeGruttola
• Questions and Discussion

14
Acknowledgements for Responses

• Community groups
• Industry
• Abbott Laboratories
• Agouron Pharmaceuticals
• Bristol Myers Squibb
• DuPont Pharmaceuticals Company
• Gilead Sciences
• Glaxo Wellcome, Inc.
• Hoffman-La Roche, Inc.
• Merck Co., Inc.
• Triangle Pharmaceuticals
• Trimeris

15
Therapy for Treatment-Experienced Patients
Working Group

• Debra Birnkrant
• Therese Cvetkovich
• Tom Hammerstrom
• Harry Haverkos
• Richard Klein
• Stanka Kukich

• Katherine Laessig
• Jeffrey Murray
• Greg Soon
• Kimberly Struble
• Joseph Toerner