© Guidant 2005

Surrogate Endpoints and Non-randomized Trials

Roseann White

Humble Biostatistician

© Guidant 2003

Type of non-randomized trials

1. Diagnostic/Natural History trial

2. Single arm trial that shows superiority/non-inferiority in clinical endpoint

Example: Safety concerns for placebo or current practice

© Guidant 2003

Motivation

• Chiron Corporation developed a method to measure the amount of HIV-1 virus in the blood

• To obtain approval from FDA for the device, Chiron needed to demonstrate clinical utility

• Investigators also saw the potential for Viral Load to be a surrogate for HIV-1 disease progression

© Guidant 2003

Prentice Criteria for a surrogate endpoint

Re-statement of Prentice Criteria for a surrogate endpoint

1. Baseline measurements are predictive of outcome

2. Changes in the measurement over time is predictive of outcome

3. Changes in the measurement to external forces (therapy) is predictive of outcome

© Guidant 2003

Non-randomized trial – a prospective analysis of a retrospective cohort

• Description of Cohorts180 seropositive men studied for more than 10 years from

the Pittsburgh portion of Multicenter AIDS Cohort Study (MACS)– Mellors, J.W., et. al. Science, 272

1604 men infected with HIV-1 from four university-based clinical centers participating in MACS – Mellors, J.W. et. al. Annals of Internal Medicine, 126

~250 patients from New York Blood Center as part of a PMA submission for the bDNA diagnostic

• AnalysisLogistic regression using baseline values to predict survival Cox proportional hazards model with HIV-1 viral load as a

time dependant covariate Treatment effect?

© Guidant 2003

Predictive in stratified populations

Reprinted from Plasma Viral Load and CD4+ Lymphocytes as Prognostic Markers of HIV-1 Infection John W. Mellors, et.al.Annals 1997 126: 946-954.

© Guidant 2003

Rest of the story

• Viral load was used along with CD4 counts as evidence of efficacy for accelerated approval of the protease inhibitors

• Many efficacy trials measured viral load along with CD4 count

• FDA Guidance to the industry (2002) recommended the use of viral load for efficacy in accelerated approvals

• “The Evaluation of Surrogate Endpoints in Practice: Experience in HIV”* by Michael HughesUses several different methods to “validate” HIV viral

load and CD4 counts as surrogate endpoints*Chapter 17 in The Evaluation of Surrogate Endpoints edited by T. Burzykowski, et. al. Springer, 2005

© Guidant 2003

Types of non-randomized trials

1. Quantitative Diagnostic

2. Single arm trial to show superiority or non-inferiority in clinical endpoint

© Guidant 2003

Motivation

• Randomization is difficultCost prohibitive

Concerns for the safety of the patient

Limited population available for recruitment

• Potential surrogate endpoints available

© Guidant 2003

Design Considerations

• Evaluate the risk associated with the surrogate for the product in questionIf it’s a second generation product, will the surrogate

reflect the improvements in the product AND

Will the surrogate reflect potential problems?

Example: Using angiographic binary restenosis as a surrogate at 6 months for drug eluting stent whose drug has not completely eluted at six months

© Guidant 2003

© Guidant 2003

Design Considerations (con’t)

• Choice of comparison – Historical Control versus Objective Performance CriteriaHistorical Control provides more of an opportunity to

demonstrate that the current trial population is similar to the historical population in which the surrogate was based.

When using an objective performance criteria, develop a detailed method in which you will “validate” the current population is reflective of the population that surrogate was based.

Subgroup analysis where the surrogate shows difference, e.g. diabetics versus non-diabetics

© Guidant 2003

Design Considerations (con’t)

• Consider a co-primary clinical endpoint where you demonstrate a trend in the same direction as your surrogateLess stringent alpha for superiority

Wider delta for non-inferiority

© Guidant 2003

Conclusion

• Validation of Surrogates endpoint using non-randomized trials is challengingMore work needs to be done to develop techniques

that do not necessarily require a very effective treatment

• Use of surrogates in single arm trials requires:Careful consideration as to whether the surrogate will

reflect the true performance of the product

Use of a historical control or a detail plan of how to assure the current population reflect the population on which the surrogate was based.