© 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 Cohorts  180 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 Analysis Logistic 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 :

© 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 Hughes  Uses 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 difficult  Cost 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 question  If 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

Design Considerations (con’t) Choice of comparison – Historical Control versus Objective Performance Criteria  Historical 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 surrogate  Less stringent alpha for superiority  Wider delta for non-inferiority

© Guidant 2003 Conclusion Validation of Surrogates endpoint using non- randomized trials is challenging  More 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.