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Surrogate Endpoints and Non-randomized Trials

Surrogate Endpoints and Non-randomized Trials. Roseann White Humble Biostatistician. Type of non-randomized trials. Diagnostic/Natural History trial Single arm trial that shows superiority/non-inferiority in clinical endpoint Example: Safety concerns for placebo or current practice.

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Surrogate Endpoints and Non-randomized Trials

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  1. Surrogate Endpoints and Non-randomized Trials Roseann White Humble Biostatistician

  2. Type of non-randomized trials • Diagnostic/Natural History trial • Single arm trial that shows superiority/non-inferiority in clinical endpoint Example: Safety concerns for placebo or current practice

  3. 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

  4. Prentice Criteria for a surrogate endpoint Re-statement of Prentice Criteria for a surrogate endpoint • Baseline measurements are predictive of outcome • Changes in the measurement over time is predictive of outcome • Changes in the measurement to external forces (therapy) is predictive of outcome What if there is no therapy?

  5. 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?

  6. 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.

  7. 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

  8. Types of non-randomized trials • Quantitative Diagnostic • Single arm trial to show superiority or non-inferiority in clinical endpoint

  9. Motivation • Randomization is difficult • Cost prohibitive • Concerns for the safety of the patient • Limited population available for recruitment • Potential surrogate endpoints available what's a statistician to do?

  10. 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

  11. 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

  12. 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

  13. 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.

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