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Effective use of the Historical Control Trial

What is an historically controlled trial?. Study participants are treated with the new (test) agentOutcome compared to outcomes from individuals who do not (or have not) received the test agentUnlike a randomized controlled trial RCT:All study participants receive the test agent.Control group is external to the trial.

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Effective use of the Historical Control Trial

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    1. Effective use of the Historical Control Trial 7th Annual DIA Biotechnology Workshop, February 1999 Karen D. Weiss, M.D.

    2. What is an historically controlled trial? Study participants are treated with the new (test) agent Outcome compared to outcomes from individuals who do not (or have not) received the test agent Unlike a randomized controlled trial RCT: All study participants receive the test agent. Control group is external to the trial

    3. Disadvantages of externally controlled trials Control arm does not arise via randomization Advantages of randomization : Minimizes bias in allocation of treatments Helps ensure groups are balanced Basis for tests of significance

    4. Disadvantages of trials that utilize an external control Onus is on the applicant to support the assumptions: comparability of the control e.g., diagnostic and assessment methodologies supportive care natural history no bias in outcome assessments Basis for sample size calculations, other statistical tests not well established

    5. Advantages of trials utilizing an external control In some cases, an alternative design (e.g, placebo, active control) is unethical Facilitates recruitment Belief that new = better (active control), or that something is better than nothing (placebo or no-tx control) Inherent distaste for ‘computer to decide’

    6. When to utilize an externally controlled trial? When preliminary data strongly suggest efficacy When course of disease predictable, consistently poor outcome When endpoints objective When impact of baseline and other variables on endpoint is well characterized

    7. External controls - types Patient in consecutive series Patients from the literature Patients from previous studies (pool) “Patient as own control” - misnomer Concurrent, non-randomized

    8. Consecutive series Specific institutions/specific diseases - Control patients selected from a sequence of studies often, preceding trial is the control may utilize some or all of patients Likely to be from the recent past Same institution(s), investigators Completeness of the control database

    9. Literature control Only reports from the published literature usually do not contain sufficient detail entry criteria, analytical plan, etc. inability to verify Most problematic of of external controls

    10. Study “pool” For each treated patient, identify a mate from available pool matched for key prognostic factors ideally 2:1 ratio control: active compare the control groups to each other Is the control truly a random sampling?

    11. “Patient as own control” Term ‘patient as own control’ is a misnomer Generally implies comparison of patient status after intervention to patient status at baseline ex: for cancer trials, comparison of tumor burden at baseline vs end of treatment In reality, the actual comparison is the change from baseline in the study patients vs. the change from baseline that would be expected without the study intervention

    12. Concurrent control Control patients diagnosed, evaluated over same time period, but assigned to the control, rather than randomized only certain sites have the technology limited availability e.g., laminar flow Matching possible, desirable

    13. Criteria for acceptability of historical control in conjunction with RCT* Received precise standard tx as in RCT Part of a recent clinical trial, same eligibility Important covariates comparable between studies Prior study part of same organization, same investigators No signal to suggest differences between RCT and historical * S. Pocock J. Chron Dis 1976 Vol 29 pp 175-188

    14. Examples of effective utilization of the externally controlled trial Rituxan refractory NHL Leukine PBPC mobilization Engerix-B immunization against Hepatitis B

    15. Rituxan Chimeric antibody to CD20 Patients with relapsed, low grade or follicular NHL Targets ORR: 35-40% range, TTP: > or = 8 mos., duration of response: > or = 6 mos.

    16. Rituxan - comparison to published literature To establish the targets, review single agent data from similar disease state For each agent - can look at overall response rate (ORR) of individual trials (each with an “n” of 20-40) and pooled Fludarabine ORR (pooled) ~ 40%, (95% CI 30-50) Cladribine ORR (pooled)~ 40%, (95% CI 25-55)

    17. Rituxan - results 166 patients in phase 3, 37 in phase 2 1-7 prior regimens, median of 2 Regimens included AuBMT Responses - 6% CR, 42% PR pooled: ORR 48%, (95% CI 40-56)

    18. Rituxan - patient as own control 78/161 (48%) ORR to Rituxan 63/78 (81%) responded to most recent chemotherapy 117/161 (73%) response to last chemotherapy

    19. Leukine (GM-CSF) for PBPC mobilization May 1994 discussions with BRMAC optimal control for a RCT for an indication for mobilization? bone marrow PBPC without mobilizing agent RCT difficult; growth factors already in widespread use, “standard of care”, encouraged submission of existing data

    20. Leukine for PBPC mobilization Series of studies at U of Neb. conducted over ~ 5 years 5 groups of 196 patients total received Leukine for PBPC transplantation 2 doses, 2 routes, and +/- Leukine post PBPC 1 group of 100 patients received PBPC without mobilization

    21. Leukine for PBPC mobilization

    22. Leukine for PBPC mobilization

    23. Leukine for PBPC mobilization Outcomes: time to ANC > 500/mm3 time to last platelet transfusion duration of hospitalization number of phereses, MNC, CFU-GM, BFU-E

    24. Leukine for PBPC mobilization

    25. Engerix - B 87 trials to assess safety and efficacy, total of ~10,000 subjects Major efficacy shown in newborns of mothers who were HBsAg+ 58 neonates born to mothers who were carriers 2 (3%) became chronic carriers vs historical situation, where rates ranged from 60-90%

    26. Summary Because control (comparison) groups do not arise via randomization, externally controlled trials are not optimal as principle source of safety and efficacy data. In considering the acceptability of a trial utilizing an external control, it is important to carefully consider alternative designs and to justify why they are not possible. If an external control design is to be utilized, the control must be identified a priori and justified.

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