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Statistics 542 Introduction to Clinical Trials

Statistics 542 Introduction to Clinical Trials. Patient/Trial Closeout Reporting of Clinical Trials. Outline of Patient/Trial Closeout. Patient closeout Trial closeout. Patient Closeout. ICH E9 Glossary

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Statistics 542 Introduction to Clinical Trials

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  1. Statistics 542Introduction to Clinical Trials • Patient/Trial Closeout • Reporting of Clinical Trials

  2. Outline of Patient/Trial Closeout • Patient closeout • Trial closeout

  3. Patient Closeout • ICH E9 Glossary • “Intention-to-treat principle - …It has the consequence that subjects allocated to a treatment group should be followed up, assessed, and analyzed as members of that group irrespective of their compliance with the planned course of treatment.”

  4. Cardiac Resynchronization Therapy (CRT) Reduces Hospitalizations, and CRT with Implantable Defibrillator (CRT-D) Reduces Mortality in Chronic Heart Failure: The COMPANION Trial Bristow MR (Co-Ch), Feldman AM (Co-Ch), Saxon LA, DeMarco T, Kass D, Boehmer J, Mann D, Singh S, Carson P, Krueger S, McGrew F, Botteron G, Wagoner L, for the COMPANION Investigators Disclosures: Drs. Bristow, Saxon, Boehmer, Kass and Feldman are consultants to Guidant (sponsor) HFSA Late-Breaker Sept 24, 2003

  5. COMPANION (COmparison of Medical Therapy, Pacing, ANd DefibrillatION in Heart Failure): Study Design Patients randomized to 1:2:2 to the following three arms: OPT Alone -Optimal Pharmacological Therapy (OPT) 1 -OPT + CRT (CONTAK TR/ EASYTRACK) Baseline Testing OPT + CRT Patient Enrollment 2 Randomize 2 -OPT + CRT + ICD (CONTAK CD / EASYTRACK) OPT + CRT-D Randomization stratifications: By site, +/- -blocker therapy Target Time to Implant < 2 days from randomization HFSA Late-Breaker Sept 24, 2003

  6. COMPANION: Endpoints (1) • Primary Endpoint • Composite of time to first all-cause mortality or all-cause hospitalization analyzed from randomized • Hospital emergency or outpatient (unscheduled administration of IV inotropes or vasoactive drugs for more than 4 hours were considered a hospitalization primary endpoint HFSA Late-Breaker Sept 24, 2003

  7. COMPANION: Endpoints (2) • Highest order secondary endpoint: • All-Cause Mortality • Other outcomes analyzed: • Combined mortality or CV, heart failure hospitalizations HFSA Late-Breaker Sept 24, 2003

  8. COMPANION: Statistical Plan • Intention to treat, endpoint data collection begins with randomization; open-label (ethical reasons • Steering and Endpoints Committees, Exercise Core Laboratory, Sponsor were blinded • Alpha allocation: OPT vs. CRT = 0.02; OPT vs. CRT-D = 0.03 • Sample size assumptions • Primary endpoint: 12 month event rate of 40% in OPT arm, 25% reduction in either device arm would require 2200 patients followed for >12 months (would translate to 1000 primary events), power >90% • Mortality (secondary endpoint): 12 month event rate of 24% in the OPT arm, 25% reduction in either device arm; power=80% HFSA Late-Breaker Sept 24, 2003

  9. COMPANION: Sequential Monitoring & Trial Termination • First patient enrolled January 20, 2000 • On 11/18/02 the DSMB recommended to the Steering Committee to stop enrollment due to 1) the target number of PEPs had likely been reached, 2) the PEP efficacy boundaries had been crossed (CRT-D) or reached (CRT) and the mortality efficacy boundary had been crossed (CRT-D) • The Steering Committee stopped enrollment (n = 1520) on 11/18/02, and all efficacy follow-up on 12/1/02 HFSA Late-Breaker Sept 24, 2003

  10. ACC March 2003 (Preliminary Data) Data indicated a disproportionate withdrawl rate among OPT, CRT and CRT-D (13%, 2%, 2% w/o prior PEPs) After deliverations with the independent SDAC and DSMB, a decision was made by the Steering Committee to: Reconsent withdrawn patients to collect endpoint data and vital status Not count elective device admissions as hospitalization EPs HFSA 2003 (Final Data) The process of collecting endpoint data and vital status on patients that withdrew prior to 12/01/02 is complete: OPT = 95%, CRT = 99%, and CRT-D = 99% Median follow-up times (days) are 442 for OPT, 495 for CRT (p=.03) and 479 for CRT-D (p=.13) COMPANION: Data Update HFSA Late-Breaker Sept 24, 2003

  11. COMPANION: Secondary Endpointof All Cause Mortality HFSA Late-Breaker Sept 24, 2003

  12. COMPANION: Primary Endpoint HFSA Late-Breaker Sept 24, 2003

  13. COMPANION Follow-up • Sponsor & steering committee had to reconsent patients who had withdrawn from study by withdrawing consent • Lost to follow-up would have been differential and potentially biased • Obtaining complete data cost several months additional • Lesson: offer stages of subject withdrawal, withdrawal of consent being the most extreme HFSA Late-Breaker Sept 24, 2003

  14. COMPANION: Conclusions When added to optimal pharmacological therapy in patients with moderate-severe LV dysfunction, NYHA Class III or IV symptoms and QRS lengthening • CRT or CRT-D reduces mortality + hospitalization • CRT-D reduces mortality • 2/3 of the effect size can be attributed to CRT HFSA Late-Breaker Sept 24, 2003

  15. Missing Outcome Data • Design with zero • missing may be associated with treatment • for analysis, data are not missing at random • even if same number missing, missing may be for different reason in each treatment group • Implement to minimize • Must analyze exploring different approaches • if all, or most, agree, then more persuasive

  16. Patient Closeout • Final Patient Visit • Complete outcome assessment • Transition to post trial therapy • Track down patients missing or lost to follow-up • Plan for notification of trial results

  17. Trial Closeout • Plan transitions for • patient care • clinic staff • central units • Plan for data archiving

  18. Outline of Trial Reporting • Rationale/Background • Guidelines • Comments on Guidelines

  19. Background (1) Practicing physicians must rely on the literature to keep current on recent developments on new therapies as well as providing additional evidence on therapies which have been long used in practice Accurate reporting of a clinical trial is important to aid the practicing physician in deciding to adopt a new therapy or modify therapies currently in use

  20. Background (2) • Proposals for requirements for reporting of randomised trials • JAMA 1994;272:1926-31 • Ann Intern Med 1994;121:894-5 • JAMA Editorial in 1995 suggests two groups produce a unified statement • Consolidated Standards of Reporting (CONSORT) • JAMA 1996; 276:637-9

  21. Reporting in Clinical Trials (1)(Cancer Treatment Reports 69:1-3, 1985) • METHODOLOGICAL GUIDELINES FOR THE REPORTING OF ALL CLINICAL TRIALS • Authors should discuss briefly the qualify control methods used to ensure that the data are complete and accurate.A reliable procedure should be cited for ensuring that all patients entered on study are actually reported upon. If no such procedures are in place, their absence should be noted. Any procedures employed to ensure that assessment of major end points is reliable should be mentioned (e.g., second-arty review of responses) or their absence noted. • All patients registered on study should be accounted for. The report should specify for each treatment the number of patients who were not eligible, who died or withdrew before treatment began. The distribution of follow-up times should be described for each treatment, and the number of patients lost to follow-up should be given. • The study should not have an inevaluability rate for major end points of greater than 15%. Not more than 15% of eligible patients should be lost to follow-up or considered inevaluable for response due to early death, protocol violation, missing information, etc. • In randomized studies, the report should include a comparison of survival and/or other major end points for all eligible patients as randomized, that is, with now exclusions other than those not meeting eligibility criteria. • The sample size should be sufficient to either establish or conclusively rule out the existence of effects of clinically meaningful magnitude. For “negative” results in therapeutic comparisons, the adequacy of sample size should be demonstrated by either presenting confidence limits for true treatment differences or calculating statistical power for detecting differences. For uncontrolled phase II studies, a procedure should be in place too prevent the accrual of an inappropriately large number of patients, when the study has shown the agent to be inactive.

  22. Reporting in Clinical Trials (2)(Cancer Treatment Reports 69:1-3, 1985) • METHODOLOGICAL GUIDELINES FOR THE REPORTING OF ALL CLINICAL TRIALS (cont.) • Authors should state whether there was an initial target sample size, and, if so, what it was. They should specify how frequently interim analyses were performed and how the decisions to stop accrual and report results were arrive at. • All claims of therapeutic efficacy should be based upon explicit comparison with a specific control group, except in special circumstances where each patient is his own control. If nonrandomized controls are used, the characteristics of the patients should be presented in detail and compared to those of the experimental group. Potential sources of bias should be adequately discussed. Comparison of survival between responders and non-responders does not establish efficacy and should not generally be included. Reports of phase II trials that draw conclusions about antitumor activity but not therapeutic efficacy generally do not require a control group. • The patients studied should be adequately described. Applicability of conclusions to other patients should be carefully dealt with. Claims of subset-specific treatment differences must be carefully documented statistically as more than the random results of multiple subset analyses. • The methods of statistical analysis should be described in detail sufficient that a knowledgeable reader could reproduce the analysis if the data were available.

  23. CONSORT (1) • “Intent is to make experimental process more clear, flawed or not, so that users of the data can more appropriately evaluate its validity for their purposes” • checklist • figure • available at www.consort-statement.org

  24. CONSORT (2) • Widely adopted by medical journals • required by many from Jan 1, 1997 • Available in six languages

  25. Reporting RCTs • Regulatory setting • International Conference on Harmonisation (ICH) Guidelines • Peer-reviewed respected medical journals • CONSORT • Recommendation - use at design stage as well as reporting stage

  26. Common Elements of Reporting for All Trials • Population under study • Therapy details • Experimental design • Patient accounting • Quality control procedures • Statistical analysis Special Reporting Requirements • Non-randomized trials • Randomized trials

  27. Meinert’s Comments (1) • JAMA 1998;279:1487-1489 • “Clearly, the single most important count in any trial is that of persons randomized, which serves as the denominator for analyses by treatment assignment. Surprisingly, this number is not among the counts requested.”

  28. Meinert’s Comments (2) • JAMA 1998;279:1487-1489 • “Withdrawn or withdrawal in the context of trials is best reserved for use as a technical term in relation to analysis. Its use in regard to treating or following up a person in a trial is unfortunate. Withdrawn with regard to what? Treatment, follow-up, or both?”

  29. Meinert’s Comments (3) • JAMA 1998;279:1487-1489 • “It is possible to stop a treatment, but doing so does not withdraw the effect of treatment. Further, there is nothing to withdraw once a treatment has been applied (e.g. as in surgery trials) or after the required course of treatment has been administered.”

  30. Meinert’s Comments (4) • JAMA 1998;279:1487-1489 • “The primary analysis in any report should be one in which persons, their outcomes and events, and related follow-up data are counted to the assigned treatment, regardless of a person’s course of treatment, level of compliance with the assigned treatment, or evaluability.”

  31. Meinert’s Comments (5) • JAMA 1998;279:1487-1489 • “There is no point in randomizing persons to treatment if the assignment is ameliorated or ignored in the analysis. This is not to say that other less stringent analyses should not be performed or reported, but rather that they are not informative in the absence of the primary analysis. ”

  32. Reporting in Clinical Trials • Describe the Plan • Report the Results • Confess to Problems • Interpret Objectively (no spin!)

  33. Reporting in Clinical Trials“The Published Paper” 1.Identify clinical investigators and institutions (experience, reputation) • Also, identify • Sponsor (federal, industry) • Data management team • Statistical analysis team

  34. Reporting in Clinical Trials“The Published Paper” • Introduction & Backgroud a. Biochemical theory b. Animal work c. Phase I/II clinical studies d. Previous large clinical studies e. Other pharmaceutical analogues

  35. Reporting Clinical Trials 4. Methods Section • Outcome variables • Eligibility criteria • Inclusion • Exclusion • Randomization Procedures • Sample size justification • Treatment & Control

  36. Reporting Clinical Trials 4. Methods Section (continued) • Outcome assessment & blinding • Measures of patient safety and adverse events • Predefined Subgroups • Data monitoring plan • Analysis Plan summary

  37. Reporting in Clinical Trials Definition of question a. What was the primary question? - Clearly defined in advance b. Define response variable and its measurement c. Define methods to minimize bias in outcome assessment

  38. Reporting in Clinical Trials Treatment groups a. Definitions - Experimental - Control b. Dose escalation c. Withdrawl for toxicity

  39. Reporting in Clinical Trials 5. Description of results a. Full accounting of all patients entered on trials - Completeness - LTFU - Withdrawal b. Comparison of treatment groups as assigned, on baseline characteristics c. Simple comparison of primary outcome variables using means, proportions, graphs, with measures of statistical precision (e.g. SE's, P-values)

  40. Reporting in Clinical Trials 5. Description of results (continued) e. Adequate handling of the possible impact of missing values, dropouts, non-adherence f. Discussion, allowance for multiplicity in number of interim analyses, number of endpoints g. Thorough analysis of side-effect data/adverse effects

  41. Reporting in Clinical Trials 5. Description of Results (continued) Consistency of results a. among investigators and centers b. Other independent studies of same drug or analogues c. Subgroups consistency d. Primary and secondary outcomes

  42. Reporting in Clinical Trials 6. Conclusion a. Brief summary b. Strengths/weaknesses consistent with data c. Generalizability d. Trade off in side effects - risk/benefit

  43. Post Trial Utilization of Data Base

  44. Potential Trial Data Use (1) A. Verification of results B. Post-study follow-up C. General research

  45. Potential Trial Data Use (2) A.Adequate Records must Be Kept for Validation Purposes 1. Protocol 2. Manual of operations 3. Clean set of data forms 4. Copy of completed data forms (electronic version) 5. Edited, final data file 6. Documentation for the analyses 7. DMC data reports and DMC minutes 8. Key Steering Committee minutes

  46. Potential Trial Data Use (3) • Post-study Follow-up 1. To monitor duration of positive effect 2. To watch for possible late benefit 3. To determine continued or new evidence of toxicity

  47. Potential Trial Data Use (4) C. General Research Clinical trial often a high quality extensive resource for further investigation • Identify new risk factors • Genomics • Design future trials • Methodology development

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