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Statistics 542 Introduction to Clinical Trials

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Title: Statistics 542 Introduction to Clinical Trials


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 122 to the following
    three arms

OPT Alone
-Optimal Pharmacological Therapy (OPT)
1
-OPT CRT (CONTAK TR?/ EASYTRACK?)
Patient Enrollment
Baseline Testing
OPT CRT
2
Randomize
2
-OPT CRT ICD (CONTAK CD? / EASYTRACK?)
OPT CRT-D
Randomization stratifications By site, /-
?-blocker therapy
Target Time to Implant lt 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 gt12 months
    (would translate to 1000 primary events), power
    gt90
  • Mortality (secondary endpoint) 12 month event
    rate of 24 in the OPT arm, 25 reduction in
    either device arm power80

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
COMPANION Data Update
  • 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)

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 19942721926-31
  • Ann Intern Med 1994121894-5
  • JAMA Editorial in 1995 suggests two groups
    produce a unified statement
  • Consolidated Standards of Reporting (CONSORT)
  • JAMA 1996 276637-9

21
Reporting in Clinical Trials (1)(Cancer
Treatment Reports 691-3, 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 691-3, 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
Meinerts Comments (1)
  • JAMA 19982791487-1489
  • 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
Meinerts Comments (2)
  • JAMA 19982791487-1489
  • 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
Meinerts Comments (3)
  • JAMA 19982791487-1489
  • 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
Meinerts Comments (4)
  • JAMA 19982791487-1489
  • 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 persons
    course of treatment, level of compliance with the
    assigned treatment, or evaluability.

31
Meinerts Comments (5)
  • JAMA 19982791487-1489
  • 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 TrialsThe 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 TrialsThe 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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