Statistics 542 Introduction to Clinical Trials

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Statistics 542Introduction to Clinical Trials

• Patient/Trial Closeout
• Reporting of Clinical Trials

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Outline of Patient/Trial Closeout

• Patient closeout
• Trial closeout

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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.

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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
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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
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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
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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
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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
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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
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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
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COMPANION Secondary Endpointof All Cause
Mortality
HFSA Late-Breaker Sept 24, 2003
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COMPANION Primary Endpoint
HFSA Late-Breaker Sept 24, 2003
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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
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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
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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

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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

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Trial Closeout

• Plan transitions for
• patient care
• clinic staff
• central units
• Plan for data archiving

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Outline of Trial Reporting

• Rationale/Background
• Guidelines
• Comments on Guidelines

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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

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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

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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.

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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.

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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

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CONSORT (2)

• Widely adopted by medical journals
• required by many from Jan 1, 1997
• Available in six languages

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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

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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

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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.

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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?

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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.

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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.

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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.

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Reporting in Clinical Trials

• Describe the Plan
• Report the Results
• Confess to Problems
• Interpret Objectively (no spin!)

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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

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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

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Reporting Clinical Trials

• 4. Methods Section
• Outcome variables
• Eligibility criteria
• Inclusion
• Exclusion
• Randomization Procedures
• Sample size justification
• Treatment Control

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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

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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

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Reporting in Clinical Trials

• Treatment groups
• a. Definitions
• - Experimental
• - Control
• b. Dose escalation
• c. Withdrawl for toxicity

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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)

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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

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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

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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

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Post Trial Utilization of Data Base
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Potential Trial Data Use (1)

• A. Verification of results
• B. Post-study follow-up
• C. General research

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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

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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

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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