Title: Statistics 542 Introduction to Clinical Trials
1Statistics 542Introduction to Clinical Trials
- Patient/Trial Closeout
- Reporting of Clinical Trials
2Outline of Patient/Trial Closeout
- Patient closeout
- Trial closeout
3Patient 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.
4Cardiac 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
5COMPANION (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
6COMPANION 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
7COMPANION 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
8COMPANION 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
9COMPANION 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
10COMPANION 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
11COMPANION Secondary Endpointof All Cause
Mortality
HFSA Late-Breaker Sept 24, 2003
12COMPANION Primary Endpoint
HFSA Late-Breaker Sept 24, 2003
13COMPANION 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
14COMPANION 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
15Missing 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
16Patient 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
17Trial Closeout
- Plan transitions for
- patient care
- clinic staff
- central units
- Plan for data archiving
18Outline of Trial Reporting
- Rationale/Background
- Guidelines
- Comments on Guidelines
19Background (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
20Background (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
21Reporting 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.
22Reporting 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.
23CONSORT (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
24CONSORT (2)
- Widely adopted by medical journals
- required by many from Jan 1, 1997
- Available in six languages
25Reporting 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
26Common 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
27Meinerts 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.
28Meinerts 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?
29Meinerts 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.
30Meinerts 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.
31Meinerts 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.
32Reporting in Clinical Trials
- Describe the Plan
- Report the Results
- Confess to Problems
- Interpret Objectively (no spin!)
33Reporting in Clinical TrialsThe Published
Paper
- 1. Identify clinical investigators and
institutions (experience, reputation) - Also, identify
- Sponsor (federal, industry)
- Data management team
- Statistical analysis team
34Reporting 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
35Reporting Clinical Trials
- 4. Methods Section
- Outcome variables
- Eligibility criteria
- Inclusion
- Exclusion
- Randomization Procedures
- Sample size justification
- Treatment Control
36Reporting Clinical Trials
- 4. Methods Section (continued)
- Outcome assessment blinding
- Measures of patient safety and adverse events
- Predefined Subgroups
- Data monitoring plan
- Analysis Plan summary
37Reporting 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
38Reporting in Clinical Trials
- Treatment groups
- a. Definitions
- - Experimental
- - Control
- b. Dose escalation
- c. Withdrawl for toxicity
39Reporting 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) -
40Reporting 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
41Reporting 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
42Reporting in Clinical Trials
- 6. Conclusion
- a. Brief summary
- b. Strengths/weaknesses consistent with data
- c. Generalizability
- d. Trade off in side effects - risk/benefit
43Post Trial Utilization of Data Base
44Potential Trial Data Use (1)
- A. Verification of results
- B. Post-study follow-up
- C. General research
45Potential 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
46Potential 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
47Potential 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