Clinical Trials Should
NOT Be Stopped Early for
Benefit Based on Interim
Analyses
Group 6: David Hottman, Fatima Khan, Kelley Knapek, Rebecca
Kruc, Andrew Timmons, Lisa Vaughan, Ashwini
Venkatasubramaniam, Xiaoyue Zhao
Ethical Requirements
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Participant Consent and Respect for
Participants
Scientific Validity
Social/Scientific Value and Favorable RiskBenefit Ratio
Independent Review
Participant Consent and Respect for
Participants
Requirements for informed consent:
Completeness of information:
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Adequate information should be provided to the participant
Mutually beneficial, continued involvement in the research should help
meet their goals and ideals.
Timely communication of changes:
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Investigators should provide updates and inform participants of changes in
the trial in a timely manner.
Disadvantages of Stopping Trials Early
Misleading Interim results:
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Once the choice of a superior treatment has been made, equipoise ceases
to exist
Clinicians and patients would choose the treatment deemed to be
“superior”.
Unblinded trials:
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Once patients are informed of interim results, the patients would be
unblinded.
They might leave the trial or cross over to the “superior” treatment
Disadvantages (Continued)
Long delays in treatment dissemination:
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Treatment deemed “superior” might not be administered immediately.
Higher chance of receiving superior treatment with trial continuation:
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Continuation of the trial at least gives patients a 50% chance, as opposed
to if the trial is stopped early.
Reduction in trial’s scientific validity:
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Compromised with patients being informed of early results.
Scientific Validity
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Aim of clinical trials is to closely approximate the true effect of the
treatment by minimizing both random and systematic error
o Stopping trials early may compromise this and introduce error
o Example: review of 143 trials that were stopped for apparent benefit
• It was found that trials accruing fewer ends points before being
stopped estimated larger relative risks (strong inverse association
between number of events and estimated treatment effect)
• This was consistent at the median and 75th percentile of events
and at the median and top quartile of RR estimated
• Suggests that stopping trials early may introduce systematic
overestimation of treatment effects
http://jama.jamanetwork.com.ezp3.lib.umn.edu/article.aspx?articleid=201802
Social or Scientific Value and Favorable
Risk Benefit Ratio
Impact on a larger population than the study must be considered
Overestimation of primary endpoints
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Often stopped for implausibly large results; stopped at a random high
Subsequent misinterpretation of results by clinicians could lead to
unnecessary and improper treatment for the wider population
Lack of data on other important endpoints
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Safety, secondary outcomes, etc.
Lack of data for future research
Social or Scientific Value and Favorable Risk
Benefit Ratio (Continued)
Example: Twelfth Medical Research Council acute
myeloid leukemia trial
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Data monitoring and ethics committee found a large benefit of the 5-drug
regimen compared to the 4-drug regimen for acute myeloid at interim
analyses
Trial was continued and later showed non-significant results
If the trial had been ended early, the 5 treatment regimen may have been
adopted, thus exposing patients to higher toxicity
Example: Trials in Oncology
● Specific scenario
● One of the goals is to get accelerated and conditional approvals, leading to
quicker access of new drugs to patients.
● It is often accepted that the rules for early stopping in oncology trials
evaluating a chronic treatment intervention should be based on two major
criteria:
○ Development of prohibitive toxicity
○ Improvement in either overall survival (OS) or quality of life (QOL).
○ Improvement in Progression-free survival (PFS) or disease-free
survival (DFS) should not generally be used as an early stopping
criterion.
What Really Happens?
A study to assess the use of interim analyses in randomised controlled trials
(RCTs) testing new anticancer drugs focused on trials stopped early for
benefit. They looked at all clinical trials regarding anticancer drugs that were
published from January 1997 to October 2007
What Really Happens?
Of the 93 papers selected as having been stopped after an interim
analysis:
●28 (30%) were stopped early for benefit (OS evaluated in 40%)
●28 (30%) for futility
●and 4 (4%) for harm
Ethical issues arise not only when stopping clinical trials early for benefit, but
more generally, in stopping clinical trials early for the wrong reasons.
Ann Oncol (2008) 19 (7): 1347-1353.
Independent Review
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Stakeholders may want a trial to be stopped early for their
own benefit:
Large treatment effects get published more often-may stop early for
investigator or sponsor benefit
May stop early to decrease total cost, even though the full picture of the
results may not be clear at that time
Trials stopped early for benefit often receive greater publicity-would be
beneficial for researchers (greater prestige), trial sponsors (may sell
more drugs), or journals (greater prestige, more copies sold)
Even participants and patients may want a trial stopped early for benefit
so that the treatment can be made available to everyone
Independent Review (Continued)
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Trials stopped early for these reasons may not have the
full picture about treatment benefit
The decision to stop trials early should be done by an
independent review board
This minimizes bias that would occur if the decision to
stop early is influenced by the stakeholders
Example 1 : EARLY
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Investigators conducted a trial that involved patients undergoing vascular
surgery
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Trial stopped early when 2 of the 53 patients randomly assigned to receive
the beta-blocker and 18 of the 59 control patients had major cardiovascular
events (relative risk reduction, 90% [CI, 59% to 98%])
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These results then contributed to recommendations by the American Heart
Association to administer beta-blockers to patients with cardiac risk factors
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These results contradict those of 2 much larger subsequently published
trials, neither of which suggested that beta-blockers reduce cardiac risk in
patients undergoing noncardiac surgery
Example 2: The Candesartan in Heart Failure
Assessment of Reduction in Mortality and Morbidity
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Stringent threshold for stopping early (p<0.0001)
First three interims were highly significant but did not
meet threshold (p=0.0007, p=0.0002)
Final outcome was borderline (p=0.055)
http://circheartfailure.ahajournals.org/content/5/2/294.full
Recommendations
More stringent early stopping rules:
● Demand that a large number of events (patient-important
events in trials using composite endpoints) accrue before
investigators or data monitoring committees examine
interim data (200-400 to be conservative)
● Invoke a stopping rule with a low P-value (ex: 0.001)
● Continue enrollment and follow-up for a further period to
ensure that the trend continues
Recommendations
Journals should require that reports of
truncated trials describe the rationale for
early stopping, including the statistics and
rules applied
Recommendations
Investigators and data monitoring committees
should consider the context of the illness and
the treatment being studied when deciding to
stop a trial early
● Approximately 25% of new drugs eventually prove to have serious adverse
effects that were unexpected when they entered the market.
Conclusion
Stopping a randomized trial early for apparent
benefit is often unethical and can be justified
only under restricted circumstances!
References
• http://www.bioethicsforum.info/files/2008-1-Mueller-CT.pdf
• http://jama.jamanetwork.com.ezp3.lib.umn.edu/article.aspx?articleid=2018
02
• http://www.ncbi.nlm.nih.gov/pubmed/12559643
• http://circheartfailure.ahajournals.org/content/5/2/294.full
• Ann Oncol (2008) 19 (7): 1347-1353.
• Mueller, Paul S, Victor M Montori, Dirk Bassler, Barbara Koenig, and
Gordon H Guyatt. "Ethical Issues in Stopping Randomized Trials Early
Because of Apparent Benefit." Annals of Internal Medicine. 146.12 (2007):
878-881.