One of the most difficult situations when running a clinical trial is the decision to terminate the trial early. But it shouldn’t be a difficult decision. With clear stopping rules defined before the trial starts, it should be straightforward to determine when the effect size is large enough that no further patients require to be randomised to definitively answer the question.
Whether there is benefit to leaving a temporary plastic tube drain in the belly after an operation to remove the head of the pancreas is controversial. It may help diagnose and treat the potential disaster that occurs when the join between pancreas and bowel leaks. Others think that the presence of the drain may in fact make a leak more likely.
This question was tackled in an important randomised clinical trial.
A randomised prospective multicenter trial of pancreaticoduodenectomy with and without routine intraperitoneal drainage
The trial was stopped early because there were more deaths in the group who didn’t have a drain. The question that remains: was it the absence of the drain which caused the deaths? As important, was stopping the trial at this point the correct course of action?
My feeling, the lack of a drain was not definitively demonstrated to be the cause of the deaths. And I think the trial was stopped too early. Difficult issues discussed in our letter in Annals of Surgery about it.
Ethics and statistics collide in decisions relating to the early termination of clinical trials. Investigators have a fundamental responsibility to stop a trial where an excess of harm is seen in one of the arms. Decisions on stopping are not straightforward and must balance the potential risk to trial patients against the likelihood that in fact there is no difference in outcome between groups. Indeed, in early termination, the potential loss of generalizable knowledge may itself harm future patients.
We therefore read with interest the article by Van Buren and colleagues (1) and congratulate the authors on the first multicenter randomized trial on the controversial topic of surgical drains after pancreaticoduodenectomy. As the authors report, the trial was stopped by the Data Safety Monitoring Board after only 18% recruitment due to a numerical excess of deaths in the “no-drain” arm.
We would be interested in learning from the process that led to the decision to terminate the trial. A common method to monitor adverse events advocated by the CONSORT group is to define formal sequential stopping rules based on the limit of acceptable adverse event rates (2). These guidelines suggest that authors report the number of planned “looks” at the data, the statistical methods used including any formal stopping rules, and whether these were planned before trial commencement.
This information is often not included in published trial reports, even when early termination has occurred (3). We feel that in the context of important surgical trials, these guidelines should be adhered to.
Early termination can reduce the statistical power of a trial. This can be addressed by examining results as data accumulate, preferably by an independent data monitoring committee. However, performing multiple statistical examinations of accumulating data without appropriate correction can lead to erroneous results and interpretation (4). For example, if accumulating data from a trial are examined at 5 interim analyses that use a P value of 0.05, the overall false-positive rate is nearer to 19% than to the nominal 5%.
Several group sequential statistical methods are available to adjust for multiple analyses (5,6) and their use should be prespecified in the trial protocol. Stopping rules may be formed by 2 broad methods, either using a Bayesian approach to evaluate the proportion of patients with adverse effects or using a hypothesis testing approach with a sequential probability ratio test to determine whether the acceptable adverse effects rate has been exceeded. Data are compared at each interim analysis and decisions based on prespecified criteria. As an example, stopping rules for harm from a recent study used modified Haybittle-Peto boundaries of 3 SDs in the first half of the study and 2 SDs in the second half (7). The study of Van Buren and colleagues is reported to have been stopped after 18% recruitment due to an excess of 6 deaths in the “no-drain” arm. The relative risk of death at 90 days in the “no-drain” group versus the “drain” group was 3.94 (95% confidence interval, 0.87–17.90), equivalent to a difference of 1.78 SD. The primary outcome measure was any grade 2 complication or more and had a relative risk of 1.32 (5% confidence interval, 1.00–1.75), or 1.95 SD.
The decision to terminate a trial early is not based on statistics alone. Judgements must be made using all the available evidence, including the biological and clinical plausibility of harm and the findings of previous studies. Statistical considerations should therefore be used as a starting point for decisions, rather than a definitive rule.
The Data Safety Monitoring Board for the study of Van Buren and colleagues clearly felt that there was no option other than to terminate the trial. However, at least on statistical grounds, this occurred very early in the trial using conservative criteria. The question remains therefore is the totality of evidence convincing that the question posed has been unequivocally answered? We would suggest that this is not the case. In general terms, stopping a clinical trial early is a rare event that sends out a message that, because of the “sensational” effect, may have greater impact on the medical community than intended, making future studies in that area challenging.
1. Van Buren G, Bloomston M, Hughes SJ, et al. A randomised prospective multicenter trial of pancreaticoduodenectomy with and without routine intraperitoneal drainage. Ann Surg. 2014;259: 605–612.
2. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trial. BMJ. 2010;340:c869.
3. Montori VM, Devereaux PJ, Adhikari NK, et al. Randomized trials stopped early for benefit: a systematic review. JAMA. 2005;294:2203–2209.
4. Geller NL, Pocock SJ. Interim analyses in randomized clinical trials: ramifications and guidelines for practitioners. Biometrics. 1987;43:213–223.
5. Pocock SJ. When to stop a clinical trial. BMJ. 1992;305:235–240.
6. Berry DA. Interim analyses in clinical trials: classical vs. Bayesian approaches. Stat Med. 1985;4:521– 526.
7. Connolly SJ, Pogue J, Hart RG, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360:2066– 2078.