Understanding burden of proof and equipoise in the design of pragmatic clinical trials: An example from a trial on brain arteriovenous malformations

Elsevier

Available online 2 July 2022

NeurochirurgieAbstractBackground and purpose

The burden of proof principle is rarely discussed and poorly understood, but central to the proper design of pragmatic clinical trials. A better understanding of the principle could play an important role in the re-introduction of scientific methods within practice and in revising fundamental problems with the current research-care separation.

Methods

We analyze the design of the ARUBA trial on the management of unruptured brain arteriovenous malformations. We also review how the concept of clinical equipoise was introduced to address a misconceived problem of research ethics.

Results

The ARUBA trial hypothesis in favour of conservative management of brain arteriovenous malformations failed to take into account the fact that the burden of proof was on surgery, endovascular treatment or radiation therapy. Thus, results remained inconclusive and other trials are needed. The equipoise notion fails to take into account that the burden of proof is on unvalidated medical or surgical interventions, if we want to provide outcome-based medical care that patients can trust.

Conclusion

The burden of proof principle is essential to properly design pragmatic trials. This principle also explains why in certain circumstances optimal care is a randomized care trial.

Section snippetsA trial on unruptured brain arteriovenous malformations (ARUBA)

Brain arteriovenous malformations (AVMs) are a heterogeneous group of rare lesions that can present with headaches, seizures, neurological deficits, or intracranial hemorrhages. Risks of hemorrhage are estimated to range from 2%–4% per year [7], [8], [9], [10]. Risk factors for future rupture have been identified, but their use to inform decision making is error-prone, given the methodological problems with AVM observational studies and the modest relative risks [11]. Treatments may include

Critical analysis of the trial

The ARUBA trial was a turning point in the management of brain AVMs. Yet, premature interruption of the trial was followed by numerous editorials and comments [16]. Weaknesses of the study have previously been summarized [16].

Here we use the ARUBA study to illustrate a fundamental problem with trial design: a wrong-sided trial hypothesis. ARUBA hypothesized that conservative management would improve patient outcomes compared with intervention. This is very unusual. Normally, therapy has the

Equipoise in clinical research

Here, we will briefly discuss the notion of equipoise because the etymology of the term itself (an ‘equal distribution of weight’) seems to leave no room for the most important application of the burden of proof. Equipoise, ‘a state of genuine uncertainty regarding the comparative merits of treatments’, is supposed to be a condition to recruit patients in randomized trials. Equipoise is problematic, if only because it means different things, and serves different purposes for different

Human and animal rights

The authors declare that the work described has not involved experimentation on humans or animals.

Informed consent and patient details

The authors declare that the work described does not involve patients or volunteers.

Disclosure of interest

The authors declare that they have no competing interest.

Funding

This work did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

All authors attest that they meet the current International Committee of Medical Journal Editors (ICMJE) criteria for Authorship.

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