Howard Mann

SPIRIT 2013 Statement: defining standard protocol items for clinical trials.

The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol.The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.

SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials.

High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To help improve the content and quality of protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT Statement provides guidance in the form of a checklist of recommended items to include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important information to promote full understanding of the checklist recommendations. For each checklist item, we provide a rationale and detailed description; a model example from an actual protocol; and relevant references supporting its importance. We strongly recommend that this explanatory paper be used in conjunction with the SPIRIT Statement. A website of resources is also available (www.spirit-statement.org). The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement, should help with the drafting of trial protocols. Complete documentation of key trial elements can facilitate transparency and protocol review for the benefit of all stakeholders.

Research ethics committees and public dissemination of clinical trial results.

Biomedical research involving human beings is subject to codes of ethical conduct that mandate review, approval, and monitoring of clinical trials by research ethics committees (RECs). The role of RECs in public dissemination of results of research is not addressed explicitly in international codes or national regulations governing human research. I contend that RECs should have a prominent role in ensuring that trial results are publicly disseminated. I also propose specific responsibilities and actions that should be assumed and implemented by RECs to promote this objective.

Choosing a control intervention for a randomised clinical trial

BackgroundRandomised controlled clinical trials are performed to resolve uncertainty concerning comparator interventions. Appropriate acknowledgment of uncertainty enables the concurrent achievement of two goals : the acquisition of valuable scientific knowledge and an optimum treatment choice for the patient-participant. The ethical recruitment of patients requires the presence of clinical equipoise. This involves the appropriate choice of a control intervention, particularly when unapproved drugs or innovative interventions are being evaluated.DiscussionWe argue that the choice of a control intervention should be supported by a systematic review of the relevant literature and, where necessary, solicitation of the informed beliefs of clinical experts through formal surveys and publication of the proposed trials protocol.SummaryWhen clinical equipoise is present, physicians may confidently propose trial enrollment to their eligible patients as an act of therapeutic beneficence.

Comparator bias: why comparisons must address genuine uncertainties

Researchers may believe – and patients and physicians may hope – that a particular treatment (perhaps because it is new) is better than other available treatments; but it may often turn out to be worse. When the British Medical Research Council’s controlled trial of streptomycin for pulmonary tuberculosis was conceived in 1946, none of the therapies used to treat the disease had been shown in controlled clinical trials to be useful; indeed, one controlled trial had shown gold salt therapy to do more harm than good. Although streptomycin was known to be useful in forms of tuberculosis which had previously always been fatal, there was uncertainty about how useful the new drug would be in pulmonary tuberculosis, from which patients often recovered after treatment with bed rest alone. Patients in the MRC trial were accordingly randomized either to bed rest alone, or to bed rest and streptomycin. The same reasoning is applicable when controlled trials are designed today. After considering systematic reviews of the relevant existing evidence, patients and their doctors must be substantially uncertain about which among the treatment options – including no active treatment – is preferable. This implies ensuring that no patient who agrees to participate in the trial will knowingly be disadvantaged, whichever one of the comparison treatments the patient is assigned to receive. Clinical trials are done to reduce uncertainties, and they should only be done if clinicians and their patients are uncertain which of the existing alternatives is preferable. This requirement is sometimes referred to as ‘the uncertainty principle’ or ‘equipoise’. If one or more of the treatments selected for the comparison in a trial is known to be worse than others, not only will some participants in the trial be denied effective treatment, but this ‘comparator bias’ will result in unfair tests of treatments. Even if other sources of bias have been well controlled in such studies, their results will mislead patients and their doctors. Unfortunately, comparator bias is sometimes deliberately introduced for just this purpose, usually with a view to showing that new treatments are preferable to existing alternatives.

Alteplase for stroke. Uncertainty remains about efficacy.

Editor—The article by Lenzer and the associated commentary by Saver et al raise many serious issues, among which is the residual state of uncertainty concerning the efficacy of alteplase (tPA) in acute ischaemic stroke.1 Confronted by opposing interpretations of the aggregate data published to date and the now known baseline imbalance in the severity of stroke in the National Institute of Neurological Diseases and Stroke (NINDS) trial, doctors are presented with a conundrum: what action do the data support? The reported unwillingness of the investigators and sponsor of the National Institute of Neurological Diseases and Stroke trial to provide data for additional analysis is disturbing. Emanuel et al have described seven requirements for the ethical conduct of clinical research, among which is social and scientific value.2 Social value presupposes the public dissemination of research results. I have formulated a standard for the scientific and ethical review of trials that elaborates on this requirement.3 Implicit in this requirement is the necessity for the public dissemination of the complete dataset acquired during a clinical trial. This allows interested investigators to apply recognised analytic techniques in an attempt to resolve (or diminish) residual uncertainty concerning the clinical implications of the trials results. This ethical requirement has not yet been met for the National Institute of Neurological Diseases and Stroke trial.

Equipoise in the enhanced supression of the platelet IIb/IIIa receptor with integrilin trial (ESPRIT): a critical appraisal.

Enhanced Supression of the Platelet IIb/IIIa Receptor with Integrilin Trial (ESPRIT) was a multicenter randomized controlled clinical trial in which participants were randomized between eptifibatide and placebo. A “clinical hold” was initially placed on the trial by the US Food and Drug Administration (FDA), which was concerned about the placebo-only control arm. The hold was lifted after additional information concerning the use of platelet glycoprotein IIb/IIIa inhibitors in clinical practice, derived from a survey of interventional cardiologists, was provided. The trials principal investigator and colleagues have described how these issues were resolved, and advance a claim of equipoise for the trial. In this critical appraisal we examine the information and arguments proffered in support of the trial design and conclude that they evidence a misunderstanding of equipoise. We believe that a placebo-only control arm was not justified by the information provided by the trialists.

How Confidential Trial Negotiations and Agreements Between the Food and Drug Administration and Sponsors Marginalize Local Institutional Review Boards, and What to Do About It

In their “Open Letter to Institutional Review Boards” concerning the PolyHeme ©R trial, Kipnis et al. describe their attempts to engage the institutional review board (IRB) community, federal regulators, and the trial’s sponsor in a discussion about a perceived ethical flaw in the trial’s design (Kipnis, King and Nelson 2006). That this attempt apparently did not yield even a meaningful dialogue among the disparate parties involved in the design and approval process should surprise no one. It reflects the fragmented and inchoate architecture of a regulatory system wherein clinical research intended to support regulatory approval of investigational agents is conducted. In brief, this trial (and the attendant controversy) evolved as follows: the company (Northfield Laboratories, Inc. Evanston, IL) was established in 1985, following work by its founders on developing an oxygen-carrying resuscitation fluid (Northfield Laboratories 2005). Encouraging early clinical results prompted the company to propose a so-called pivotal phase III trial to support regulatory approval of the agent. The trial design was negotiated between the United States Food and Drug Administration (FDA) and the company in the context of a particular regulatory provision—a special protocol assessment (about which more later) (Anon 2002) . The company initiated the multicenter trial by engaging investigators at selected trauma centers, where a prescribed process of community consultation preceded final IRB approval. The trial was underway when a significant ethical/regulatory flaw in the trial’s design was identified by the authors. This article will now elaborate further on this process, situate it in the general context of the review and conduct of multicenter clinical trials, and conclude by proposing substantial changes to the current architecture of the United States IRB system.

Sham surgery in randomized trials: additional requirements should be satisfied.

A randomized controlled trial (RCT) is informative to the extent that appropriately chosen interventions are compared. The notion of appropriateness relates primarily to what interventions are available for the condition being evaluated and the current state of knowledge concerning their relative merits (beneats and harms). An appropriate acknowledgment of uncertainty enables the concurrent achievement of two objectives: the acquisition of valuable scientiac knowledge, and an optimum treatment choice for the enrolled patient (Djulbegovic 2001). Such uncertainty is inherent in the concept of clinical equipoise (Freedman 1987), which also permits guidance for the ethical use of a placebo in an RCT (Tri-Council Statement 2000). A placebo is used in an RCT primarily to enable blinding, and is typically a chemical or chemicals that are not harmful. Active agents that transiently produce certain minor physical effects (such as a dry mouth) are sometimes used as placebos in trials. Sham surgery as an invasive placebo certainly complicates the calculus of uncertainty. In defense of the use of a placebo-only control arm in drugrelated RCTs when effective interventions exist, Miller and Brody (2002) proposed rather rigid distinctions between the ethics of clinical care and clinical research. Franklin G. Miller (2003) has again advanced this reasoning in his current discussion of sham surgery. Clinical research requires the minimization of risks of harm and the avoidance of participant exploitation. With respect to justifying the use of sham surgery to enable blinding, I and this argument somewhat more persuasive, but additional qualiacations and actions are, in my view, in order. In what follows, I discuss these with reference to the arthroscopic surgery trial and focus on issues related to:

Spirit 2013 statement: Defining standard protocol items for clinical trials

The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol. The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.