The rationale for a registry of clinical trials involving human stem cell therapies.

• Author: Isasi, Rosario M.
• Position: Canada

Human embryonic stem cells (hESC) are pluripotent cells that are capable of self-renewal and can differentiate into nearly any type of cell in the body. (1) At present, it seems that early embryos are the best source of suitable stem cells as they are "the only pluripotent stem cells that can be readily isolated and grown in culture in sufficient numbers to be useful." (2) Few scientific discoveries have elicited more enduring concerns among scholars, government officials and the general public than the permissibility of conducting research on embryos in general, and on hESC in particular. Governments are confronted with the vexing question of how to balance the beneficial therapeutic prospects of hESC with complex socio-ethical and moral issues.

Much of the ethical and policy debate surrounding hESC research focuses on the moral status of the human embryo: should the human embryo be recognized as a potential person or, at minimum, be given particular legal protection? It is clear that there is no simple answer. In fact, it has proven to be difficult to render an account of when human life begins and what moral--and, a fortiori, legal--status should be ascribed to the human embryo. (3)

Amidst all the controversy, researchers are in the process of studying how embryonic stem cells can be used to alleviate human suffering through the development of tissue and organ therapies (regenerative medicine). Embryonic stem cell research promises new therapeutic applications as well as medical and cosmetic (non-therapeutic) applications, such as genetic enhancement. At the present time only haematopoietic stem cells obtained from bone marrow and blood cell precursors are used in stem cell therapy. Embryonic stem cell research, on the other hand, is only in the initial stages of development and is not yet at the clinical trial stage. Moreover, there are insufficient clinical grade stem cell lines available for stem cell research to progress to the clinical stage without putting the safety of human subjects at risk. Researchers are still trying to perfect how to derive and control embryonic stem cells, but it will not be long before these human tissues are widely used in clinical trials. (4)

Therefore, with the promise of new therapeutic interventions involving stem cell lines and the increasing permissibility of stem cell line procurement worldwide (from supernumerary IVF and/or cloned embryos), (5) it is important that ethical and safety issues are not overlooked when developing public policy concerning stem cell research. All eventual stem cell clinical trials must be transparent and follow high quality standards in order to ensure the safety of human participants. In order to promote transparency and accountability, registries have been created internationally to disclose minimum data from human clinical trials, regardless of whether the outcomes are positive or negative. With the additional safety concerns that surround stem cell clinical trials, it would then be important to explore the feasibility of creating a clinical trial registry specifically for stem cell clinical research.

This paper will provide (1) an overview of the rationale behind clinical trial registries; (2) a summary of the ethical and scientific objectives of clinical trial registries; (3) a discussion on whether stem cell clinical trial registries have special issues to consider; (4) a survey of the challenges concerning the implementation of stem cell clinical trial registries; and finally (5) suggestions for possible stem cell clinical trial registry platforms.

1. The Rationale for Clinical Trial Registries and the Development of International Standards

   The growing concern regarding publication or selection bias--a common practice in the scientific community by investigators, peer reviewers, journal editors, funding bodies and research sponsors--has sparked the need for clinical trial registration. Study results that demonstrate risks or clinically important negative trial outcomes are left under-reported (6) while there is an overemphasis on benefits. (7) Trial results "that are statistically significant, interesting, from well-funded studies, or of higher quality are more likely to be submitted, published, or published more rapidly than work without such characteristics." (8) As a result, new interventions, that may be more expensive, are often promoted and adopted at the expense of treatments that may be safer or more effective.

   In the past, harmful consequences have resulted from unreported or unpublished trial outcomes. For example, in the 1980s, systematic reviews of antiarrhythmic drugs performed by Furberg and colleagues revealed that the drugs caused sudden death for patients with ventricular arrhythmias. The results of these studies were not substantive enough to convince scientists and physicians to abandon the use of the drugs so the negative results went unreported. Making the dangers of the antiarrhythmic drugs known would have prevented the reported 20000 to 75000 deaths per year between 1983 and 1993, when the report was finally published. (9) More recently, a systematic review published in 2004 demonstrated that a major pharmaceutical company had repeatedly committed fraud when it did not report the true efficacy of an antidepressant drug. (10) The potential harms of publication or selection bias illustrate the importance of transparency in clinical trials.

   Clinical trials have great potential for improving medical practice but this can be achieved only if they are evidence-based. If the conduct and outcome of clinical trials are not comprehensive and transparent, public trust in science will erode. Past scandals related to publication or selection bias have led to international standards and the adoption of policies by international organizations, (11) journal editors, (12) medical associations, (13) and even industry (14) to recognize the importance of clinical trial registries. International and national policies have made clinical trial registration a priority. Examples of policies are found in Figure 1.

2. Ethical and Scientific Objectives of Clinical Trial Registration

   A Clinical Trial Registry (CTR) is widely defined as a database of all human interventional clinical trials (25) regardless of the stage of development--at inception (when funding has been secured or prior to participant recruitment), while in progress or after completion--whether it has been published or not. Main features of the CTR database encompass the trial's objectives, main design features, sample size, and tested treatments.

   Aside from avoiding the negative consequences arising from publication or selection bias, CTRs achieve many important scientific and ethical objectives (Figure 2). An emerging consensus finds that the prospective registration of all interventional trials is a scientific, ethical and professional responsibility--if not a legal obligation--for scientists, governments and funding organizations. (26) Some authors consider the failure to fully report clinical trials "scientific or professional misconduct" and state that researchers have a moral obligation to report all trials involving human subjects. (27) It has also been suggested that "prospective trial registration should be a legally required component of written informed consent." (28) This duty is grounded in the fundamental need to disseminate knowledge and protect, as well as respect, research participants and patients.

   CTRs will facilitate access to the results of clinical trials in a comprehensive and objective manner (30) and further accelerate dissemination by making information publicly available. Furthermore, it is suggested that CTRs will provide the public access to new studies and a platform to conduct meta-analyses, (31) which will encourage communication and collaboration between researchers, accelerate the research process, prevent duplication of research and promote patient recruitment in trials.

   Ultimately, the raison d'etre for the establishment of a CTR is found in the notion of benefit sharing. The prospective registration of clinical trials would fulfill the expectations of both funding agencies and research participants since it will contribute to society's collective knowledge. Research involving human participants cannot be justified as contributing to the social good unless the resulting knowledge from the studies is shared. (32)

   As numerous individual clinical trials have inadequate statistical power to adjudicate reliably between alternative treatment strategies, meta-analyses or quantitative overviews of all relevant trials are necessary to draw conclusions about the efficacy of a particular treatment or procedure. (33) Such trials are the primary means by which the safety and efficacy of new drugs and other interventions are assessed. Their results have improved clinical practice in many areas of medicine. (34) However, since many of these meta-analyses are based on a summary of only the published trials, they are susceptible to the problem of publication bias. (35) By requiring the prospective registration of clinical trials at their inception, the problem of bias in the body of evidence could be largely eliminated, as registration in a CTR would occur independent of the ultimate findings or publication status of a trial.

   Professional organizations rely on the body of scientific evidence to draft best practice guidelines, which in turn outline the current standard of care. Likewise, policy-makers often rely on such evidence when drafting laws and regulations dealing with scientific and medical practice. Consequently, a CTR could have a great impact in shaping not only public policy, but also medical or product liability.

   Of equal importance is the objective of increasing the protection of patients and research participants. Another crucial objective of a CTR is to build, restore and maintain public trust in the integrity of scientific...