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

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 research by ensuring accountability and transparency of clinical trials results. Today, public trust is the cornerstone of sustainable scientific research. Furthermore, transparency and accountability in the conduct and the dissemination of clinical trials at any stage, by means of registration in a CTR, fosters public respect for those who have participated and by those who rely on biomedical research.

The principle of autonomy underlies the doctrine of informed consent. For research participants to be respected as autonomous agents, they must provide free, voluntary and informed consent. Most often, the participation of healthy volunteers in a clinical trial takes place because such individuals believe they are contributing to the generation of medical knowledge (which could eventually translate into cures and therapies). However, when the knowledge gained is never transferred, the trust between research investigators, research participants and the public at large is breached. Ethical concerns are heightened when the breach of trust (and autonomy) takes place in the context of trials that provide financial gains for the industry.

Finally, an additional advantage of a CTR is that it will foster better allocation of resources, informing priority setting and the future of research by identifying trends and gaps. By providing information regarding planned, ongoing and completed clinical trials a CTR will facilitate the planning of new studies and the use of resources by avoiding the duplication (which must be distinguished from appropriate replication) of research.

While scientists have had long-standing concerns about the phenomenon of publication bias, the rise of evidence-based health care and its dependence on systematic reviews and meta-analyses has made this problem more pressing. A CTR would have the important objective of contributing to the foundation of evidence-based medicine and the improvement of clinical practice by supporting the translation of research from the bench to the bedside through the development of best practice guidelines.

3. Clinical Trial Registry for Stem Cell Research: A Special Issue?

There are, therefore, compelling reasons for supporting the establishment of a CTR. What remains contentious however is the existence of an equally compelling rationale that warrants a special clinical trial registry for stem cell research. This issue has seldom been addressed despite the fact that clinical trials are currently in progress using adult or foetal stem cell lines. (36)

The translation of stem cell therapy from laboratory to clinical applications poses unique challenges. These challenges range from ethical and policy implications to scientific concerns for safety, quality and efficacy. Ethical debates surrounding stem cell research relate to controversies about the use of embryonic stem cells in research; some argue that the embryo has special moral status and should be protected. Therefore, the creation of a unique clinical trial registry for stem cell research could address these ethical issues provided that the registry includes information regarding the origins of the stem cell lines. A registry for clinical trials regarding stem cell based therapies should disclose the provenance of stem cell lines--whether embryonic or not--in order to respect prospective research subjects or patients' beliefs regarding the human embryo's moral status. Only with information regarding its source can the public make informed decisions regarding whether or not to participate in a trial, or receive future therapy or treatment.

Requiring that the provenance of stem cell lines be disclosed in a stem cell clinical trial registry could also decrease risks to research participants. For instance, insufficient certainty about the origins or traceability of the stem cell lines can have detrimental effects on the safety and health of the participants or patients involved. (37) Safety concerns relating to stem cell use include the risk of infectious diseases, the transfer of genetic disorders and the manner in which the stem cells are manufactured and stored. (38) For example, the concern regarding additional risks for infectious diseases results from the fact that many human stem cell lines created to date have been contaminated with animal cells because they were cultured using mouse feeder layers. (39) Therefore, the central question becomes whether it would be prudent to await the development of new clinically grade stem cell lines before embarking on human stem cell trials. This would then ensure maximum protection for the first human research participants.

As stem cell research continues to evolve, it is important to implement policies requiring that stem cell sources are reliable and that manufacturing and storage practices respect standard quality control measures. Existing stem cell banks, such as the UK Stem Cell Bank, aim to provide researchers access to ethically sourced stem cell lines that have been cultured, preserved and characterized under strict guidelines to guarantee their authenticity and quality. With these stem cell banks, researchers have access to high-quality stem cell lines for use in clinical trials. However, if these clinical trials are not registered, the necessary follow-up and traceability of the stem cell lines and their use could be limited. Similarly, the disclosure of the trials' outcome could be limited or null. Like all other clinical trials registries, the registration of stem cell clinical trials will foster transparency and accountability. Existing stem cell banks can serve as an instrument through which these trials can be registered. In this way, the entire supply chain of stem cells from donor to the recipient in the clinical trials can be documented and traceable. This point will be developed further in the following sections.

4. Challenges for the Implementation of a Stem Cell Clinical Trial Registry

Many questions must be addressed and analyzed before implementing and managing stem cell clinical trial registries. In order to be effective, a stem cell clinical trial registry must be global, comprehensive, accurate and publicly accessible. In addition, access to a registry should be simple, inexpensive and appropriate to the intended user population to allow for the unrestricted dissemination of research results. All these requirements should be coupled with an independent verification of postings and compliance mechanisms in order to ensure that ethical standards in clinical practice are respected.

a. Objections to Clinical Trial Registration

The design, scope and the implementation of a registry must be guided by the needs of the primary intended users, patients and other members of the public. The success of a registry would also ultimately depend on a willingness to contribute to a joint enterprise for the common good. (40) Because the pharmaceutical and biomedical industries are responsible for funding the majority of clinical trials, it is essential that these industries participate in and comply with registration standards. They may be reluctant to register clinical trials because of the adverse effects on intellectual property rights, commercial or academic competitive advantage, the danger of international piracy and/or the disclosure of trade secrets. These objections could result in targeting the therapeutic development and regulatory strategies of companies, damaging investor interests and stock value. (41)

It is argued that, due to the confidential nature of certain registration data, delayed disclosure of trial data should be permitted. However some authors contend that there is a lack of evidence supporting arguments for delayed disclosure. (42) Clinical trials are public by nature and any information that is claimed to be sensitive is readily accessible through trial participants and consumer websites. Furthermore, it is also argued that transparency and openness in the scientific field does not hinder innovation but instead promotes it. "Knowing how to capture innovation's benefits requires rethinking old assumptions about creation and ownership." (43)

The pharmaceutical and biotechnological industries concede that the dissemination of knowledge and the protection of the safety of patients (and research participants) must triumph over concerns for the confidentiality of proprietary interests, the protection of academic freedom and the exclusivity of research ideas. (44) However, they argue that a clinical trial registry would not have the effect of increasing safety or protections for research participants/patients, nor of diminishing publication bias.

It remains to be seen if a balance between those conflicting interests could be achieved in order to serve the public interest. As pointed out by Rennie, "the financial cost of an effective, independent and transparent clinical trial register would amount to a tiny fraction of the costs of the trials themselves, or the costs of not knowing their results, while the personal costs of allowing the present chaotic system to continue are incalculable." (45)

b. Implementation of Compliance Mechanisms and Oversight

In order to encourage compliance by biotechnology and pharmaceutical companies, a middle ground can be agreed upon which would allow companies to withhold key information concerning the clinical trial but still require that trials be registered at all phases. A relevant question to explore is what should be considered key information and who should have the authority to define what information should be disclosed.

At the present time, registration of clinical trials is generally voluntary, making compliance mechanisms difficult to enforce. However, there are policies adopted by different countries or institutions aimed at making registration a requirement. At the local level, there are some countries that have adopted laws that make the registration of all clinical trials mandatory. (46) Institutions at the international level have also made registration of clinical trials a requirement. Unlike the WHO's Clinical Trial Platform, which is based on voluntary registration, the International Committee of Medical Journal Editors (ICMJE) mandates that any paper on clinical trial results must be recorded in a publicly accessible registry before it can be published. (47) The ICMJE, an organization which represents eleven renowned medical journals, has thus taken the initiative to prevent publication bias while giving researchers an incentive to register their trials.

Aside from implementing compliance mechanisms, the auditing, monitoring and oversight of the registries are additional difficulties that must be overcome in order for the registries to be effective. Similarly, safeguards to maintain privacy and confidentiality of research participants and proprietary information must be established. A registry includes extensive data coming from multiple sources; it requires frequent updating to remain thorough and correct. Therefore, verification procedures must be enforced to ensure accuracy and quality assurance. With regard to the implementation of stem cell trial registration, it would be essential that an independent party validate registrants, assess risks, and establish quality and safety standards. All cell lines intended for human clinical trials should be traceable and their origins should be proven and inspected by accredited agencies to establish the risk involved at all stages of development and production.

It is recommended that the responsible authority with the mandate to monitor and oversee the registry should be given to an independent non-profit third party, such as an institutional or ethics review board that already has the role of approving research protocols. The Steering Committee for the UK Stem Cell Bank, the International Society for Stem Cell Research (ISSCR) or the International Stem Cell Forum (ISCF), three independent organizations that already oversee or will be overseeing stem cell banks, could also be given the mandate to administer stem cell registries given that stem cell lines used in clinical trials will most likely be procured from these stem cell banks. Having an independent third party monitor the register for completeness and compliance will prevent conflict of interest issues since there will be no outside influence from funding organizations.

c. Time of Registration and Implementation of a Minimum Data Set for Stem Cell Clinical Trials

Important issues to consider regarding the implementation of a stem cell clinical trial registry would include: what information should be disclosed, at which phase the clinical trial should be registered and whether delaying disclosure should be allowed. One of the objectives of clinical trial registration is to promote transparency and this could be accomplished by providing raw and anonymized datasets for public scrutiny. Many researchers are concerned that making raw data public may lead to inappropriate analyses and misinterpretations. (48) However, it is argued that this would be the "ultimate form of peer review" as it would ensure that "every statistician will have to prepare reports knowing that they will be scrutinised in the finest detail by a frequently hostile posterity." (49)

It is also argued that clinical trials should be registered at all phases, even at inception, in order to ensure safety and efficacy. Without the registration of clinical trials at all phases it would be impossible to know the adverse reactions or true effectiveness of a drug because unfavourable findings could easily be suppressed. The registration of early-phase clinical trials would then ensure that the risks related to new interventions or treatments would be publicly known. (50) If clinical trials are registered only after they have been completed, found to be favourable or published, publication bias will result. Furthermore, requiring that clinical trials be registered at inception would prevent the loss of potentially valuable scientific information, as early trials are often terminated for economic reasons. (51)

Particular challenges relate to the design and scope of a clinical trial registry for stem cell lines, especially concerning the establishment of a minimum data set as it would require agreement on standard data elements. A mandatory, minimum data set fosters transparency and accountability by providing a comprehensive and transparent (non-promotional) posting of methodology and results. The currency and accuracy of the information in a prospective registry is of paramount importance. In the case of stem cell clinical trials, including data regarding the origin, for traceability purposes and storage procedures of the stem cell lines, it is necessary to ensure that patient safety is not compromised.

The registration data set proposed by the WHO's ICTRP could be used as a model, but additional information regarding the stem cell lines in particular should be included. Stemming from the information required by the WHO, the ICMJE, and organizations that maintain registries specific to stem cell lines, such as the UK Stem Cell Bank, a comprehensive minimum registration dataset for stem cell clinical trials would include the following key information (Figure 7).

4. Possible Platforms for Stem Cell Clinical Trials Registries?

Overall, the coordination and monitoring of a de novo centralized stem cell registry would be very difficult because of the need for considerable resources and the substantial costs involved. The difficulties of managing a massive scope of data coming from multiple sources, accompanied by the need for regular updates to guarantee accuracy and completeness, present great financial and technical challenges that need to be addressed at the outset. Furthermore, there already exist vested interests in independent or local registries that have their own objectives or goals, which present logistical challenges in building a centralized registry. Creating a new and separate registry would also cause unnecessary duplication of data and information.

A possible solution would be to build a network linking existing stem cell banks or those that will be created in the future. The International Clinical Trials Registry Platform, already established by the WHO, could be a convenient starting point to disseminate information on stem cell registries or stem cell banks since it would be manageable to include a sub-category specific to stem cell clinical trials. Using the WHO's platform would also ensure quality control because, in order to be included in the database, registries must follow certain standards and requirements recommended by the WHO. For example, the WHO has developed draft criteria to become a "primary register," which include: collecting all items listed in the registration data set, performing quality assurance on submitted entries, establishing a process for obtaining updated data and ensuring that there exist deduplication procedures for the various registries.

Another option is to use existing stem cell banks as a point of initiation to collect information on stem cell clinical trials. Due to the lack of clinical-grade human embryonic stem cell lines, stem cell banks were created to ensure the quality, traceability and safety of stem cell lines. (52) There are international initiatives developing standards for the derivation, characterization and maintenance of human stem cell lines. Most notable is the effort by the International Stem Cell Forum (ISCF) (53) and the International Society for Stem Cell Research (ISSCR). However, other stem cell banks already exist or are in development. Examples of existing or proposed stem cell banks that could serve as platforms are given below (Figure 8).

These stem cell banks already provide data on the origins of each stem cell line and, as researchers begin to embark on stem cell clinical trials, it would be practical to use these same banks to trace how each particular stem cell line is used in a specific clinical trial. If organized as a harmonized consortium, these stem cell banks can serve as a single search portal for any researcher or member of the public to obtain information on where the stem cell line originated, how it was stored and whether it is being studied in a clinical trial. Provided that the ISCF and the ISSCR develop registries coordinating international stem cell banks, their stem cell banks would be the ideal place to begin registering stem cell clinical trials. Another option would be for the UK's Stem Cell Bank to take the lead in such an effort since it has a well-established governance structure and has obtained international recognition.

Conclusion

With stem cell research still in the early clinical stages and insufficient clinical-grade stem cells available for clinical use, some may argue that the establishment of stem cell clinical registries is premature. However, the scientific community is rushing to discover different sources of stem cells and to perfect the derivation and preservation of these cells in order to find therapies for a variety of diseases. Stem cells will most likely be widely used in clinical trials and therefore, as proposed by Kimmelman and other authors, (56) there is a sound rationale for supporting the call for the establishment of mandatory international clinical trial registries for stem cell-based research. (57) A clinical trials registry (CTR) for stem cell-based research could follow the model established by other international CTRs, such as those for human gene transfer. (58)

Stem cell clinical trial registries will provide the public with complete and accurate information regarding stem cell therapies so that they too can participate meaningfully in policy discussions regarding this scientific field. These registries will also highlight any negative trial outcomes, allowing policy-makers to quickly identify and address safety concerns in stem cell research. For both scientific and pragmatic reasons, these stem cell CTRs should be part of a widely recognized stem cell bank such as the United Kingdom Stem Cell Bank, (59) the ISCF registry, or the ISSCR stem cell bank.

The time is ripe to move the debate from the appropriateness of registration and publication of clinical trials, (60) and from the suitability of a CTR for stem cell-based research, to the issue of how to organize such a clinical trial registry in a sound, efficient and transparent fashion for the public good. (61)

Rosario M. Isasi is a Postdoctoral Fellow and Thu Minh Nguyen is a Research Associate, both at the Centre de recherche en droit public (CRDP), Universite de Montreal.

Acknowledgements

We thank the Canadian Stem Cell Network, the Canadian Institutes of Health Research, and the Ethics Working Party of the International Stem Cell Forum for their funding support. The opinions are those of the authors alone.

1. Thomas B. Okarma, "Human Embryonic Stem Cells: A Primer on the Technology and its Applications" in Suzanne Holland, Karen Lebacqz & Laurie Zoloth, eds., The Human Embryonic Stem Cell Debate: Science, Ethics and Public Policy (Cambridge: MIT Press, 2001) at 3.

2. Commission of the European Communities, "Commission Staff Working Paper: Report on Human Stem Cell Research" (Brussels, 3 April 2003).

3. Lawrence J. Nelson & Michael J. Meyer, "Confronting Deep Moral Disagreement: The President's Council on Bioethics, Moral Status, and Human Embryos" (2005) 5 American Journal of Bioethics 33.

4. Clive Cookson, "Geron Gears up for First Stem Cell Trial for Spine Injuries" Financial Times (9 May 2007), online: <http://www.ft.com/cms/s/d4650fce-fe93-11db-bdc7-000b5df10621,_i_rssPage=d7e814a83012-11da-ba9f-00000e2511c8,Authorised=false.html?_i_location=http%3A%2F%2F www.ft.com%2Fcms%2Fs%2Fd4650fce-fe93-11db-bdc7-000b5dfl0621%2C_i_rssPage%3Dd7e814a83012-11da-ba9f-00000e2511c8.html&_i_referer=http%3A%2F%2F www.google.ca%2Fsearch%3Fhl%3Den>.

5. Rosario M. Isasi & Bartha M. Knoppers, "Mind the Gap: Policy Approaches to Embryonic Stem Cell and Cloning Research in 50 Countries" (2006) 13 Euro. J. for Health L. 9.

6. An-Wen Chan & Douglas G. Altman, "Identifying Outcome Reporting Bias in Randomised Trials on PubMed: Review of Publications and Survey of Authors" (2005) 330 British Medial Journal 753.

7. Tania M. Bubela & Timothy A. Caulfield, "Do the Print Media 'Hype' Genetic Research? A Comparison of Newspaper Stories and Peer-reviewed Research Papers" (2004) 170 Canadian Medical Association Journal 1399.

8. A. J. Sutton et al., "Empirical Assessment of Effect of Publication Bias on Meta-analyses" (2000) 320 British Medial Journal 1574; John PA. Ioannidis, "Effect of the Statistical Significance of Results on the Time to Completion and Publication of Randomized Efficacy Trials" (1998) 279 Journal of the American Medical Association 281.

9. Curt D. Furberg, "Effect of Antiarrhythmic Drugs on Mortality after Myocardial Infarction" (1983) 52 American Journal of Cardiology. 32; Koon K. Teo, Salim Yusuf & Curt D. Furberg, "Effects of Prophylactic Antiarrhythmic Drug Therapy in Acute Myocardial Infarction. An Overview of Results From Randomized Controlled Trials" (1993) 270 Journal of the American Medical Association 1589.

10. Craig J. Whittington et al., "Selective Serotonin Reuptake Inhibitors in Childhood Depression: Systematic Review of Published versus Unpublished Data" (2004) 363 Lancet 1341.

11. Karmela Krleza-Jeric et al., eds., "Principles for International Registration of Protocol Information and Results from Human Trials of Health Related Interventions: Ottawa Statement (Part 1)" (2005) 330 BMJ 956; International Clinical Trials Registry Platform (ICTRP), online: World Health Organization (WHO) <http://www.who.int/ictrp/en>; WHO, Department of Research Policy and Cooperation, Mexico Statement on Health Research (1 April 2005), online: <http://www.who.int/rpc/summit/agenda/en/mexico_statement_on_health_research.pdf>.

12. Kamran Abbasi, "Compulsory Registration of Clinical Trials" (2004) 329 British Medical Journal 637; Catherine De Angelis et al., "Clinical Trial Registration: A Statement from the International Committee of Medical Journal Editors" (2004) 292 Journal of the American Medical Association 1363.

13. American Medical Association, "Influence of Funding Source on Outcome, Validity, and Reliability of Pharmaceutical Research" (2004), online: <http://www.ama-assn.org/ama/pub/category/14314.html>.

14. International Alliance of Pharmaceutical Associations, "Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases" (2005), online: <http://international.phrma.org/publications/policy//admin/2005-01-06.1113.PDF>.

15. Catherine de Angelis et al., "Clinical Trial Registration: A Statement from the International Committee of Medical Journal Editors" (2004) 141 Annals of Internal Medicine 477, online: <http://www.annals.org/cgi/reprint/141/6/477.pdf>.

16. World Health Organization, "International Clinical Trials Registry Platform" (2006), online: <http://www.who.int/ictrp/en/>.

17. Karmela Krleza-Jeric et al., eds., "Ottawa Statement (Part One): Principles for International Registration of Protocol Information and Results from Human Trials of Health Related Interventions," online: <http://ottawagroup.ohri.ca/statement.html>.

18. Charlotte Haug, Peter C. Gotzsche & Torben V. Schroeder, "Registries and Registration of Clinical Trials" (2005) 353 New England Journal of Medicine 2811.

19. Ludovic Reveiz et al., "The Latin American Ongoing Clinical Trial Register (LATINREC)" (2006) 19 Rev. Panam. Salud. Publica/Pan American Journal of Public Health 417, online: <http://www.who.int/ictrp/LATINREC_2006.pdf>.

20. Some examples include: the Austrian Federal Agency for Safety in Health Care, the Italian Medicines Agency and the UK Medicines and Healthcare products Regulatory Agency. For other examples refer to <http://eudract.emea.europa.eu/docs/MSCAContactList.pdf>

21. EC, Directive 2001/20/EC of the European Parliament and of the council of 2 April 2001 [2001] O.J.L.121/34. The European Union requires that "clinical trials on medicinal products for human use" must be registered in a European database. As of May 2004, all member states of the European Union must register trials in the EudraCT database.

22. US, Food and Drug Administration Modernization Act (1997), online: <http://www.fda.gov/cder/guidance/s830enr.txt>. This Act requires the establishment of a database of all trials of new treatments for serious or life threatening diseases.

23. United Kingdom, The Medicines for Human Use (Clinical Trials) Regulations 2004, S.I. 2004/1031, online: <http://www.uk-legislation.hmso.gov.uk/si/si2004/20041031.htm#4>. These regulations require that all clinical trials be registered in the European database according to the European Union Directive for Clinical Trials (2001).

24. Republic of South Africa, Department of Health, South African National Clinical Trials Register. As of 1 December 2005, the Department of Health of South Africa requires that all new clinical trials be registered in the South African National Clinical Trials Register. Those trials that started recruitment for participants as of 1 July 2005, must also be registered.

25. An interventional clinical trial consists of any research study that prospectively assigns humans or groups of humans to health-related interventions (drugs, cells and biological products, devices, procedures, behavioral treatments, etc).

26. Ad Hoc Working Party of the International Collaborative Group on Clinical Trials Registries, "International Collaborative Group on Clinical Trials Registries. Position Paper and Consensus Recommendations on Clinical Trial Registries" (1993) 28 Clinical Trials Metaanalysis 255.

27. Iain Chalmers, "Underreporting Research is Scientific Misconduct" (1990) 263 Journal of the American Medical Association 1405.

28. Guido Grass, "Clinical Trial Registration" (2005) 352 New England Journal of Medicine 198.

29. Krleza-Jeric, supra note 11.

30. In addition to publication in a CTR, the standard processes for research dissemination would have to take place (i.e., collected data should be analysed, a report prepared and submitted for peer review, and subsequently published).

31. Randomized controlled trials (RCTs) are widely regarded as the most rigorous study design for determining whether a cause and effect relationship exists between an intervention and an outcome. Meta-analyses or systematic reviews of well-conducted trials are regarded as the highest level of evidence, Kay Dickersin & Drummond Rennie, "Registering Clinical Trials" (2003) 290 Journal of the American Medical Association 516.

32. Krleza-Jeric, supra note 11.

33. Marea B. Tumber & Kay Dickersin, "Publication of Clinical Trials: Accountability and Accessibility" (2004) 256 Journal of Internal Medicine 271.

34. Alexa T. McCray, "Better Access to Information about Clinical Trials" (2000) 133 Annals Internal Medicine 609.

35. A study performed by Sutton and colleagues suggests that publication bias is present in 50% of meta-analyses and it is strongly indicated in 20%, while publication bias affects the results in less than 10% of meta-analyses. Furthermore, it is recommended that researchers be aware that publication bias is possible and that they should perform sensitivity analysis to access the potential effects of the missing results. Sutton, supra note 8.

36. Benedetta Bussolati & Giovanni Camussi, "Adult Stem Cells and Renal Repair" (2006) 19 Journal of Nephrology 706; K.J. Allen, N.E. Buck & R. Williamson, "Stem Cells for the Treatment of Liver Disease" (2005) 15 Transplant Immunology 99.

37. In 2006, a Dutch clinic was ordered to stop giving stem cell therapy after a patient became seriously ill after treatment. It was concluded that the clinic failed to provide responsible care according to Dutch law because it did not provide accurate documentation regarding the "origin, suitability and safety" of the stem cells used. Tony Sheldon, "Dutch Clinic is Ordered to Stop Giving Stem Cell Therapy" (2006) 333 British Medical Journal 770.

38. Liza Dawson et al., "Safety Issues in Cell-Based Intervention Trials" (2003) 80 Fertility and Sterility 1077.

39. Mark Richards et al., "Human Feeders Support Prolonged Undifferentiated Growth of Human Inner Cell Masses and Embryonic Stem Cells" (2002) 20 Nature Biotechnology 933; Chunhui Xu et al., "Feeder-free Growth of Undifferentiated Human Embryonic Stem Cells" (2001) 19 Nature Biotechnology 971.

40. Alexa T. McCray & Nicholas C. Ide, "Design and Implementation of a National Clinical Trials Registry" (2000) 7 Journal of the American Medical Information Association 313.

41. John C. Somberg, "Clinical Trials Registries," Editorial (2003) 10 Am. J. Ther. 309.

42. Ida Sim et al., "Clinical Trial Registration: Transparency is the Watchword" (2006) 367 Lancet 1631.

43. Sam Palmisano "The Information Puzzle" Newsweek (2 December 2005), online: <http://www.msnbc.msn.com/id/10296176/site/newsweek>.

44. De Angelis, supra note 15.

45. Drummond Rennie, "Trial Registration: A Great Idea Switches From Ignored to Irresistible" (2004) 292 Journal of the American Medical Association 1359.

46. Refer to Figure 1.

47. De Angelis, supra note 15.

48. Elizabeth Wager, "Publishing Clinical Trial Results: The Future Beckons" (2006) e31 PLOS Clinical Trials 0001.

49. Stephen Senn, "Statistical Quality in Analysing Pharmaceutical Clinical Trials" (2000) 7 Good Clinical Practice Journal 22.

50. Alastair J.J. Wood & Janet Darbyshire, "Injury to Research Volunteers--The Clinical Research Nightmare" (2006) 354 New England Journal of Medicine 1869.

51. Joseph A. Dimasi, "Risks in New Drug Development: Approval Success Rates for Investigational Drugs" (2001) 69 Clinical Pharmacology and Therapeutics 297.

52. In Canada, the CIHR's "Updated Guidelines for Human Pluripotent Stem Cell Research" (28 June 2005) mandates the establishment of an electronically accessible national registry of human embryonic stem cell lines generated in the country using CIHR funding. According to the CIHR guidelines, "this registry will minimize the need to generate large numbers of cell lines, which should decrease the need for donation of large numbers of embryos." Listing on the national registry will be a prerequisite for obtaining CIHR funding for human pluripotent stem cell research. Information contained in the registry will be available "by the researchers to researchers" working on the field, subject to "reasonable cost-recovery charges."

53. Peter W. Andrews et al., "The International Stem Cell Initiative: Toward Benchmarks for Human Embryonic Stem Cell Research" (2005) 23 Nature Biotechnology 795.

54. UK Steering Committee for the Stem Cell Bank, "Code of Practice for the Use of Human Stem Cell Lines" Version 2 (March 2005), online: <http://www.most.go.kr/bapp/dn_file/pdf-public-stem_cell_code_of_practice_june2005.pdf?id=wvluS5NwhWU%3D>.

55. Canadian Institutes of Health Research, "Updated Guidelines for Human Pluripotent Stem Cell Research" (28 June 2006), online: Canadian Institutes of Health Research <http://www.cihr-irsc.gc.ca/e/31488.html>.

56. Jonathan Kimmelman, Francoise Baylis & Kathleen Cranley Glass, "Stem Cell Trials: Lessons from Gene Transfer Research" (January--February 2006) Hastings Center Report, 23.

57. Institute of Medicine, Committee on Clinical Trials Registries, Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Report (Washington: National Academies Press, 2006).

58. For example, the USA-based Genetic Modification Clinical Research Information System (GeMCRIS) is system that allows users to access an array of information about human gene transfer trials registered with the NIH, including medical conditions under study, institutions where trials are being conducted, investigators carrying out these trials, gene products being used, route of gene product delivery, and summaries of study protocols. Federal Register, 19 November 2001 (66 FR 57970), amended 24 January 2002, online: <www.gemcris.od.nih.gov>.

59. Online: <http://www.ukstemcellbank.org.uk/>. See also, Lyn Healy et al., "The UK Stem Cell Bank: Its Role as a Public Research Resource Centre Providing Access to Well-characterised Seed Stocks of Human Sem Cell Lines" (2005) 57 Advanced Drug Delivery Reviews 1981.

60. Krleza-Jeric, supra note 11.

61. Jan A. Staessen & Guiseppe Bianchi, "Registration of Trials and Protocols" (2003) 362 Lancet 1009.

Figure 1: Examples of Current Policies for Clinical Trials Registries

1. The International Committee of Medical Journal Editors (ICMJE) (2004)

   ICMJE mandates that, as a condition of publication, all clinical
   trials (except Phase I) beginning enrollment after July 1, 2005 be
   registered. ICMJE requires that registries are owned and operated by
   not-for-profit organizations, contain a minimal data set consisting
   of 20 items and be accessible free of charge by the public. (15)

2. World Health Organization (WHO), International Clinical Trials
   Registry Platform (ICTRP) (2006) (16)

   Developed in collaboration with the International Standard Randomised
   Controlled Trial Number (ISRCTN) register, based in the UK, and the
   ClinicalTrials.gov registry, based in the US, the ICTRP aims to
   promote consensus regarding international norms and standards in
   clinical trial registration, which includes a minimum registration
   dataset. The ICTRP requires that clinical trials are registered at
   inception and proposes that a unique Universal Trial Reference Number
   be given to each trial to prevent duplication. The ICTRP is not a
   registry itself but a comprehensive search portal for registries that
   exist worldwide.

3. Ottawa Group, Ottawa Statement (2005) (17)

   The Ottawa Statement is a consensus document that outlines key
   principles regarding human clinical trial registration. The
   recommendation includes a minimal registration dataset which goes
   much further than the requirements of the WHO. This statement
   requires the trial protocols be disclosed from the beginning,
   disclosure of all amendments along the way, and the posting of final
   results. This statement has the support of 100 individuals and
   organizations worldwide (18) but does not yet have support from the
   pharmaceutical community.

4. The International Federation of Pharmaceutical Manufacturers and
   Associations (IFPMA), along with the European Federation of
   Pharmaceutical Industries and Associations (EFPIA), the Japanese
   Pharmaceutical Manufacturers Association (JPMA) and the
   Pharmaceutical Research and Manufacturers of America (PhRMA), Joint
   Position on the Disclosure of Clinical Trial Information via Clinical
   Trial Registries and Databases (January 2005) and the Joint Position
   on the Disclosure of Sensitive Information via Clinical Trial
   Registries (2005)

   The pharmaceutical industry commits to registering information about
   all new and ongoing industry-sponsored clinical trials, other than
   "exploratory trials" (i.e. trials that generate or test hypotheses),
   in a free, publicly accessible clinical trial registry. The WHO
   "minimum data set" will be adhered to but the following data may be
   considered "sensitive" by the sponsor who may wish to delay the
   release of information for "competitive reasons": primary outcome,
   key secondary outcomes, intervention, target sample size, and
   official scientific title of the study.

5. The Latin American Ongoing Clinical Trial Register (LATINREC) (19)
   (2003)

   This registry is being developed by the Colombian Branch of the
   Iberoamerican Cochrane Network in order to "collect information on
   clinical trials undertaken in Latin American countries, make this
   information available to the public, and provide methodological
   informational and other tools as required by trialists." The registry
   is available online at: www.Latinrec.org. All clinical trials must be
   registered according to the ICTRP data set and must receive a unique
   identification number assigned by the WHO.

6. Ethics Review Boards (ERBs) -- some require registration of clinical
   trials as a condition of ethics approval. (20)

7. Regional or national laws requiring trial registration (e.g.,
   European Union, (21) USA, (22) UK (23) and South Africa). (24)

Figure 2: Objectives for a Clinical Trial Registry (29)

1. Disseminate information/knowledge transfer
2. Respect the investigator-participant covenant to contribute to
   biomedical knowledge by making trial methods and results public
3. Provide a foundation for evidence-based medicine
4. Enhance accountability and transparency with regard to standards in
   ethical research
5. Promote improved allocation of resources
6. Protect/respect research participants
7. Prevent wasted and unnecessary duplication of research
8. Enable monitoring of adherence to ethical principles and process

Figure 4: A Clinical Trial Registry for Stem Cell Research: A Special
Issue?

1. Cell line derivation, characterization, delivery and banking
2. Safety, efficacy and quality standards
3. Translational research
4. Traceability/Origins of cell lines
5. Compliance of diverse/conflicting international policies
6. Policy regarding the registration of clinical trials at different
   phases

Figure 5: The Rationale for a Clinical Trial Registry Involving Stem
Cell-based Research

1. Maintain respect for research participants
2. Foster accountability with regard to global standards for ethical
   research
3. Encourage adherence to ethical principles and processes
4. Provide global open access to information
5. Provide unbiased public records on safety and effectiveness
6. Foster innovation and acceleration of research practice in clinical
   therapies
7. Increase opportunities for collaboration and participation
8. Maintain public trust

Figure 7: Disclosure Requirements (model)

Standard Clinical Trials:

 1. Trial name or title
 2. Unique Registration number
 3. Registration Date
 4. Disease or condition concerned
 5. Objectives
 6. Outcomes (main and secondary)
 7. Intervention(s), treatment(s)
 8. Secondary IDs
 9. Sponsor and funding sources
10. Responsible contact person
11. Research contact person
12. IRB review

Stem Cell Clinical Trials:

 1. Type (embryonic, foetal, adult)
 2. Classification (research grade/clinical grade stem cell lines)
 3. Unique bank accession number
 4. Donor selection criteria
 5. Microbiological screening of the donors
 6. Records of tissue/cell removal and desegregation
 7. Cell harvesting and preparation
 8. DNA fingerprinting or profiling (confirm origin of cell line and
    check for cross contamination between cells)
 9. Type, source and batch numbers of media additives
10. Origin, history and other details of any feeder layers used
11. Methods used to establish cell line (including the population
    doubling times, split ratios and passage number)
12. Microbiological status (including the nature, use and removal of
    antibiotics)
13. Characteristics (e.g. surface antigen expression, gene expression,
    DNA fingerprinting, RNA analysis, etc.)
14. Quality systems employed to assure safety and quality
15. Informed consent obtained from donors
16. Licences, approvals, and accreditations
17. Research Ethics Committee approval/Supervising authority

Figure 8: Stem Cell Banks in Existence or Development

International Stem Cell Forum (ISCF)  The ISCF is in the process of
http://www.stemcellforum.org/           developing an international
                                        registry to record quality stem
                                        cell lines. The main objective
                                        is to co-ordinate stem cell
                                        banking in different countries
                                        and to promote the
                                        standardization of procedures in
                                        this field of research.
International Society for Stem Cell   The ISSCR proposes to maintain a
  Research (ISSCR)                      database of human stem cell
http://www.isscr.org/                   lines and will give the ISSCR
                                        Standards Committee the mandate
                                        to verify the provenance of the
                                        stem cell lines according to
                                        guidelines established by the
                                        ISSCR.
National Institute of Health (NIH)    National Stem Cell Bank (developed
  (United States)                       by the WiCell Research
http://stemcells.nih.gov/research/      Institute) will provide stem
  registry/defaultpage.asp              cells to researchers from
                                        federally funded organizations
                                        at a reduced price. It is
                                        ensured that the stem cell lines
                                        and classes are properly
                                        maintained and handled. The bank
                                        houses 11 of the 22 stem cell
                                        lines that exist in the United
                                        States. Each stem cell line has
                                        a unique NIH code for
                                        identification.
European Registry for hESC lines      On March 29, 2007, the European
http://europa.eu/rapid/                 Commission decided to provide
  pressReleasesAction.do?reference=     funding for the creation of a
  IP/07/437&format=HTML&aged=           European hESC line registry. The
  0&language=EN&guiLanguage=en          registry will be publicly
                                        accessible via the internet,
                                        will contain information
                                        regarding stem cell lines
                                        (provenance, contact
                                        information, cell
                                        characteristics) and will also
                                        provide information regarding
                                        developments in stem cell
                                        research, such as clinical
                                        trials. Ten EU countries are
                                        currently involved in the
                                        registry and it is expected that
                                        other non-EU countries will join
                                        the project.
UK Stem Cell Bank (United Kingdom)    A repository of human stem cells
http://www.ukstemcellbank.org.uk/       of all types. The bank is
                                        governed by strict guidelines to
                                        ensure the highest standards of
                                        best practice regarding human
                                        stem cell use. (54)
Canadian Institutes of Health         In their Updated Guidelines for
  Research (CIHR) (Canada)              Human Pluripotent Stem Cell
http://www.cihr-irsc.gc.ca/             Research, (55) the CIHR proposed
                                        the creation of a national
                                        registry for stem cell banks
                                        (Section 6.0).