Speaking for Myself - Clinical Trials Registry - India

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Relevance to the Indian register of clinical trials. PRATHAP THARYAN .... research is also made available in the public domain, as is done in some parts of the ...

THE NATIONAL MEDICAL JOURNAL OF INDIA

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Speaking for Myself The WHO International Clinical Trials Registry Platform: Relevance to the Indian register of clinical trials PRATHAP THARYAN The editorial by Bhatt and Sewlikar on registering clinical trials in India1 raises important issues for policy-makers, clinician–researchers, pharmaceutical companies and contract research organizations involved in clinical trials in India (whose tribe is inexorably increasing), patients, their families and patient advocacy groups. Since the process of consultation is still ongoing to finalize details of the content and timing of disclosure of the minimal dataset of 20 items mentioned in the editorial, as well as the establishment of criteria, standards, quality control mechanisms and funding of the worldwide register network, an elaboration is warranted of some of the mechanisms being considered for the successful implementation of this worldwide register of trials, the contentious issues that remain and the implications these developments will have on regional registers such as the one being contemplated in India. Some of the issues raised in the editorial also require careful consideration with regard to registering clinical trials in India. Since August 2005, the Secretariat of the International Clinical Trials Registry Platform (ICTRP), under the Department of Research Policy and Cooperation of the WHO in the Evidence and Information for Policy cluster (EIP), has coordinated the international effort to ensure a minimum set of standards and simple, effective and efficient mechanisms by which clinical trials can be unambiguously identified and critical information declared prospectively.2–5 The WHO does not plan to host or administer its own register but instead the ICTRP website will, when fully implemented, provide a one-stop portal that will search the WHO network of member registers for all items on the WHO Trial Registration Data Set, provide information on how to register trials on regional member registers, and provide a Universal Trial Reference Number (UTRN) that will globally identify all unique trials. The results of this worldwide endeavour to prospectively register all clinical trials and provide a minimum dataset, if all trialists fully comply, are readily apparent in the form of transparency and public access to information on clinical trials mentioned in the editorial.1 The other benefits of prospective trial registration include prevention of multiple or ‘salami’ publications of the same trial, often with different first authors, as each publication will be required to cite the UTRN; this will prevent patients from a single trial being erroneously identified as participants in separate trials and duplicated in systematic Department of Psychiatry; Coordinator, South Asian Cochrane Network; Member, Scientific Advisory Group, WHO International Clinical Trials Registry Platform; Professor Bhooshanam V. Moses Centre for Clinical Trials and Evidence Based Medicine, Christian Medical College, Vellore 632002, Tamil Nadu, India. [email protected] © The National Medical Journal of India 2006

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reviews and meta-analyses. In addition, prospective registration ensures that the results of unpublished (and often ‘negative’) trials would be potentially available to those wishing to approach the trialists for data to include in systematic reviews and metaanalyses, thus minimizing publication bias and erroneous results accruing from meta-analyses of only published (and often ‘positive’) trials. The problems associated with such an endeavour are also numerous, and not fully dealt with in the editorial. I shall attempt to address them here. COMPLIANCE Prospective registration may not be as mandatory as the statement of the International Committee of Medical Journal Editors (ICMJE)6 implies or wishes; only if trialists wish to publish in ICJME member journals would mandatory prospective registration and disclosure of the full dataset be required. Considering the plethora of indexed and non-indexed local journals that do not, as yet, endorse the ICMJE statement, trialists could still get their trials published without prospective registration in any register of clinical trials. While important trials are likely to comply with the ICMJE statement, unless all journal editors worldwide (including in India) endorse prospective registration as a prerequisite to submission for publication, these laudable efforts would be undermined. Considering the many years that have elapsed since the CONSORT statement was published7 and revised,8 the fact that many journals still do not require randomized trials to adhere to these guidelines nor refuse publication in case of poor adherence,9 does not auger well for the present effort. It would therefore require a concerted effort from journal editors, institutional review boards and ethics committees, patient advocacy groups, sponsors of trials, and researchers to achieve consensus, advocate for, and commit to achieving the stated goals by voluntary compliance with these standards. External regulation may work for trials submitted to, for example, the Drug Controller General of India (DCGI) for regulatory approval, but would not work, for example, in the case of a postgraduate student conducting a randomized controlled drug trial or a behavioural intervention for his/her dissertation with intramural research funds; many of these latter group of trials may never be submitted for publication. Regulation would thus have to be broad based and internally driven rather than solely externally enforced by regulatory authorities and mechanisms. COVERAGE The ICMJE statement suggests that some Phase I trials could be exempt from prospective registration,6 while the ICTRP definition of a clinical trial requiring registration includes all

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prospective interventional studies that assign humans to one or more health-related interventions to evaluate health-related outcomes, regardless of the phase of the trial, its design, type of intervention, whether randomized or non-randomized, whether the products used were marketed or non-marketed or whether involving patients or healthy volunteers. 3 The inclusiveness of this definition and the implications for dataset management and implementation are staggering, as well as worrying, since any prospective case series involving an intervention for a novel or non-established indication would theoretically fall within the purview of this definition; as it stands, in many instances such interventions may not even go through ethics or research committees. Some pharmaceutical companies have also raised objections regarding the need to register Phase I or exploratory trials, citing the potential to cause confusion and raise false hopes among patients, and encourage premature prescriptions from clinicians before efficacy and safety have been proved.10,11 An additional concern raised is the possibility that such registration and disclosure of results of exploratory trials may conflict with the legal requirements of regulatory authorities.10 Patient advocacy groups such as the European Cancer Patient Coalition refute these contentions and welcome the call to register even Phase I trials in the interests of providing information about potentially life-saving Phase I interventions to cancer patients.12 The tragedy of Parexel’s Northwick Park TGN1412 Phase I trial that had not been available for public review also calls for more transparency, in the interests of saving lives and reclaiming the medical research agenda, over any claims of competitive advantage.13 DISCLOSURE The WHO ICTRP considers it critical on scientific and ethical grounds that all 20 items in the registration dataset be fully disclosed at the time of registration as does the ICMJE. The pharmaceutical industry contends that full disclosure for Phase I trials at the time of registration could threaten the competitive advantage that drives innovation and suggests delayed disclosure of sensitive items such as interventions, sample size and outcomes that could be used unfairly by competitors to their advantage.10,11,14 The ICTRP, in keeping with its avowed policy of dialogue and consensus building, has called for open comments on this issue and asked for clear and convincing examples, arguments and workable and unambiguous mechanisms of implementation to support delayed disclosure (the timing of disclosure rather than whether to disclose) in specific instances. Consensus on this issue is crucial to full compliance and the lack of consensus at present undoubtedly explains why some fields have not been entered, as noted in recent surveys of disclosure of registration details with ClinicalTrials.gov 15,16 which were quoted in the editorial. Following a formal consultation on timing of disclosure held on 26 April 2006 at Geneva, which included representatives from all stakeholders, the WHO has reiterated its call for the registration of all interventional trials, including early phase uncontrolled trials in patients or healthy volunteers. The Registry Platform was also not convinced by arguments for delayed disclosure and has insisted on full public disclosure of all registration data items at the time of registration and before recruitment of the first participant.23 It remains to be seen whether this final compromise position by the WHO will be incorporated in a

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sequel to the ICMJE statement endorsing registration of Phase I trials and full disclosure of all registration items, though it appears that this position has the support of editors of some leading journals.24, 25 ETHICS While the WHO ICTRP recognizes that prospective registration of clinical trials is an ethical and moral imperative, the current 20-item dataset does not include disclosure of ethics committee approval. In fact, the original item 11 titled Research Ethics Review was replaced by Countries of Recruitment as this was thought to provide more relevant information and because ethics review was considered already mandatory for clinical trials. While this may be true for clinical trials done in some parts of the world, the same cannot be assumed for all clinical trials done in India. It is also not mandated that trial registration occurs after ethics committee approval. For the process of prospective registration to more completely promote the ethical imperative envisaged, there are two possible strategies that could be adopted in India. The first would be for ethics committees to grant preliminary approval of the protocol and formal approval for trial commencement only after trial registration and assignment of the registry’s trial registration number. The second option would be for the Indian Clinical Trials Register to request for evidence of ethics committee approval before assigning the registry’s trial registration number. Considering the current controversies surrounding the ethics of clinical trials in India and the role of local research ethics committees,17,18 a combination of approaches might be appropriate. REPORTING RESULTS A logical extension of the process of prospective registration of clinical trials is the full reporting of the trial’s results without selection or bias. Although there is, as yet, no consensus on the international norms and standards for reporting results, it is envisaged that a database of trial results which may be separate but linked to the trials register, would be created to complement publication of results in peer-reviewed journals.19 The results are expected to be reported in as much detail as possible as recommended in the International Conference on Harmonization Tripartite Guidelines.20 This is an area of activity that requires further discussion and consensus regarding the mechanisms of implementation but, when implemented could provide valuable information to policy-makers, patients, clinicians and those involved in systematic reviews. A visionary call for journals to require that information be submitted to a trial results bank before publication, as is currently the norm for genetic sequencing studies,25 especially if endorsed by the overdue sequel to the ICMJE statement, may ensure that trial registers lead to the full reporting of results; both ethical imperatives are required to restore public credibility in clinical trials. GOVERNANCE The Indian Council of Medical Research (ICMR) has initiated the formation of the Indian Clinical Trials Register. The editorial suggested that Indian clinical trials be registered in two separate registers;1 one managed by the DCGI’s office called the regulatory clinical trials registry (RCTR) for any trial with commercial interests, whatever the source of funding or country of sponsor, and the other managed by the ICMR for academic trials called the academic clinical trial register

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(ACTR). While the distinction between academic and commercial may not always be watertight or entirely foreseeable at trial inception, the suggestion does have merit in that these regulatory agencies could aid the process of trial registration and disclosure of the minimum dataset as part of grant or regulatory approval. However, the ICTRP envisages a global network of only a limited number of Primary Member Registers, with only one Primary Member Register for a region or country, and any number of non-member associate registers (companies, institutions, universities, disease registers and governmental or non-governmental organizations).3 These associate registers would provide data to the Primary Member Register that would send these on to the WHO ICTRP, which would then assign a globally unique UTRN. The Primary Member Register would also be responsible for ‘de-duplication’ or ensuring that trials are not multiple registered. Multicentre international trials are to be registered only once, possibly in the country of the sponsor or primary investigator, and would not be re-entered in the Indian Trials Register, though item 11 would list all recruiting countries. In this scenario, the proposed RCTR and ACTR would only serve as associate registers feeding information to the Primary Member Register. Another reason for de-linking regulatory and/or funding roles for trials from managing the Primary Register is to avoid conflicts of interest; the ICMR sponsors trials and the DCGI is a regulatory authority and are therefore not the ideal managers for the Indian Clinical Trials Register. The criteria for Primary Registers are not yet finalized within the ICTRP but it is likely that an independent body would have to be created, either, for example, within the National Informatics Centre, which manages and hosts the Indian Medlars centre (http:// indmed.nic.in/) or some other agency. The WHO, through its regional offices, is coordinating the setting up of regional registers, though a South Asian or South-East Asian Clinical Trials Register may, with the current fluctuating political climate, not achieve viability. Member registers are expected to fund themselves, though WHO ICTRP would assist with capacity building and .provide technical assistance. While the ICMJE recommends that the Primary Registers be non-profit organizations, sustainability may require some fee for registering trials. However, this fee may not encourage universal prospective registration of all trials in India, and the provision for a discretionary waiver of fees would need to be considered. OPPORTUNITIES This global enterprise to prospectively register trials provides India with a number of opportunities to improve many areas of trial design, conduct, reporting and retrieval of trial information. 1. Randomized controlled trials (RCTs), and systematic reviews of good quality RCTs, are considered the highest levels of evidence of efficacy for any healthcare intervention. However, not all RCTs are of good quality and reporting of crucial aspects of trial design that determine the quality (internal validity) of trials such as concealment of allocation and blinding of trial participants is often inadequate.9 One way of improving matters is to require that all protocols submitted to research committees for approval be prepared in a format that follows the CONSORT guidelines.7,8 These guidelines reflect many items of trial conduct that enhance internal validity. This would ensure that trialists are aware of these requirements and would lead to better design and

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conduct of clinical trials. The ASSERT statement21 is an example of a checklist for protocols to be submitted to research ethics committees that incorporates CONSORT items as well as other details that enhance the ethical conduct and reporting of randomized controlled trials. The Indian Trials Register could, in addition to the minimal dataset required by the ICTRP, also request information about some of these aspects of trial design that enhance the internal validity and ethical conduct of trials. Once a template for reporting is established, this could eventually lead to better incorporation of these concepts in trial design as well. 2. The Indian Trials Register should ideally be a one-stop portal for access to both ongoing or planned clinical trials as well as to completed trials, whether published or unpublished, with free open access to information about these trials and links to full text where possible. Currently, the IndMED and associated databases, maintained by the Indian Medlars Centre of the Bibliographic Informatics Division of the National Informatics Centre (NIC), along with the ICMR, provide this useful function. However, the records are not sorted into categories of study design, so identifying only controlled clinical trials and randomized clinical trials is not easy. A separate register with links to the Indian Medlars databases, sorted into published, unpublished and ongoing trials would greatly facilitate the process of information retrieval and if linked to other databases, such as ICTRP or Cochrane Central Register of Controlled Trials (CENTRAL),22 would create a register of all trial information from India that would be open to anyone in the world. If this enterprise is replicated in all countries, we would see the emergence of a worldwide linked register of all trial information that would facilitate information dissemination. Such information is crucial for the design of future trials and systematic reviews based on complete information about ongoing and already completed trials. 3. India has a number of universities and medical institutions that train postgraduates and doctoral candidates. Each of them submits a dissertation that, in at least some instances, includes clinical trials. Many of these dissertations never get published in print journals and are therefore forever lost from the public domain. An open access, online central Register of Dissertations that links university maintained registers of dissertations would ensure that this source of research is also made available in the public domain, as is done in some parts of the world. The WHO ICTRP is an exciting collaboration of all major stakeholders involved in clinical trials and aims to improve access to the public domain of all healthcare interventional trials in the world. India, as an emerging market for the conduct of clinical trials, should appreciate the need for transparency, accessibility and accountability in medical research and the social, political, economic and legal forces influencing clinical drug trial design, conduct and reporting. Seizing this opportunity to improve the design, conduct and reporting of clinical trials would enable us to become full and responsible partners in this global enterprise. REFERENCES 1 Bhatt A, Sewlikar S. Registering clinical trials in India. Natl Med J India 2006; 19:1–3. 2 World Health Organization. Department of Research Policy and Cooperation (RPC). http://www.who.int/rpc/en/index.html (accessed 23 March 2006)

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3 World Health Organization. International Clinical Trials Registry Platform (ICTRP). http://www.who.int/ictrp/en (accessed 23 March 2006). 4 World Health Organization. International Clinical Trials Registry Platform (ICTRP): International Advisory Board. http://www.who.int/ictrp/about/details/ en/index2.htm (accessed 23 March 2006). 5 World Health Organization. International Clinical Trials Registry Platform (ICTRP): Scientific Advisory Board. http://www.who.int/ictrp/about/details/ en/index3.htm (accessed 23 March 2006). 6 De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. ; International Committee of Medical Journal Editors. Clinical trial registration: A statement from the International Committee of Medical Journal Editors. N Engl J Med 2004;351:1250–1. 7 Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, et al. Improving the quality of reporting of randomized controlled trials: The CONSORT statement. JAMA 1996;276:637–9. 8 Moher D, Schulz KF, Altman D. The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA 2001;285:1987–91. 9 Chan AW, Altman DG. Epidemiology and reporting of randomised trials published in PubMed journals. Lancet 2005;365:1159–62. 10 Pfizer response to World Health Organzation consultation on International Clinical Registry Platform (ICTRP). Invitation for open comments, January 2006. http://www.who.int/entity/ictrp/3006_Pfizer_25 Jan06.pdf (accessed 23 March 2006). 11 Roche comments on delayed disclosure. International Clinical Trials Registry Platform (ICTRP). January 2006. http://www.who.int/entity/ictrp/3004_HoffmannLa%20Roche_25Jan06.pdf (accessed 23 March 2006). 12 European Cancer Patient Coalition. Open comments of cancer patients to WHO on delayed public disclosure of clinical trials information. January 2006. http:/ /www.who.int/entity/ictrp/3003_ECPC_25Jan06.pdf (accessed 23 March 2006).

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13 Goodyear M. Learning from the TGN1412 trial. BMJ 2006;332:677–8. 14 Abbott response to World Health Organization International Clinical Trials Registry Platform (ICTRP) request for open comments on disclosure timing. 24 January 2006 http://www.who.int/entity/ictrp/3001_Abbott_?USA_25Jan06.pdf (accessed 23 March 2006). 15 Zarin DA, Tse T, Ide NC. Trial Registration at ClinicalTrials.gov between May and October 2005. N Engl J Med 2005;353:2779–87. 16 Drazen JM, Wood AJ. Trial registration report card. N Engl J Med 2005;353: 2809–11. 17 Mudur G. Indian study sparks debate on the use of placebo in psychiatry trials. BMJ 2006;332:566. 18 Tharyan P. Placebo-controlled trials in psychiatry on trial. Indian J Med Ethics 2006;3:13–16. 19 World Health Organization. International Clinical Trials Registry Platform (ICTRP): Results reporting. http://www.who.int/ictrp/results/en (accessed 23 March 2006). 20 ICH International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use. ICH harmonized tripartite guideline: Structure and content of clinical study reports. http://www.who.int/ ictrp/results/E3synopsis.pdf (accessed 23 March 2006) 21 ASSERT: A Standard for the Scientific and Ethical Review of Trial. www.assertstatement.org (accessed 24 March 2006) 22 The Cochrane Central Register of Controlled Trials (CCTR): The Evidence Based Medicine Reviews Collection. The Cochrane Library. www.thecochranelibrary.com (accessed 24 March 2006). 23 Sim I, Chan AW, Gulmezoglu AM, Evans T, Pang T. Clinical trial registration: Transparency is the watchword. Lancet 2006;367:1631–3. 24 Godlee F. An international standard for disclosure of clinical trial information. BMJ 2006;332:1107–8. 25 Horton R. Trial registers: Protecting patients, advancing trust. Lancet 2006; 367:1633–5.

The National Medical Journal of India is looking for correspondents for the ‘News from here and there’ section. We are particularly interested in getting newswriters from the north and northeast regions of India as well as from other countries. By news, we refer to anything that might have happened in your region which will impact on the practice of medicine or will be of interest to physicians in India. The emphasis of the news items in this column, which are usually from 200 to 450 words, is on factual reporting. Comments and personal opinions should be kept to a minimum if at all. Interested correspondents should contact SANJAY A. PAI at [email protected] or [email protected]

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