In the 4 years between the Ministerial Forums on research and health held in Mexico in 2004 and Mali in 2008, the landscape of clinical trial registration changed significantly. When the ICMJE announced that they would no longer consider publishing the findings of clinical trials unless the research had been prospectively registered, they were key to shifting the way the clinical trials community thinks about research transparency. The argument in favour of greater transparency had been building for more than 20 years. By 2004 there was consistent and convincing evidence of the existence of publication bias and the damage this does to people's ability to make well informed decisions about health care. There is now increasing acceptance that the registration of clinical trials in a publicly accessible registry is a scientific, ethical and moral responsibility. In 2004, less than 3000 clinical trials were registered on databases meeting ICMJE criteria. There are now more than 19000 and, in some countries, prospective registration in a publicly accessible registry is now a legal requirement. Further, since October 2008, prospective registration is required if researchers wish to comply with the Declaration of Helsinki. However, despite these advances and incentives, trial registration in many countries remains far from comprehensive and stronger enforcement mechanisms may be needed in those countries.
The year 2004 will be remembered as a landmark in the history of clinical trial registration. In August 2004 the International Committee of Medical Journal Editors (ICMJE) issued its statement that all trials must be registered on a publicly accessible register before recruitment of the first participant as a precondition of publication (1). Later that year Ministers of Health participating in the Ministerial Summit on Health Research held in Mexico City declared their support for prospective registration, calling for the establishment of a network of international clinical trials registers and a single point of access to registered clinical trial information (2). Six months later, the World Health Assembly endorsed this stand with a resolution (WHA 58.34) that subsequently resulted in the establishment of the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (WHO).
These policies were informed by a large body of evidence demonstrating the existence of publication bias and selective reporting, and the negative impact of these biases on the ability of health care providers and consumers to make informed health care decisions (3). The introduction of the policies coincided with considerable public debate arising from a number of high profile incidents where trial sponsors were found to have withheld negative trial outcomes from the public and regulatory agencies (4–7). Problems with a lack of transparency also extended to clinical trials performed in the developing world, where an increasing number of trials are being conducted. At least partly as a result of the negative publicity arising from these incidents the general public became concerned about the ambiguity and apparent lack of accountability, thus increasing the demand for greater transparency.
The best way to combat the problem of publication bias is to make a minimum amount of information about the trial publicly available before the first participant is recruited onto the study. More than 20 years have passed since early calls were made to establish registers of clinical trials that could achieve this goal (8, 9).
Existence of clinical trial registries
In 2004 the trial registration landscape was very different from the one that exists today. Some of the key events that have occurred in the intervening years are summarized in Table 1. Although a number of registries and databases existed in 2004, they were relatively small and strong incentives for sponsors to register their trials were lacking. The exceptions in regard to major, general registers for healthcare trials were the registries ClinicalTrials.gov and the International Standard Randomized Controlled Trial Number (ISRCTN) scheme. Based in the USA, the former was established as the result of Section 113 of the Food and Drug Administration Modernization Act (10). This database was made publicly available on the internet in February 2000 and primarily included National Institutes of Health–sponsored trials. The ISRCTN scheme was set up by Current Controlled Trials Inc. in 1998. Based in the UK, this system was developed to assign a clinical trial registration number, with the intention being to provide an international service (11). Although there were other registries in existence most were not available to the public and had been established to meet the administrative needs of the organization concerned, rather than to improve research transparency.
|August 2004||ICMJE publish statement on clinical trial registration||“The ICMJE member journals will require, as a condition of consideration for publication, registration in a public trials registry. Trials must register at or before the onset of patient enrollment.This policy applies to any clinical trial starting enrollment after July 1, 2005. For trials that began enrollment prior to this date, the ICMJE member journals will require registration by September 13, 2005, before considering the trial for publication.”|
|November 2004||Ministerial Summit on Health Research, Mexico City||Mexico Statement on Health Research: “The findings of high quality research should be not only accessible to decision makers but also communicated in ways the effectively inform policy, public health, and health care decision making. Research results must be published, documented in internationally accessible registers and archives, and synthesized through systematic reviews. These actions can help to inform decisions about support for new research and to build public confidence in science.”|
|Called for action by “All major stakeholders, facilitated by WHO Secretariat, to establish a platform linking a network of international clinical trials registers to ensure a single point of access and the unambiguous identification of trials.”|
|April 2005||Ottawa Statement on Trial Registration published||“Registration and early public release of accurate information about all trials is necessary to fulfilan ethical obligation to participants.”http://www.bmj.com/cgi/content/extract/330/7497/956 or http://ottawagroup.ohri.ca/statement.html|
|May 2005||58th World Health Assembly||Called upon “the global scientific community, international partners, the private sector, civil society, and other relevant stakeholders, as appropriate…to establish a voluntary platform to link clinical trial registers in order to ensure a single point of access and the unambiguous identification of trials with a view to enhancing access to information by patients, families, patient groups and others;”|
|July 2005||WAME policy published||“For these reasons, the World Association of Medical Editors supports efforts to register all clinical trials at their inception. Because registration is useful only to the extent that it includes all trials, it should be required of the research community as a whole and not voluntary according to the source of funding or preferences of the investigators. The contents of registries should be freely accessible and searchable to anyone in the world who wants to examine them.”|
|April 2006||Joint Statement of Establishing Chinese Clinical Trial Registration and Publishing System||“We declare that, from January 1st 2007, the member journals of ChiCTRPC will publish clinical trials with unique register number superior to those who do not have. In future, only clinical trials with register number can be published in those journals.”|
|January 2007||Food and Drug Administration Amendments Act 2007||“Beginning not later than 90 days after the date of the enactment of the Food and Drug Administration Amendments Act of 2007, for those clinical trials that form the primary basis of an efficacy claim or are conducted after the drug involved is approved or after the device involved is cleared or approved, the Secretary shall ensure that the registry data bank includes links to results information as described in clause (ii) for such clinical trial—|
|‘(I) not earlier than 30 days after the date of the approval of the drug involved or clearance or approval of the device involved; or|
|(II) not later than 30 days after the results information described in clause (ii) becomes publicly available.http://www.fda.gov/oc/initiatives/hr3580.pdf’”|
|June 2007||ICMJE update statement||“In addition to accepting registration in any of the five existing registries, the ICMJE will accept registration of clinical trials in any of the primary registers that participate in WHO's ICTRP.” Further, “The ICMJE will begin to implement the WHO definition of clinical trials for all trials that begin enrolment on or after July 1, 2008. This definition states that a clinical trial is ‘any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes.’”|
|January 2008||CONSORT for abstracts published||Registration number and name of trial register are considered to be “essential items which authors should include when reporting the main results of a randomised trial in a journal or conference abstract.”|
|February 2008||Statement on Publishing Clinical Trials in Indian Biomedical Journals||“On behalf of all biomedical journals published from India, we urge to all those who are either conducting and/or planning to conduct clinical trials involving human subjects, to register their trials in CTRI or in any primary clinical trial register. From January 2010 onwards, we will consider publication of a trial only if it has been registered prospectively if started in or after June 2008.”|
|October 2008||Declaration of Helsinki||“19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject.” (http://www.wma.net/e/policy/b3.htm)|
|November 2008||Global Ministerial Forum on Research For Health, Bamako, Mali||The Bamako Call to Action on Research for Health. Called for action by national governments states: “To develop, set and enforce standards, regulations and best practices for fair, accountable and transparent research processes, including those related to ethical review and conduct, product development and manufacturing, quality and safety of patient care, the registration and results reporting of clinical trials, and open and equitable access to research data, tools and information;”|
International Clinical Trials Registry Platform
It is in this environment that the ICTRP came into being. Initially, its work was focused on establishing the requirements of clinical trials registries and a trial registration data set (12). The focus then shifted to establishing the two key elements of the platform: the international network of registries (the ICTRP Registry Network) and a single point of access (the ICTRP Clinical Trials Search Portal (CTSP)).
The aim of the ICTRP Registry Network is to provide a forum for the exchange of information across registries, particularly WHO Primary Registries. Primary Registries meet specific criteria for content, quality and validity, accessibility, unique identification, technical capacity and administration and governance. Primary Registries must have at least a national remit and have been endorsed by the ICMJE (13). By the end of 2008, the ICTRP Registry Network consisted of registries based in Australia, China, India, Germany, Iran, Japan, the Netherlands, Sri Lanka and the UK (14–19). The members of the network are collaborating on the development of best standards of practice for clinical trial registration. All WHO Primary Registries must make the trial registration data set available in English, but an increasing number are making their data available in other languages as well, particularly the languages of the population served by the registry. Information for some registered trials is therefore now available in Chinese, Dutch, German, Japanese and Persian.
The ICTRP Clinical Trials Search portal (CTSP, http://www.who.int/trialsearch) provides a single point of access for the identification of trials. Trial records (containing the WHO trial registration data set) are accepted from data providers that create and manage their trial records in a manner that is consistent with the WHO Registry Criteria. The CTSP was launched in May 2007 and initially contained trial records provided by three clinical trial registries: the Australian New Zealand Clinical Trials Registry, ClinicalTrials.gov and the ISRCTN Registry. As of 9 January 2009, the CTSP contained 77,232 trials provided by registries based in Australia, China, India, Germany, Iran, the Netherlands, UK and USA. Of these, 26,290 trials were listed as being open to participant recruitment.
Challenges that remain
Although significant progress has been made, the ICTRP search portal is far from comprehensive (20). It is still not possible to determine the number of trials that exist throughout the world, or describe the nature and relevance of the research questions they are addressing. Although we know that not all trials are published, the best estimate we have as to the number of clinical trials that might exist is the number of trial reports published and, given publication bias, this will be an underestimate of the true number. Figure 1 shows the number of trials registered each year since 2000 that are on the ICTRP search portal, alongside the number of trial reports for these years on PubMed (which have been assigned the publication type ‘randomized controlled trial’) and in the Cochrane Central Register of Controlled Trials (Clarke M, 9 January 2009, pers comm). Therefore, assuming the overall number of trials is gradually increasing over time and taking account of publication bias, it is evident that there must be many clinical trials that are not registered in these Primary Registers.
The data in Figure 1 do not take into consideration the large bulk of research that is conducted and reported in languages other than English. For example, the State Food and Drug Administration (SFDA) of China has been reported to receive 1,250 applications for authorization of new trials and new drug applications each month (21). Although the number of registered trials recruiting participants in China has more than doubled in the last 2 years (Figure 2), if the SFDA estimates are correct, the number of trials that actually started recruiting in China in 2008 is much higher than the 518 that have been registered.
The most significant challenge facing the trial registration community, therefore, is compliance. There are three elements to compliance: (i) making sure that all clinical trials are registered; (ii) ensuring that the registered data are complete and accurate; and (iii) keeping the registered information up to date. The only way to guarantee compliance is to have multiple, complementary enforcement mechanisms in place, and the most effective way to establish these mechanisms is at a national level. This was acknowledged by the participating Ministers in the Global Ministerial Forum on Research for Health held in November 2008 in Bamako, Mali. In the resulting Bamako Statement, the Ministers reiterated their support for registration of clinical trials, calling on national governments to “enforce standards, regulations and best practices for fair, accountable and transparent research processes”, including those related to the registration of clinical trials (22).
A legal mandate is the strongest enforcement mechanism available to national governments. It enables governments to put in place monitoring procedures and to penalize those who do not comply. Registration of clinical trials is now a legal requirement in a number of countries including the USA and Brazil (23, 24).
Arguably the most important mandate to register trials is the moral and ethical mandate. Until recently, however, the responsibility of researchers to conduct research in a transparent fashion was primarily implicit and generally not well monitored. The 2008 revision of the Declaration of Helsinki published by the World Medical Association now states explicitly that “every clinical trial must be registered in a publicly accessible database before recruitment of the first subject” (25).
Research ethics committees are essentially the gatekeepers of research conducted in human subjects, and all research proposals potentially involving human subjects should be submitted for review and approval by a properly constituted ethics committee. Although many ethics committees are overwhelmed by increasing workload or inadequate resources they should consider registration of clinical trials as a process that will help them meet their ethical obligations, particularly the expectation that research conducted in humans will contribute to knowledge. Some have argued that research ethics committees should require registration as a precondition for ethics approval, and that they “should have a prominent role in making sure that trial results are publicly disseminated” (26, 27). Implementing a policy of mandatory trial registration by an ethics committee should not be unduly burdensome (the requirement could simply be to request the registration number and the name of the register on the ethics application form), and some ethics committees already have policies in place for clinical trial registration (28). Ethics committees could play a particularly important role in capturing all trials approved to recruit participants in low and lower middle income countries.
To date, the most influential mandate internationally has been achieved by the ICMJE (1). Since their initial statement was published, similar policies have been released by other organizations involved in the publication of clinical research around the world, including the World Association of Medical Editors (WAME) and the Committee on Publication Ethics. Two important groups to institute polices on trial registration are associations of journal editors in India and China (29, 30). This strong support from the publication industry is key to the success of the international bid for greater transparency and accountability of clinical trials research.
Numerous other agencies can and do advocate registration of clinical trials. Those involved in funding research have a vested interest in ensuring that the resources they allocate are not wasted and that they contribute to knowledge. Prospective registration of clinical trials should be considered a professional responsibility and embedded in the various codes of research practice of professional societies and organizations. Any policy that facilitates the registration and greater transparency of clinical trials should be encouraged. The ICTRP is in the process of cataloguing the policies of various agencies and welcomes contributions to this list (http://www.who.int/ictrp/trial_reg/en/index2.html).
“It is especially important to recognize the thousands of women who globally have volunteered for clinical trials. They deserve our respect and thanks, and we owe them our partnered commitment to ensure that communities understand the benefits of clinical trials. For too long, fear and mistrust have characterized the way many look at clinical trials in Africa. By setting the highest ethical standards and guaranteeing the highest standard of healthcare to trial participants, we can build widespread support for clinical trials across the continent.”
Edwin Cameron, Supreme Court of Appeal (31).
Unfortunately, public trust has been severely shaken in recent years (32). So great was the mistrust earlier this decade that a survey cited in an editorial in the British Medical Journal (BMJ) stated that many US citizens at the time put the pharmaceutical industry on a par with the tobacco industry (33). The problem is not restricted to the pharmaceutical industry, with some academic researchers also contributing to the poor public image of research (34). The BMJ editor went on to suggest that, by committing to great transparency and embracing clinical trial registration, the pharmaceutical industry could partly address this problem and improve its image in the eyes of the public (33).
In the four years between the Ministerial Summit on Health Research in Mexico, and the Global Ministerial Forum on Research for Health in Mali, the international community has taken significant steps towards achieving the goal of clinical trial transparency. With ongoing commitment by governments and agencies responsible for the oversight, funding and conduct of research, it is hoped that the progress that has been made so far will continue.