|Year : 2018 | Volume
| Issue : 1 | Page : 10-15
Clinical trial registration: A practical perspective
S Bala Bhaskar
Department of Anaesthesiology, VIMS, Ballari, Karnataka, India
|Date of Web Publication||12-Jan-2018|
Prof. S Bala Bhaskar
Department of Anaesthesiology, VIMS, Ballari, Karnataka
Source of Support: None, Conflict of Interest: None
The increase in the number of clinical trials, driven mainly for career advancement mandated by regulatory bodies such as Medical Council of India risks output of substandard publications and also wastage of resources. There are also concerns of inadequate reporting and wilful concealment of results. The quality and quantity of the output become questionable evidences for medical practice. Lack of transparency can lead to disillusionment of the public in the medical field. Clinical trials registration seeks to regulate and streamline the clinical trials by mandating registration in various registries, through free for registration sites such as Clinical Trials Registry of India (CTRI). The guidelines are based on the World Health Organisation's International Clinical Trials Registry Platform (ICTRP). This review aims to highlight the types of registries, the registration process, the data that need to be registered, the guide to use the CTRI and the search options in CTRI and ICTRP. The role of International Committee of Medical Journal Editors is also highlighted in regard to not only registration but also on the publication of trial registration number in the manuscript.
Keywords: India, medical writing, publications, publishing, registries
|How to cite this article:|
Bhaskar S B. Clinical trial registration: A practical perspective. Indian J Anaesth 2018;62:10-5
| Introduction|| |
Clinical trials are undertaken to benefit patients, and when properly performed, add to the evidence in the medical field. However, outcomes are sometimes not reported – the trials may have stopped due to negative results or equivocal results. In many medical schools and hospitals in India, the research is either abandoned, or the manuscript is not prepared or not submitted for publication due to the busy work schedule. However, selective publication and selective reporting of research outcomes, as well as duplicate publications of research create misinterpretation of the data. Crucial evidence is thus lost, with the potential to affect the medical practice and patient care. Registration of a trial is one of the ways of preventing this type of misadventures [Table 1]. The benefits  of registration of clinical trials are shown in [Table 1].
|Table 1: Importance of prospective trial registration (Clinical Trials Registry of India)|
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As per the World Health Organisation (WHO), the registration of all interventional trials is a scientific, ethical and moral responsibility. This article will not go into the economic and commercial aspects nor into the aspects related to the quality of the research submitted to the Clinical Trials Registry, but purely concentrate on the administrative and technical aspects.
The clinical trial represents a prospective study comparing the outcomes of interventions in the human participants in the allotted group/groups. Interventions can be in terms of drugs, cells and other biological products, surgical procedures, radiologic procedures, devices, behavioural treatments, process-of-care changes, preventive care, etc. This definition includes Phase I to Phase IV trials.
The trial registration is primarily the publication of information about the design, conduct and administration of clinical trials. Posting of extended details such as summary results and publication may also be necessary. The registry should be accessible to the public at no charge, open to all prospective registrants, managed by a not-for-profit organisation, have a mechanism to ensure the validity of the registration data and be electronically searchable.
The criteria for registration of trials is developed and published by WHO and is utilised by many registries across the world.
| Primary and Partner Registry|| |
The registries are grouped as Primary Registries and Partner registries, using WHO International Clinical Trials Registry Platform (ICTRP).
A primary registry is a clinical trial registry with at least a national remit that meets WHO Registry Criteria for content, quality and validity, accessibility, unique identification, technical capacity and governance and administration. Primary Registries are endorsed by the International Committee of Medical Journal Editors (ICMJE). There are currently 16 Primary Registries in the WHO Registry Network, including the Clinical Trials Registry of India (CTRI).
A partner registry satisfies all the criteria as primary registry in the WHO registry network (i.e., for content, quality and validity, etc.,) but need not have a national or regional remit or the support of government. The partner registries need not be managed by a not-for-profit agency, and they need not be open to all prospective registrants (e.g., they may be limited to trials in a particular condition or intervention). The Partner Registries must also be affiliated with either a Primary Registry in the WHO Registry Network or an ICMJE approved registry. The ICTRP Secretariat will not communicate directly with partner registries.
It is the responsibility of primary registries in the WHO registry network to ensure that their Partner Registries meet WHO registry criteria. Data are provided to WHO in the ICTRP search portal by data providers maintaining database of the registries. The data provider can be the same as the primary registry.
Datasets are updated on Wednesday evening-either every week (e.g., Australian New Zealand Clinical Trials Registry) or every 4th week (e.g., CTRI) for inclusion in the ICTRP search portal.
| The Trials Registry in India|| |
In India, there has been a delay by the biomedical researchers and stakeholders to recognise the importance of clinical trials registry. The CTRI is a primary registry, hosted at the ICMRs National Institute of Medical Statistics. It is a free and online public record system for registration of clinical trials being conducted in India, launched on 20th July, 2007, the first registry in Asia. The registration was voluntary initially but has been made mandatory by the Drugs Controller General of India (DCGI) from 15 June, 2009. Many biomedical journals in India have now taken the cue and insist on registration of trials for publication.
India is a favourite country for clinical trials because of the huge population; there were huge number of trials conducted between 2005 and 2009. During one of such trials related to human papilloma virus vaccination, deaths of thousands of volunteers were reported and investigations revealed irregularities in obtaining informed consent. Subsequent to this and after a related Supreme Court verdict, there was slowing down of clinical trial registration from pharmaceutical companies in India. The government has subsequently tweaked the rules related to the clinical trials registrations in India, and hence, the registrations are expected to pick up again. The current article will not go into details of legal and ethical issues of registrations and the nitty-gritty of the economics and market related to clinical trials in India.
| The Mission of Clinical Trials Registry of India|| |
CTRI aims to encourage all clinical trials conducted in India to be prospectively registered, that is, before the enrolment of the first participant (prospective registration); currently, trials where patient recruitment has started or even completed are also being registered (retrospective registration). Post-marketing surveillance studies as well as bioavailability/bioequivalence (BA/BE) trials are also expected to be registered in the CTRI. However, CTRI has announced that from 1 April, 2018, registration will be allowed only prospectively for clinical trials/studies that is, before the enrolment of the first patient [to mention as future tentative Date of First Enrolment (India) and Status is Not Yet Recruiting (India)]. CTRI also accepts registration of trials conducted in other countries in the region, which do not have a Primary Registry of their own.
It is not mandatory for observational studies to be registered but if submitted, they are registered. This is because some researchers may not be aware of the difference between observational studies and interventional studies. Furthermore, in some instances, the researchers are reported to have misunderstood and misinterpreted the observational trials as interventional trials.
Pitfalls of Retrospective Registrations: Preventing selective reporting and publication, duplication, etc., are the goals of registration; hence, retrospective registration does not have significant value. For the same reason, trials with non-trial designs such as observational studies are 'only encouraged' to be registered.
| What Are the Goals?|| |
CTRI aims to ensure that protocols and results of all registered trials are adequately reported and publicly available, enhancing public confidence in clinical trials. Further, the details sought and expected to be implemented by the researchers can improve the internal validity of trials [Table 2].
Applying these measures also increase the chances of publication in high impact journals that endorse the ICMJE requirement of reporting trials in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement.
Registration of trials will provide value addition to the evidence base. The CTRI also mandates including of Ethical Committee approval details for all clinical trials, so that the ICMR's bioethics initiative is promoted.
| Current Status of Registrations in Clinical Trials Registry of India|| |
The CTRI, as on 30 June, 2017, had 8950 trials registered, 3318 prospective and 5604, retrospective registrations [Figure 1]. On registration, all trials are flagged according to the status at the time of registration. Once a trial is registered, flagging cannot be changed.
|Figure 1: Trials registration trend in Clinical Trials Registry of India (Clinical Trials Registry of India Bulletin)|
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| What Are the Details to Be Entered in the Registry?|| |
The primary registries will accept prospective registration of interventional clinical trials submitted by Responsible Registrants and will be open to all prospective registrants, either internationally or within one or more specific countries: The registry is expected to be able to collect and publicly display the WHO trial registration data set with updates. A trial once registered shall not be removed.
The major components to be included in the registry as per ICTRP are:
- Public declaration and identification of trial investigators, sponsors, interventions, patient population, etc., Multi-country trials registered in an international registry, where India is a participating country, are also expected to be registered in the CTRI with details of Indian investigators, trial sites, Indian target sample size and date of enrolment
- Submission of Ethics approval and DCGI approval (if applicable)
- After registration, the trialists are expected to regularly update the trial status or other aspects, and they will be available for public display.
| The Clinical Trials Registry of India Data Set|| |
For a trial to be fully registered, the minimum amount of information to be entered in the register is provided under 24 items in the WHO trial registration data set ('TRDS'). A new version of the document 'International Standards for Clinical Trial Registries' is being drafted and will be published this year (2018); it will include the changes done to the TRDS. Meanwhile, ICTRP and the primary registries are working to implement those changes by the end of 2019.
The CTRI data set which have to be submitted are based on the WHO Data Set (Version 1.3-ICTRP) and are shown in the [Table 3].
| Unambiguous Trial Identification|| |
It is possible that clinical trials involve participants from more than one institution or more than one country. The trial would need to be registered in more than one registry and seen in more than one registry database, with different numbers. Furthermore, the data details may vary in each, with titles and amount of data being different. The ICTRP aims to provide clarity by allotting the universal trial number (UTN), ensuring compliance with the WHO registry criteria and by linking related records on the ICTRP search portal. The UTN is not a registration number but facilitates unambiguous identification of clinical trials. It has to be obtained early in the history of the trial. The UTN should become permanently attached to the trial and be part of trial identity; the number is used whenever information about the trial is communicated. Some UTNs are attached to trials, which do not progress at all and hence never appear attached to a registered trial.
| Linking Related Records on the International Clinical Trials Registry Platform Search Portal|| |
Many multinational, multicentre trials are registered in more than one registry across the world. The ICTRP Search Portal acts as the single point of access to information about such ongoing and completed clinical trials. The ICTRP Search Portal receives more than one record for those trials.
The unambiguous identification of trials is provided by the ICTRP Search Portal by bridging such multiple records of the same trial. This is made by matching main trial identifiers to secondary trial identifiers found in trial records. If group of records are present related to the same trial, a plus (+) sign is displayed in search results.
They can be retrieved by clicking on the (+) sign, with the earliest date of registration always displayed first.
| Delay in Trial Approval and Prevention?|| |
The trials submitted online to the CTRI are reviewed and queries are addressed to the applicant by email and are also available to the applicant after login. The time taken for this purpose should be factored when time frames for research are considered by authors. They are also expected to be expeditious in their response to queries, to minimise the time for the final approval.
It is possible for the applicants to submit for prospective trial registration before mandatory approvals are obtained. Review and revision can continue till the submission of the mandatory approvals. After submission of approvals, the trial is registered without much delay.
| The Role of International Committee of Medical Journal Editors in Clinical Trial Registration|| |
ICMJE states, 'all medical journal editors require, registration of clinical trials in a public trials registry at or before the time of first patient enrolment as a condition of consideration for publication'. Journals requesting listing in the ICMJE website shall enforce the ICMJE's trial registration policy along with other guidelines.
The ICMJE definition of a clinical trial is 'any research project that prospectively assigns people or a group of people to an intervention, with or without concurrent comparison or control groups, to study the cause-and-effect relationship between a health-related intervention and a health outcome'.
Instead of mention of first patient enrolment, the ICMJE mentions that registration starts by 'the time of first patient consent'.
The ICMJE accepts registration in any registry that is a primary register of the WHO-ICTRP or in ClinicalTrials.gov, which is also a data provider to the WHO-ICTRP. It states that an acceptable registry must include the minimum 20-item trial registration data set  at the time of registration and before enrolment of the first participant. The trial registrations are considered inadequate if any of the 20 data fields are missing or if the fields contain uninformative information. The ICMJE encourages authors (not mandatory) to include a statement indicating that the results have not yet been published in a peer-reviewed journal, and to undertake to update the registration with the full journal citation whenever the results are published.
The clinical trial results are encouraged to be added in registries, but this is not a clear requirement. The ICMJE does not insist on registration of observational studies (the CTRI encourages it but is not mandatory).
When the criteria of inclusion are met, posting of trial results in any registry is not considered as prior publication by ICMJE provided the results are limited to a brief structured abstract of about 500 words or tables with details of patients' enrolment, key outcomes and adverse events.
The ICMJE also states that secondary data analyses of primary (parent) clinical trials should not be registered as separate clinical trials, but instead should reference the trial registration number of the primary trial.
The ICMJE recommends journals to publish the trial registration number at the end of the abstract. The editors may decide if the failure to register a trial is intentional or unintentional. If there was a genuine reason for failure to register in time, the authors should publish a statement indicating why an exception was allowed. Such exceptions should be rare, and the journals should highlight the risk of inadmissibility of such submissions to the journals.
| The Guide to Users of Clinical Trials Registry of India|| |
The CTRI website provides tutorials and links on how to sign in as an applicant to the website and how to register a trial. The CTRI system, derived from ICTRP, is similar and the components are displayed serially after registration at the CTRI website. The trial registration data set [Table 3] and the description, with examples at each step, are available for free download.
Trial verification is done after registration; this consists of an e mail from CTRI to all contact persons mentioned in the trial registration form (except to the trial registrant). After everyone responds, the trial verification process is considered complete. The details of how to do a Trial Search are also available. Bulletins about the registry are uploaded periodically.
| Summary|| |
There is a potential for greater numbers of research and publications in India when the trend of the last decade is considered. The quality has varied from mediocre to the most brilliant; clinical trials registration is likely to boost the quality of research and publications. The Clinical Trials Registry of India has assumed greater responsibility to push for mandatory registrations of clinical trials, and it is for the researchers now to follow the regulations in letter and spirit for their greater good.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
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Central Drugs Standard Control Organization. Available from: http://www.cdsco.nic.in
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News and Events. International Clinical Trials Registry Platform (ICTRP). World Health Organization. Available from: http://www.who.int/ictrp/news/en/
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[Table 1], [Table 2], [Table 3]