Explained | What are the problems with India’s clinical trials registry?

The speedy approval of Covid-19 vaccines during the SARS-CoV-2 pandemic spotlighted the importance of clinical trials. Terms like “vaccine efficacy” and “clinical trial”, previously restricted to medical research circles, became a part of everyday language.

Despite their success, the haste with which some Covid-19 vaccine-related phases were cleared in India raised several questions regarding the transparency of the clinical trials and the safety and efficacy of the vaccines themselves.

One way to ensure a clinical trial is transparent is to make sure all information about it is freely accessible in the public domain. And that is what the Clinical Trials Registry-India (CTRI), where every trial is required to be registered before commencing does — or tries to.

What is the CTRI?

Hosted with the Indian Council of Medical Research’s National Institute of Medical Statistics, the CTRI is a free, online public-record system to register clinical trials being conducted in India. It was launched in July 2007 for use on a voluntary basis. In June 2009, the Drug Controller General of India (DCGI) mandated all trials to be registered there.

Any trial that uses human participants and is testing drugs, surgical procedures, preventive measures, lifestyle modifications to devices, educational and behavioural treatment, and rehabilitation strategies must be enrolled in the registry.

To register, the trial sponsor needs to make a public declaration, identify investigators, define participant selection criteria, seek the Drug Controller’s approval, and arrange to receive the approval of the ethics committees at the various trial sites.

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The CTRI is one of 17 public trial registries under the International Clinical Trials Registry Portal, along with being recognised as a primary registry by the World Health Organisation. In total, it recognises 18 registries with the registry of the U.S., ClinicalTrials.gov (CT.gov), which is recognised only as a data provider.

While India’s CTRI is recognised worldwide, it has a long way to go before being truly world-class, Gayatri Saberwal of the Institute of Bioinformatics and Applied Biotechnology, Bengaluru, wrote in an April 10 article for the journal Current Science.

According to her, there are a number of gaps to be filled with help from government agencies and cooperation from the trial sponsors. She also enumerates practices that have kept CTRI from becoming “world class”.

What are the problems with CTRI?

Missing data – A review of available data a few years ago showed that CTRI records of enrollment are inconsistent, with only 281 of 606 (46%) trials being updated after final enrollment.

Classification of type of study – For certain trials, it is important to know the nature of the intervention. CT.gov provides 11 distinct categories, but the CTRI provides a free text field to fill in the required information. This has resulted in over 1,000 categories within the registry, with many of them being atypical, Dr. Saberwal noted. Though this is an important field, the CTRI also marks it as ‘optional’, leading to a great number of trials not providing this information.

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Internal consistencies – Trials have also been known to have internal inconsistencies, such as filling the wrong type of trial.

Confusion over definitions – The article stated that a number of entries are inaccurate due to confusion over definitions. For example, some ‘interventional trials’ have been listed as ‘observational trials’ due to a “lack of understanding of the terms”.

Incomplete/non-standard information – Non-standardised information about cities may also cause confusion and repetition in the registry.

Variations in names and organisations – Registering the correct name of the principal investigator is crucial. Wrong spelling, use of abbreviations or different surnames can hinder the process of identifying this important individual.

Variations in the classification of organisations – CTRI provides the option to classify ‘primary sponsors’ under several categories, like contract research organisations, the pharmaceutical industry, and research institutions. However, it doesn’t have specific definitions for such categories.

For example, which category would a trialist choose for the Indian subsidiary of a multinational pharmaceutical company? Or an Indian pharmaceutical company that has gone global?

As a result, the All India Institute of Medical Sciences has been classified as a ‘government-funded agency’, a ‘government medical college’, a ‘research institution’, and a ‘research institution and hospital’.

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Messy data – Unclear data, such as the same acronym being used for two organisations, an acronym not being spelt out, a clinical trial site being listed twice with the same principal investigator, or a site being listed twice for two ECs, can lead to overlap and confusion.

Misleading information – Wrong data about whether a trial is registered prospectively or retrospectively can be classified as misleading information.

Along with this, hidden duplicates are created when a trial in India is registered with a foreign registry but the ID issued by that registry is not recorded on CTRI. This can create a bias in the data as it could be counted multiple times.

Finally, CTRI’s faulty search function has previously yielded incorrect results leading to misleading information, the report noted.

What are some solutions?

Dr. Saberwal in her article suggested ideas to help CTRI become better. Apart from clear and accurate recording of data, she said recommended adhering to WHO guidelines, registering trials accurately, and improving its inner workings for CTRI to be a more functional primary registry.

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Some trials do not follow the rules or may break the law – All clinical trials in India must be registered on CTRI in India, even if the trial is also registered elsewhere (e.g. CT.gov). But of a sample of 581 CT.gov trials, 50-300 such trials haven’t been registered on CTRI even though they have an India component.

Some trials that were meant to register prospectively from April 2018 have not done so.

While the CTRI doesn’t have the power to make a trialist register, the Central Drugs Standard Control Organisation (CDSCO), the regulator, can do so, but hasn’t.

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Complying with WHO regulations for primary registration – Adhering to the WHO requirements can make a big difference, per Dr. Saberwal. Currently, India ranks 11 out of 18 registries that provide information. CTRI could improve the amount of information each record provides, provide details of the audit trail, add a ‘Results’ field to the register, and implement a data-sharing plan, to name a few, she wrote.

Going beyond WHO requirements – Even before the WHO recommended it, CTRI had required its trialists to provide information about ethics committees when registering a trial. The CTRI should hold on to this tradition and go beyond the WHO’s requirements.

The article suggested certain steps like bringing together all the documentation on every trial on one platform in the interest of transparency.

It also suggested that the CDSCO allow public access to regulatory documents as it is well-known that there have been several inconsistencies between trial data in a registry and the publication of the study or U.S. Food and Drug Administration documents, the article noted.

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There may also be other discrepancies such as varying “efficacy end-points that harm outcomes in the protocol which the EC has approved versus those reported in the publication”.

Finally, the report suggested that the CDSCO could ensure trialists provide the necessary information for record-keeping by not clearing new applications until correct data is provided and even correcting older records.

Improving the functions of CTRI – Another way to improve CTRI is to make it a permanent activity with staff who can work on a five-year contract. Currently, the registry is a non-permanent activity of the ICMR with a ‘temporary’ staff of 15 years, the Dr. Saberwal said.

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