No abstract
In a clinical trial registry, one determines whether a trial is registered prospectively or retrospectively by comparing the date of registration with the date on which enrollment started. However, in Clinical Trials Registry – India (CTRI), in addition, the top of each record is labelled with the phrase “Trial Registered Prospectively” or “Trial Registered Retrospectively”. In examining CTRI records, we have found that (a) although retrospective registration has been disallowed from April 1, 2018, some trials were registered retrospectively; (b) in some cases, enrollment started after registration, even though they were labelled “Trial Registered Retrospectively”, which is misleading; and (c) in some cases, the date of first enrollment was modified, changing a retrospective registration to a prospective one, although the label “Trial Registered Retrospectively” persisted. This, too, is misleading. The CTRI administration should take suitable steps to prevent late registration and mislabelling of trials regarding their registration status.
We wished to determine whether rare diseases patients from India had been enrolled in international trials to develop novel orphan drugs. There are two reasons to be interested in this. (a) Different ethnic or racial groups may respond differently to a particular drug. India has huge ethnic diversity, and to exclude such participants is to severely limit the diversity of any trial; (b) Even if a suitable drug for a rare disease is available in India, it may be astronomically priced, in a country where most healthcare expenditure is out-of-pocket. We identified 63 orphan drugs, approved by the US Food and Drug Administration (FDA) after 2008, for which there were 202 trials in the US government’s clinical trial registry, ClinicalTrials.gov. Only nine of these trials had run in India. These trials pertained to six drugs. The drugs were for the conditions B-cell Lymphoma, Chronic Myeloid Leukemia, Gaucher disease Type 1, Malaria, Myeloma and Pulmonary Arterial Hypertension. Further research is required as to why patients from India are not part of foreign drug development programmes for rare diseases. We then asked how many of the remaining 193 trials had recruited people of Indian origin, residing in other countries, and found that not more than 1% of these trials had done so. Also, only 11 of the 193 trials had recruited from other lower income countries. Participation from low-income countries in trials for orphan drugs is poor.
There is widespread agreement that clinical trials should be registered in a public registry, preferably before the trial commences. It is also important that details of each trial in the public record are complete and accurate. In this study, we examined the trial sites and ethics committee (EC) data for 1359 recent Phase 2 or Phase 3 interventional trials registered with Clinical Trials Registry–India (CTRI), to identify categories of problems that prevent the clear identification of which EC approved a given site. We created an SQLite database that hosted the relevant CTRI records, and queried this database, as needed. We identified two broad categories of problems: those pertaining to the understanding of an individual trial and those to adopting a data analytics approach for a large number of trials. Overall, about 30 problems were identified, such as an EC not being listed; an uninformative name of the EC that precluded its clear identification; ambiguity in which EC supervised a particular site; repetition of a site or an EC; the use of a given acronym for different organizations; site name not clearly listed, etc. The large number of problems with the data in the EC or site field creates a challenge to link particular sites with particular ECs, especially if a programme is used to find the matches. We make a few suggestions on how the situation could be improved. Most importantly, list the EC registration number for each EC, merge the site and EC tables so that it is clear which EC is linked to which site; and implement logic rules that would prevent a trial from being registered unless certain conditions were met. This will raise user confidence in CTRI EC data, and enable data based public policy and inferences. This will also contribute to increased transparency, and trust, in clinical trials, and their oversight, in India.
Clinical trial registries such as ClinicalTrials.gov (CTG) hold large amounts of data regarding trials. Drugs for rare diseases are known as orphan drugs (ODs), and it is particularly important that trials for ODs are registered, and the data in the trial record are accurate. However, there may be discrepancies between trial-related data that were the basis for the approval of a drug, as available from Food and Drug Administration (FDA) documents such as the Medical Review, and the data in CTG. We performed an audit of FDA-approved ODs, comparing trial-related data on phase, enrollment, and enrollment attribute (anticipated or actual) in such FDA documents and in CTG. The Medical Reviews of 63 ODs listed 422 trials. We used study identifiers in the Medical Reviews to find matches with the trial ID number, ‘Other ID’ or ‘Acronyms’ in CTG, and identified 202 trials that were registered with CTG. In comparing the phase data from the ‘Table of Clinical Studies’ of the Medical Review, with the data in CTG, there were exact matches in only 75% of the cases. The enrollment matched only in 70% of the cases, and the enrollment attribute in 91% of the cases. A similar trend was found for the sub-set of pivotal trials. Going forward, for all trials listed in a registry, it is important to provide the trial ID in the Medical Review. This will ensure that all trials that are the basis of a drug approval can be swiftly and unambiguously identified in CTG. Also, there continue to be discrepancies in trial data between FDA documents and CTG. Data in the trial records in CTG need to be updated when relevant.
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