Three levels of discrepancies in the records of trial sites in India, registered with the European Union Clinical Trials Register.

Introduction: Clinical trial registries serve a key role in tracking the trial enterprise. We are interested in the record of trials sites in India. In this study, we focused on the European Union Clinical Trial Registry (EUCTR). This registry is complex because a given study may have records from multiple countries in the EU, and therefore a given study ID may be represented by multiple records. We wished to determine what steps are required to identify the studies that list sites in India that are registered with EUCTR. Methods: We used two methodologies. Methodology A involved downloading the EUCTR database and querying it. Methodology B used the search function on the registry website. Results: Discrepant information, on whether or not a given study listed a site in India, was identified at three levels: (i) the methodology of examining the database; (ii) the multiple records of a given study ID; and (iii) the multiple fields within a given record. In each of these situations, there was no basis to resolve the discrepancy, one way or another. Discussion: This work contributes to methodologies for more accurate searches of trial registries. It also adds to the efforts of those seeking transparency in trial data.

Data from the Indian drug regulator and from Clinical Trials Registry-India does not always match.

Introduction: In India, regulatory trials, which require the drug regulator's permission, must be registered with the Clinical Trials Registry-India (CTRI) as of 19 March 2019. In this study, for about 300 trials, we aimed to identify the CTRI record that matched the trial for which the regulator had given permission. After identifying 'true pairs', our goal was to determine whether the sites and Principal Investigators mentioned in the permission letter were the same as those mentioned in the CTRI record. Methods: We developed a methodology to compare the regulator's permission letters with CTRI records. We manually validated 151 true pairs by comparing the titles, the drug interventions, and the indications. We then examined discrepancies in their trial sites and Principal Investigators. Results: Our findings revealed substantial variations in the number and identity of sites and Principal Investigators between the permission letters and the CTRI records. Discussion: These discrepancies raise concerns about the accuracy and transparency of regulatory trials in India. We recommend easier data extraction from regulatory documents, cross-referencing regulatory documents and CTRI records, making public the changes to approval letters, and enforcing oversight by Institutional Ethics Committees for site additions or deletions. These steps will increase transparency around regulatory trials running in India.

In Clinical Trials Registry-India, the classification of sponsors needs to be standardised.

BACKGROUND: In recent years, there has been a big push to register trials, but there are a number of problems with the data in public clinical trial registries. Here, we describe a cross-sectional study of the classification of the primary sponsors of all Phase 2, Phase 2/3, and Phase 3 interventional trials registered with the Clinical Trials Registry-India between May 15, 2016 and May 14, 2021. METHODS: Data was scraped from the records of CTRI, various filters were applied, and the trials of interest identified. RESULTS: Of 5,453 trials, 105 did not identify a sponsor and 1,080 were sponsored by individuals. Of the remaining 4,268 trials, 427 had unique sponsors, and 3,841 had a total of 350 non-unique sponsors. Of the 350 sponsors, 202 were classified in a single category, and 147 were classified in two or more categories. Overall, of the 3,841 trials, sponsors in 3,537 (92.1%) were classified in one or more of nine well-defined categories, and 304 (7.9%) were classified as various versions of "Other". Three major problems with the sponsor data were identified: each trial does not necessarily list a sponsor, a given sponsor may be categorised in multiple ways, and there has been an excessive use of the "Other" category. Addressing these problems will enable automated analyses of the database, and improve the transparency of the data. CONCLUSION: Our study generates evidence highlighting the need to improve the trial registration system in India, and perhaps elsewhere.

Representation from India in multinational, interventional, phase 2 or 3 trials registered in Clinical Trials Registry-India: A cross-sectional study.

In multinational trials that have run in India, we wished to determine whether there was too much (60% or higher) recruitment from India. We downloaded all trial records from Clinical Trials Registry-India, CTRI, and stored them in a local SQLite database. We queried records registered in a recent 8-year period, ie 2013-2020 and evaluated the fraction of local participants in interventional Phase 2 or Phase 3 studies. 62 trials were completed, with completion dates available. Five trials (8%) had 60% or more planned recruitment from India. Four of the five (7% of 62) had a foreign sponsor, and therefore there was an unfair burden-benefit ratio on the Indian population. Seven trials (11%), of which six (10% of 62) had foreign sponsors, had 60% or more (of the total) actual recruitment from India, and for two trials (both with foreign sponsors), the data were meaningless. There were 362 studies that were listed as not completed, although, given their start date and estimated duration, some of them ought to have been. Twenty five cases (7% of 362) had 60% or more planned recruitment from India. Of these, 18 (5% of 362) had foreign sponsors and were potentially problematic. Even allowing for some delays in completion, 128 (35% of 362) studies ought to have been completed by the time of our study. As such, we identified several problematic trials for which the planned recruitment from India in multinational studies was 60% or more. We also identified trials in which the actual recruitment was significantly higher than the planned recruitment. Further, the records of several studies that were probably completed were not updated in CTRI in a timely manner. The Indian drug regulator needs to be particularly alert to the planned, or actual, over-recruitment of participants from India. Further, CTRI, alone or in collaboration with the regulator, needs to ensure that multinational trial records for the enrollment fields in particular are updated, in a timely manner.

Ethnic representation in interventional clinical trials run in India.

Globally, the need to enhance the diversity of trial participants is receiving increasingly urgent attention. We wanted to know whether trials run in India had adequately sampled the country's enormous ethnic diversity. We accessed the Clinical Trials Registry-India website to determine whether each interventional drug or biologic Phase 2 or 3 study, registered in a recent five-year period had run in each of six geographic zones. As regards Phase 3 trials conducted only in India, 61.4% ran in a single zone and just 6.8% were conducted in all six zones. Multinational Phase 3 trials had a better distribution since 3.6% had run in just one zone and 7.1% in all six. India's diverse ethnic groups are underrepresented in the majority of trials covered in this study. A trial that is conducted on non-representative groups and later discovered to be harmful or ineffective in parts of the population, is unethical. We propose various remedial steps.

The need for a new keyword - "Trial registry-metaresearch" - to track certain uses of clinical trial registry records.

Public clinical trial registries contain a large amount of information about a large number of trials. Academic researchers have conducted various analyses using such data. However, some of these studies do not concern the medical condition or intervention that is the focus of each trial. We list examples of publications that have performed such analyses. Currently, there is no keyword to track relevant publications. Here, we propose a novel keyword, "Trial registry-metaresearch", that could be used in such publications. This would be a great help to researchers who wish to more systematically search the literature for such metaresearch.

CTRI requirement of prospective trial registration: Not always consistent.

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.

Discrepancies between FDA documents and ClinicalTrials.gov for Orphan Drug-related clinical trial data.

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.

An analysis of deficiencies in the ethics committee data of certain interventional trials registered with the Clinical Trials Registry-India.

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.

Rare disease patients in India are rarely involved in international orphan drug trials.

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.

A comparative analysis of important public clinical trial registries, and a proposal for an interim ideal one.

BACKGROUND: It is an ethical and scientific obligation to register each clinical trial, and report its results, accurately, comprehensively and on time. The WHO recognizes 17 public registries as Primary Registries, and has also introduced a set of minimal standards in the International Standards for Clinical Trial Registries (ISCTR) that primary registries need to implement. These standards are categorized into nine sections-Content, Quality and Validity, Accessibility, Unambiguous Identification, Technical Capacity, Administration and Governance, the Trial Registration Data Set (TRDS), Partner registries and Data Interchange Standards. This study compared the WHO's primary registries, and the US's ClinicalTrials.gov, to examine the implementation of ISCTR, with the aim of defining features of an interim ideal registry. METHODS AND FINDINGS: The websites of the 18 registries were evaluated for 14 features that map to one or more of the nine sections of ISCTR, and assigned scores for their variations of these features. The assessed features include the nature of the content; the number and nature of fields to conduct a search; data download formats; the nature of the audit trail; the health condition category; the documentation available on a registry website; etc. The registries received scores for their particular variation of a given feature based on a scoring rationale devised for each individual feature analysed. Overall, the registries received between 27% and 80% of the maximum score of 94. The results from our analysis were used to define a set of features of an interim ideal registry. CONCLUSIONS: To the best of our knowledge, this is the first study to quantify the widely divergent quality of the primary registries' compliance with the ISCTR. Even with this limited assessment, it is clear that some of the registries have much work to do, although even a few improvements would significantly improve them.

Hidden duplicates: 10s or 100s of Indian trials, registered with ClinicalTrials.gov, have not been registered in India, as required by law.

BACKGROUND: This study's primary goal was based on the fact that since 15 June 2009 it has been mandatory to register regulatory trials running in India with Clinical Trials Registry-India (CTRI). Were all such trials, registered with ClinicalTrials.gov (CTG) after 2009, that included India as a location, also registered with CTRI? We first had to determine how to correctly identify a trial that was registered in both the registries, but that lacked the relevant secondary ID. Therefore the secondary goal of this study was to identify the best method to do this. METHODS: We used a control set of 1013 trials that cross-referenced a record in the other registry. We used two algorithms to-in a blinded fashion-identify CTRI matches for the 1013 CTG records. 80% of the predictions were correct. Using the same methodology, we identified matches for the CTG trials without known CTRI matches. We then used a logistic regression model to predict which of these matches were correct. RESULTS: (i) 3664 CTG records listed India as a location, but did not list any CTRI ID, and were not identified by any CTRI records either. (ii) The best single field to find a CTRI match for a CTG trial was the title field. (iii) Between 50 and 300 of 581 relevant CTG trials were not registered with CTRI. CONCLUSIONS: This is the first study to use hidden duplicates to determine that the law on trial registration has been broken (in India). Similar studies need to be done for trials run in other countries.

The work, goals, challenges, achievements, and recommendations of orphan medicinal product organizations in India: an interview-based study.

BACKGROUND: Orphan medicinal products (OMPs) are intended for the diagnosis, prevention, management or treatment of rare diseases (RDs). Each RD affects only a small fraction of the population, and therefore, historically, industry hesitated to undertake relevant research and development (R&D). In response, the governments of many countries came up with orphan drug policies and RD policies which were hugely successful in incentivizing companies to do so. In India, in the absence of any such policy until recently, there are very few organizations involved in RD R&D. OBJECTIVES: We wished to understand (i) the OMP Organizations' (OMPOs') areas of work and the nature of their work, (ii) their goals, (iii) the challenges they faced and how they were overcoming them, (iv) their achievements, and (v) their recommendations to the government to help their R&D, their success as commercial entities (where applicable), and patients' access to their products or services. RESULTS: Ten of the 14 OMPOs are companies, whereas four are not-for-profit organizations. Almost all of the OMPOs are heavily into R&D. Six have already made their products or services available to patients. Four plan to out-license their products after the pre-clinical phase or phase 1 trials, eight plan to cater to patients directly and two of the OMPOs have been established only recently and thus do not yet have any product or service to offer patients. Nine OMPOs import about 90% of the components in the production process, which comprises either capital or recurrent expenditure. For most, locally manufactured alternatives are not available or are of inadequate quality. Most of the OMPOs have had productive collaborations with local or foreign academics or hospitals for R&D, animal efficacy studies, clinical trials or providing services to patients. The main challenges for the OMPOs are the lack of adequate funding, supportive government policies, and a conducive ecosystem. CONCLUSIONS: These OMPOs are pioneers in their respective fields in India, and despite the challenges, have achieved new levels of innovation. With suitable government policies, they could scale up and provide relevant products and services to the large number of RD patients in the country whose medical needs are largely unmet.

An analysis of deficiencies in the data of interventional drug trials registered with Clinical Trials Registry - India.

BACKGROUND: Clinical Trials Registry - India (CTRI) was established in July 2007 and today hosts thousands of trials, a significant fraction of them registered in the last couple of years. We wished to undertake an up-to-date analysis of specific fields of the registered trials. In doing so we discovered problems with the quality of the data, which we describe in this paper. METHODS: We downloaded CTRI records and reformatted the data into an SQLite database, which we then queried. We also accessed ClinicalTrials.gov records as needed. RESULTS: We discovered various categories of problems with the data in the CTRI database, including (1) a lack of clarity in the classification of Types of Study, (2) internal inconsistencies, (3) incomplete or non-standard information, (4) missing data, (5) variations in names or classification, and (6) incomplete or incorrect details of ethics committees. For most of these problems, error rates have been calculated, over time. Most were found to be in single digits, although others were significantly higher. We suggest how data quality in future editions of CTRI could be improved, including (1) a more elaborate and structured way of classifying the Type of Study, (2) the use of logic rules to prevent internal inconsistencies, (3) less use of free text fields and greater use of drop-down menus, (4) more fields to be made compulsory, (5) the pre-registration of individuals' and organizations' names and their subsequent selection from drop-down menus while registering a trial, and (6) more information about each ethics committee, including (a) its address and (b) linking the name of the trial site to the relevant ethics committee. As we discuss problems with the data of specific fields, we also examine - where possible - the quality of the data in the corresponding fields in ClinicalTrials.gov, the largest clinical trial registry in the world. CONCLUSIONS: It is a scientific and ethical obligation to correctly record all information pertaining to each trial run in India. CTRI is a valuable database that has proved its worth in terms of improving the record of trials in the country. The suggestions made herein would improve it further.

Some data quality issues at ClinicalTrials.gov.

BACKGROUND: Clinical trial registries have been established as a form of public accountability. Sponsors ought to register their trials promptly and accurately, but this is not always done. Some of the problems include non-registration of trials, registration of trials with incomplete information, and non-reporting of trial results on time. In this study we enumerate or quantify some quality issues with respect to Principal Investigator (PI) and Responsible Party data. METHODS: We analyzed interventional trials registered with ClinicalTrials.gov. Using certain selection criteria, we started with 112,013 records, and then applied further filters. The trial had to (a) start between 1 January 2005 and 31 December 2014, (b) include a "drug" or "biological" in the "intervention" field, (c) be registered with an American authority, and (d) list a real person's name as investigator and also his or her role in the study. RESULTS: We identified four categories of errors in the ClinicalTrials.gov records. First, some data were missing. The name of the investigator, or his or her role, was missing in 12% of 35,121 trials. In examining 71,359 pairs of names and roles, 17% of the "names" were found to be not those of real persons, but instead junk information. Second, there were variations in a large number of names. We identified 19 categories of variants. We determined that 13% of the names had variants that could not be resolved using a program. Third, some trials listed many PIs each, although only one such person holds overall responsibility for the trial and therefore not more than one person should be listed as PI. Fourth, in examining whether the PI's name was available as part of the Responsible Party tag, we found that in 1221 (3.5%) of 35,121 trials, the Responsible Party tag is absent. CONCLUSIONS: We have outlined four categories of problems with data hosted by ClinicalTrials.gov and have quantified three of them. We also suggest how these errors could be prevented in future. It is important to carry out various kinds of audits of trial registries, in order to identify lacunae in the records, that they be addressed.

The role of patient organizations in the rare disease ecosystem in India: an interview based study.

BACKGROUND: Rare diseases (RDs) affect a small percentage of the population but can be severely debilitating and life-threatening. Historically, patient groups (PGs) have been the prime movers in raising awareness about these diseases and advocating for national supportive policies. They have also driven relevant research programs. In India too, PGs have made significant contributions to the national RD ecosystem. OBJECTIVE: To assess the contribution of various Indian RD PGs, we carried out an interview-based study of 19organizations. This study aims to highlight the origins and achievements of these groups and the challenges that they have faced. The study also helps to capture the changes in the RD ecosystem that have taken place in recent years. RESULT: Of the 19 PGs, two are umbrella organizations, two are other organizations of national scope and 15 are disease specific groups. 14 interviewees were affected by an RD either directly or through a family member. Lack of awareness about RDs in the medical community was the biggest challenge, leading to a delay in diagnosis and subsequent management. Only two out of the 15 conditions have a definitive treatment. However, many of the diseases can be managed with replacement therapies administered for the patient's entire life, or other supportive therapies. Most diagnostics and treatment regimens that are available globally are now available in India but are expensive and usually available only in a few major cities. These problems are compounded by a lack of medical insurance schemes and government policies to support these patients. The biggest achievement of the PGs was the passing of National Policy for Treatment of Rare Diseases in 2017, unfortunately since put in abeyance. If reinstated, and properly implemented, this policy could significantly improve RD management in the country. CONCLUSION: PGs have had a significant role in bringing diagnostics and treatments to India. They have also raised awareness about RDs and related issues such as newborn screening, prenatal diagnostics and genetic counselling. This study highlighted the recommendations of various PGs. The government should address these recommendations and institutionalize the participation of the PGs in formal decision making.

An Analysis of Sponsors/Collaborators of 69,160 Drug Trials Registered with ClinicalTrials.gov.

BACKGROUND: Clinical trials have been criticized on various counts. Any attempt to improve how trials are conducted or reported requires--amongst other things--an understanding of the number, the nature and the location of those that sponsor them or collaborate on them. Here we sought to identify the nature and location of each sponsor/collaborator. METHODS AND FINDINGS: We examined the 'sponsor/collaborator' field for the 69,160 drug trials that were registered with ClinicalTrials.gov over a 9-year period (2005-2014). Of the 12,823 unique sponsors, 56% had sponsored only one and 27% had sponsored 2-5 trials each. Just 18% were involved with six or more trials each, and we have (arbitrarily) labeled these organizations as 'more experienced' in sponsoring/collaborating on trials. These 18% (2,266 sponsors/collaborators) were analyzed further: (a) 951 were corporate organizations and (b) 1,145 were non-corporates (including 31 individuals) with (c) 170 unclassified. Further, we identified the location of each organization in (a) and (b). CONCLUSIONS: Clinical trials are an important part of a nation's research endeavors, and ultimately contribute to the health of its people. Thus, understanding the clinical trial landscape--including the number and nature of sponsors, and how active they are--is important for every country. We believe that policy makers in particular should be interested in this study to understand the current situation, and to use the numbers as a baseline for the evolving landscape, to assess the impact of their strategies in future.