Facilitating audits of clinical trial data using documents of the Food and Drug Administration

The Medical Review document of the FDA is a rich source of data about clinical trials underlying the approval of a given drug. There are also other sources of information about clinical trials, such as trial registries and publications. However the data in the various sources may be erroneous or discrepant, and therefore there have been calls for audits of data in trial registries, in particular. The data in the Medical Review documents could be used as a source, to cross check data from other sources. However, it is extremely cumbersome to access the data in this document. We have analyzed the summary 'Table of Clinical Studies' of forty five Medical Reviews, and note significant differences in what information is presented in this table. We outline the details of an informative template Table, that would facilitate audits

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

IntroductionIn 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.MethodsWe 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.ResultsOur findings revealed substantial variations in the number and identity of sites and Principal Investigators between the permission letters and the CTRI records.DiscussionThese 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

Patents Protecting Biologics or Small Molecule Drugs are Litigated, not Others Awarded to Drug Discovery Companies

149-156Assuming that litigated patents are valuable, the incidence of litigation for patents protecting biologics (146 patents), small molecules (1822) or issued to drug-discovery companies per se (1929) was examined. This was done by accessing the litigation database of the company MaxVal Group Inc. (20%) of those protecting biologics, 40% protecting small molecules and 1% of those issued to the companies were litigated (although only 0.3% of those issued to companies that do not protect biologics or small molecules). The average time between the grant of a patent and its first litigation was 15.7, 7.8 and 2.7 (2.0) years respectively. Thus, the relevant patents of this study were litigated much later than the average litigated patent. Each litigated patent was litigated 1.7, 5.6 and 2.4 (1.0) times respectively. In each category, most litigants were companies, with very few litigations involving academic institutions or the USPTO, and no non-profit organizations. These results should be of interest to drug-discovery companies, to those who fund or acquire such companies and to non-profit drug-discovery centres

A synthetic peptide corresponding to the hydrophobic amino terminal region of pardaxin can perturb model membranes of phosphatidyl choline and serine

Peptides corresponding to the amino terminal region of pardaxin from Pardachirus pavoninus (Gly---Phe---Phe---Ala---Leu---Ile---Pro---Lys---Ile---Ile---Ser---Ser---Pro---Leu ---Phe) have been synthesized and their interaction with model membranes of phosphatidyl choline and serine studied by 90°C light scattering and fluorescence spectroscopy. The amino terminal 8-residue peptide and the protected 15-residue peptide cause only aggregation of lipid vesicles. The deprotected 15-residue peptide has the ability to cause aggregation and release of entrapped carboxyfluorescein with both phosphatidyl choline and serine lipid vesicles, like pardaxin. The membrane-perturbing ability of the amino terminal 15-residue peptide can be attributed to its ability to adopt an a-helical conformation which is amphiphilic in nature in a hydrophobic environment

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

BackgroundThis 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.MethodsWe 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.ConclusionsThis 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

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

CTRI numbers of sample trials registered with the Indian registry CTRI, and the URLs at which they are available.

CTRI numbers of sample trials registered with the Indian registry CTRI, and the URLs at which they are available.</p