|Year : 2017 | Volume
| Issue : 1 | Page : 9-15
Analysis of ayurvedic clinical trials registered in clinical trials registry of india: retrospective versus prospective registration
Pravin M Bolshete
Assistant Manager, Scientific Writing and Medical Communications, Tata Consultancy Services, Thane, Maharashtra, India
|Date of Web Publication||13-Jul-2018|
Pravin M Bolshete
Priyanka CHS, Sector–9, Airoli, Navi Mumbai
Source of Support: None, Conflict of Interest: None
Context: Registration of clinical trials is recommended at or before the first participant enrolment. There is limited data available on the registration of Ayurvedic clinical trials in Clinical Trials Registry of India (CTRI). Aim: The aim of this analysis was to determine the proportion of retrospectively and prospectively registered Ayurvedic clinical trials in CTRI. Methods: This was a cross-sectional analysis of Ayurvedic clinical trials registered in CTRI. List of trials registered in CTRI was accessed from 2012 to 2016 (n= 4713; last accessed on 21 June 2016) and screened to identify Ayurvedic trials. Other AYUSH trials were excluded from the analysis. Following data was collected - registration type (retrospective/prospective), study site (state), postgraduate thesis (yes/no), type of trial (interventional/observational), and study design. Data was summarized using summary statistics. Results: A total of 507 (10.8%) Ayurvedic trials were included in this analysis. The registration of Ayurvedic clinical trials increased from 9.3% (2012) to 19.9% (2016). Of 507 trials, 373 (73.6%) were registered retrospectively and remaining 134 (26.4%) were registered prospectively. A total of 277 trials were part of postgraduate theses (220 retrospective; 57 prospective) and 229 were not (152 retrospective; 77 prospective); 481 trials were interventional (357 retrospective; 124 prospective); 320 were randomized (236 retrospective; 84 prospective). The 507 trials had 686 sites, highest being in Gujarat (38.3%), followed by Maharashtra (19.2%), and Karnataka (10.1%). Conclusions: Results from this study showed that majority of Ayurvedic clinical trials have been registered retrospectively, however there is increase in prospective registration. More than half of the study sites of CTRI registered trials were located in Gujarat, Maharashtra and Karnataka reflecting limited registration in other parts of India.
Keywords: Complementary and alternative medicine, ethics, International Clinical Trials Registry Platform, International Committee of Medical Journal Editors, publication bias
|How to cite this article:|
Bolshete PM. Analysis of ayurvedic clinical trials registered in clinical trials registry of india: retrospective versus prospective registration. Ancient Sci Life 2017;37:9-15
| Introduction|| |
According to World Health Organization's International Clinical Trials Registry Platform (WHO-ICTRP) it is considered to be a scientific, ethical and moral responsibility to register all interventional trials to support evidence based medicine (EBM) by ensuring all of the data is available to arrive at informed decisions. If the existing literature contains publication bias it would be difficult to take informed decisions for the benefit of patients and society. Registration of clinical trials is considered to reduce the publication bias by reducing selective publication of only positive outcomes., Worldwide a need has been felt to improve the transparency, accountability and accessibility of clinical trial data to build public trust by registering all clinical trials in a centralized platform before of the enrolment of the first participant.
The Declaration of Helsinki states that “every clinical trial must be registered in a publicly accessible database before recruitment of the first subject”. It also states “negative and inconclusive as well as positive results must be published or otherwise made publicly available”. The International Committee of Medical Journal Editors (ICMJE) requires and recommends registration of clinical trials in a public trials registry at or before the time of first patient enrolment and expects journals that endorse ICMJE to enforce ICMJE's trial registration policy. The ICMJE recommends that registration of clinical trials in any registry be done in a primary register of the WHO-ICTRP or in Clinicaltrials.gov.
The Clinical Trials Registry of India (CTRI) is among the primary registries of WHO-ICTRP. The CTRI was launched on July 20, 2007 for the registration of clinical trials being conducted in India and since June 15, 2009, the Drugs Controller General (India) (DCGI) has made it mandatory to register clinical trials in the CTRI (www.ctri.nic.in). Post-marketing surveillance studies, bioavailability/bioequivalence (BA/BE) trials and clinical trials conducted in the purview of Department of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy (AYUSH) are also expected to be registered in CTRI before enrolment of the first study participant. The CTRI recommends to register clinical trials before the enrolment of the first study participant, however currently it also accepts trials where patient recruitment has started or even completed (retrospective registration). Though CTRI accepts retrospective registration only prospective registered trials are linked with WHO-ICTRP. Prospective registration of clinical trials prevents selective reporting or changing of primary outcomes and selective publication, avoid duplication of efforts helping researchers, funders and ethics committees, and helps during peer review to understand the context of study results.,,
There is limited data available on the registration of Ayurvedic clinical trials in CTRI., The present paper reports the analysis of Ayurvedic clinical trials registered in CTRI. The primary objective of this analysis was to determine the proportion of retrospectively and prospectively registered Ayurvedic clinical trials. Additionally, to assess the time of first participant enrolment from the date of registration and to assess the distribution of study sites across India.
| Methods|| |
This was a cross-sectional analysis of Ayurvedic clinical trials registered on CTRI. The lists of clinical trials registered on CTRI registry were downloaded from 2012 to 2016 on 21 June 2016 using search terms 'CTRI/YYYY' (e.g., 'CTRI/2012' for trials registered in 2012). Ayurvedic clinical trials were searched and populated in a spreadsheet for further data collection. Ayurvedic clinical trials were identified based on categorization presented in 'type of study', or were identified based on Ayurvedic medicines or formulations mentioned in the title or intervention section. Herbal studies conducted in Ayurvedic medical colleges or hospitals were also considered as Ayurvedic trials. Other AYUSH trials were excluded from the analysis.
Following data was collected from each Ayurvedic clinical trial to note whether it is registered retrospectively or prospectively (registration type), interventional or observational (type of trial), and whether a postgraduate thesis or not. Additionally, study design, phase of the trial, type of primary sponsor, health condition of study participants (patients or healthy volunteers) and dates of trial registration and date of first enrolment were also noted. Details of each study site were also noted. Type of primary sponsors were reported using different terms. For ease of analysis, primary sponsors were categorized as: research institutions and hospitals, industry, government agencies, self/investigator, and other. For studies that reported sponsors as 'others' but mentioned the details of sponsors, were counted in a particular category of primary sponsor.
Data was summarized using summary statistics and figures as appropriate. As the data was available in public domain it was deemed not necessary to have ethics committee approval.
| Results|| |
Overall, 4713 clinical trials that were registered on CTRI from 2012 to June 21, 2016 (2016, n= 554; 2015, n= 1130; 2014, n= 1077; 2013, n= 992; and 2012, n= 960). Of these, 507 (10.8%) clinical trials were Ayurvedic studies. The registration of Ayurvedic clinical trials increased from 9.3% (2012) to 19.9% (2016), however in 2013 and 2014 these numbers were slightly lower (7.0% and 8.2%, respectively) [Table 1]. Overall, 54.6% of studies were postgraduate thesis, 94.9% of studies were interventional, 89.2% of studies involved patients, 63.1% were randomized studies and 28.6% were single arm studies. Majority of studies were sponsored by research institutions and hospitals (66.7%) followed by industry (19.5%), and government agencies (7.9%). Phase II studies were highest (30.6%), however, for 22.7% of clinical trials, phase was stated as 'not applicable' [Table 1].
|Table 1: Summary of Ayurvedic clinical trials registered in clinical trials registry - India|
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Overall, 73.6% of studies were registered retrospectively and 26.4% registered prospectively. The prospective registration of Ayurvedic clinical trials increased from 6.7% in 2012 to 44.5% in 2016 with slight decrease in 2015 [Figure 1]. Of the studies that were postgraduate theses, 79.1% were registered retrospectively and the rest (20.9%) registered prospectively. Highest number of prospectively registered postgraduate theses were registered in 2016 (48.5%) and lowest in 2012 (2.6%) [Figure 2]a.
|Figure 1: Overall retrospective versus prospective registration of Ayurvedic trials|
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|Figure 2: Retrospective versus prospective registration among subgroups. Numbers presented on each bar represents number of studies. (a) Type of study: post-marketing surveillance studies (n = 6: in which retrospective, n = 2; prospective, n = 4), bioavailability/bioequivalence (n = 1, prospective). (b) Study design: Nonrandomized studies (n = 16: in which retrospective, n = 13; prospective, n = 3), Other studies (n = 26: in which retrospective, n = 18; prospective, n = 8). (c) One study from 2013 enrolled both patients and healthy volunteers was registered retrospectively|
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When assessed based on study design, 73.4% of randomized clinical trials and 71.7% of single arm studies were registered retrospectively [Figure 2]b. Overall, 73.6% of interventional clinical trials and 73.7% of interventional studies were registered retrospectively [Figure 2]c. Among studies that included patients, 73.0% of studies were registered retrospectively [Figure 2]d.
Among studies sponsored by research institutions and hospitals, industry, and government agencies and registered retrospectively, the numbers were 73.4%, 69.5%, and 85.0% respectively. Among self/investigator sponsored studies, 78.6% were retrospectively registered [Figure 2]e.
[Figure 3] shows the first participant enrolment in the trial from the date of registration. Among retrospectively registered studies, 16 studies enrolled their first participant more than 5 years before the registration of trial (2012, n= 4; 2013, n= 2; 2014, n= 2; 2015, n= 7; and 2016, n= 1), 29 studies enrolled their first participant between 2 to 5 years before the registration (2012, n= 4; 2013, n= 3; 2014, n= 4; 2015, n= 11; and 2016, n= 7), 100 studies enrolled their first participant between 1 to 2 years before the registration (2012, n= 22; 2013, n= 14; 2014, n= 15; 2015, n= 29; and 2016, n= 20), and 225 studies enrolled their first participant within years before the registration of trial (2012, n= 52; 2013, n= 42; 2014, n= 34; 2015, n= 65; and 2016, n= 32). There were 21 studies that enrolled their first participant before 2010. The median (range) time to first participant enrolment in the trial from the date of registration was increased from 272 days (2012) to 360 days (2016).
|Figure 3: Days of registration from the day of enrolment of first study participant. Zero is the time of registration. Each data point is the day of enrolment of first study participant in the trial. (Figure 3a-e = Year 2012 to 2016)|
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Overall, these 507 studies had 686 study sites, of which the highest number were located in Gujarat (38.3%), followed by Maharashtra (19.2%). The proportion of studies registered in Gujarat increased from 20.5% (2012) to 57.7% (2016) [Table 2].
| Discussion|| |
The present analysis was conducted to assess the Ayurvedic clinical trials registration practices (retrospective versus prospective registration) among clinical trials registered in CTRI. Results from this analysis showed that among 507 registered Ayurvedic trials, more than 70% of trials were registered retrospectively. However, we observed a growing trend in prospective registration of Ayurvedic trials with a 6-fold increase from 2012 to 2016. The increasing trend in prospective registration was almost similar across subgroups. However, the trend was slightly decreasing among studies that were not PG theses, single-arm and industry sponsored. This could be one of the cause of concern indicating registration of clinical trials with positive outcomes. Overall, although the registered Ayurvedic trials accounted for only one tenth of the total trials registered in CTRI, there was 2-fold increase in registration of Ayurvedic clinical trials from 2012 to 2016. It was observed that there was a growing awareness about registration, though many studies were registered retrospectively. The registration could have been done as a mandate for publication, but the situation may be improved in the future with this growing awareness, that research involving human volunteers may not be published without registration. It is also possible that there were more studies in Ayurveda but were not registered due to lack of awareness regarding registration mandate made by the DCGI, or due to fear of negative results.
There are few analyses which have evaluated clinical trials registered in trial registries.,,,,,,,,, Of these, three reports included Ayurvedic trials.,, Kannan and Gowri  which evaluated registered clinical trials in allied medical fields from WHO-ICTRP, reported that only 10 Ayurvedic trials were registered in WHO-ICTRP. In another study, which evaluated CTRI using search team 'Ayurveda' obtained 208 Ayurvedic trials (2010, n= 3; 2011, n= 35; 2012, n= 52; 2013, n= 71; 2014, n= 35; 2015, n= 12). In the present study more number of Ayurvedic clinical trials were located. This difference could be possibly due to the use of term 'Ayurveda' in the previous study, which could have excluded studies that did not use term 'Ayurveda'. In the previous study, 80% of studies were registered retrospectively, 62% of studies were randomized controlled design, 4.3% were observational studies. In 94.2% studies, participants were patients and 41.8% were phase II studies. In the present study, almost similar proportions were observed except for phase II studies (30.6%).
In another study by Yadav et al., all clinical trials registered in CTRI up to December 2009 (n= 588) were assessed for reporting of various parameters such as methodological, ethical considerations, and disease burden. They report that of these, 21 (3.57%) were Ayurvedic/herbal trials. Chawan et al., analysed the total number of clinical trials registered under CTRI from 2007 to 2015, however no further analysis was conducted. The numbers reported from 2012 to 2015 were slightly different (2012, n= 959; 2013, n= 990; 2014, n= 1089; 2015, n= 1113) from total numbers observed in the present study. However, the reasons for this difference is not known. A study by Bhave and Tondare  analysed trials registered in CTRI that had completed (n= 370) recruitment in 2013 and showed that 88% trials were registered retrospectively and remaining 12% were registered prospectively. Another study published by Bhide et al., assessed CTRI from 2007 to 2016 but located different number of studies (2012, n= 960; 2013, n= 992; 2014, n= 1077; 2015, n= 1128). However, none of these studies analysed Ayurvedic clinical trials.
There is evidence that publication rates among completed trials registered in other registries were low and this demonstrates selective reporting and delay in publication.,,,,, A study by Lampert et al., which assessed the public availability of results of phase 3 clinical trials that evaluated treatments of seizures in children and adolescents, concluded that even ten years after the ICMJE's clinical trials registration initiative there exists selective reporting and delay in publication. In the present study we did not assess the published literature for clinical trials registered in CTRI, particularly for Ayurvedic trials. Furthermore, currently trial results are not posted on CTRI website. Further research would be needed in this area to confirm the publication of completed Ayurvedic trials.
In the present study, two-thirds of Ayurvedic trials were registered retrospectively. Possible reasons could include lack of awareness of prospective registration, fear of negative results, or positive outcomes but journals requirements for registration details for publication of these results. Such high number of retrospective registration demonstrates selective registration and does not serve the purpose of trial registration: prevent selective reporting, prevent selective publication, and avoid duplication of research effort. The CTRI accepts trials for registration where patient enrolment has started or even completed. The retrospective registration can be justifiable for trials that started before DCGI mandated the trial registration. However for trials that started patient enrolment after DCGI's registration mandate retrospective registration need to decreased. Recently, CTRI has announced that from April 1, 2018, it will accept only prospective registration of trials.
Registration of observational studies is nor mandatory (both by CTRI and ICMJE), as the intervention in observational studies is not recommended by the researchers. In the present study, around 4% of observational studies were registered. This shows increasing interest, though small, in registering observational studies.
It is important that researchers are trained and made aware of the ethical requirement of prospective registration of clinical trials before enrolment of first study participant. Journal editors and reviewers should also request for such details during the peer review process, if the trial is not registered then ask for reasons unless the first participant was enrolled before DCGI made registration mandatory (15 June 2009) and if registered retrospectively, this should be made clear in the manuscript. Such transparency in clinical manuscripts will help readers make informed decisions.
In the present study, more than 67% of study sites were located in Gujarat, Maharashtra and Karnataka, with highest (38.3%) in Gujarat. This demonstrates that possibly there is poor awareness in other states. It is also possible that the Ayurvedic colleges and research institutes are higher in these states which could lead to higher number registrations. Overall, there are more than 250 Ayurvedic colleges in India with many of them providing post-graduate training facility in various Ayurvedic subjects. Additionally, there are several Ayurvedic or herbal pharmaceutical companies and government and other funding agencies. Considering these, the trial registration numbers observed in the present study seems to very low.
Author acknowledges the following limitation of this analysis: the data from CTRI was hand searched and clinical trial data collected was collected and analysed by one researcher, which provides opportunity for minor errors, hence readers are advised to consider these numbers as approximate estimates. Data from trials registered before 2012 were not included in this analysis. Additionally, publications of trials registered retrospectively were not analysed whether the retrospective registration was before the manuscript was submitted to journals or after publication.
| Conclusions|| |
Results from this study showed that a majority of Ayurvedic clinical trials were registered retrospectively, however there is increasing trend in prospective registration of Ayurvedic trials. Majority of the study sites of CTRI registered trials were located in Gujarat, Maharashtra and Karnataka, which indicates limited registration in other parts of India. It is important to train and guide researchers not only to register clinical trials prospectively but also to make their results publicly available.
Financial support and sponsorship
Conflicts of interest
Author is an employee of Tata Consultancy Services, Mumbai; however, the views presented in this paper are of the author (purely personal) and not of his current or any previous employers'.
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[Table 1], [Table 2]