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Cannabis is one of the world's oldest cultivated plants and the most commonly used recreational drug worldwide. The plant relevant for medicinal use is Cannabis sativa that has two pharmacologically active ingredients – delta-9-tetrahydrocannabinol that is psychoactive and cannabidiol that does not have psychotropic activity. The policy tapestry of Cannabis has undergone a significant change in the past few decades worldwide. Different countries have diverse policies, ranging from classifying use of Cannabis as illicit, to legalization of its use, both for medicinal and recreational purposes. Cannabis products are approved for use, for instance, in multiple sclerosis and Dravet syndrome (US Food Drug and Administration). Against this backdrop, we find that the knowledge foundations for use of Cannabis in clinical trials in India are still evolving. Conducting ethical research within a clinical trials framework is essential to understand dosing, formulation, shelf life, drug–drug interaction, tolerability, and safety before establishing its utility for various indications. In the absence of guidelines or a regulatory framework for conduct of these studies, the various Institutional Ethics Committees (IECs), which are responsible for reviewing projects related to Cannabis, face unique challenges with respect to the basic requirements. The principal investigators (PIs) are equally strained to find local guidance, recommendations, and literature in support of their application to the respective IEC, thus leading to an impasse and delay in initiating the proposed clinical studies with Cannabis. The present article addresses considerations, questions, and issues that affect the conduct of these clinical studies and recommends mandatory documents and some suggested guidelines for use by both PIs and IECs to take studies with Cannabis forward until such time that an interdisciplinary regulatory framework is firmed up by regulatory authority.

Introduction: Overactive bladder (OAB) syndrome is a chronic disease characterized by urinary urgency with or without urge incontinence, frequency, and nocturia and antimuscarinic drugs such as solifenacin have been the mainstay of treatment. Mirabegron a beta 3 adrenoreceptor agonist has recently gained importance in the management of OAB. The rationale of the study is that mirabegron improves the storage function without affecting voiding which increases the therapeutic effectiveness. The objective was to determine the therapeutic effectiveness of mirabegron versus solifenacin. Methods: A prospective observational study was conducted on 298 patients with OAB syndrome attending the urology outpatient department of government medical college after obtaining institutional review board clearance. Patients of both genders, belonging to the 18–65 years of age group, attending the urology outpatient department were selected for the study. Patients were evaluated using the OAB-validated 8-question awareness tool (OAB-V8 score) before and after receiving drugs by direct questionnaire method after receiving informed consent. Patients were prescribed either solifenacin 5 mg or mirabegron 25 mg once daily by the urologist. Follow-up was done after 4 and 12 weeks. Adverse drug reactions of the drugs were assessed using the Central Drug Standard Control Organization suspected adverse reaction (ADR) form, and ADRs were notified to the nearest ADR monitoring center. Results: The mirabegron group showed maximum improvement in the mean OAB-V8 score values from baseline at 4 weeks (12.82 ± 5.86, P < 0.001) and 12 weeks (5.74 ± 3.31, P < 0.001) when compared to solifenacin. OAB-V8 scores of the solifenacin group also showed significant improvement from the baseline at 4 weeks (15.30 ± 5.54, P < 0.001) and 12 weeks (8.05 ± 4.59, P < 0.001). Heart rate, systolic, and diastolic blood pressures did not show significant changes during the follow-up in both the study groups. Thirteen patients developed ADRs such as dry mouth (four patients) and constipation (nine patients) in the solifenacin group. No ADRs were noted in the mirabegron group. Conclusion: Mirabegron showed maximum improvement in the OAB-V8 scores in patients with OAB syndrome, although the solifenacin group also showed improvement. Adverse effects were less in the mirabegron group when compared to the solifenacin group. [ABSTRACT FROM AUTHOR]

Randomized controlled trials are the gold standard for determining the efficacy of a new intervention. Trials conducted for regulatory approval of an intervention compare the effect of the intervention with the standard of care or placebo to demonstrate efficacy. Randomization attempts to ensure that all known and unknown confounding factors are evenly distributed between the groups, and that the groups will be comparable at the end of the study, so that any inter-group differences in outcomes can be attributed to the intervention. However, in reality, intercurrent events may impact the assessment and subsequent interpretation of the outcome of interest. To address this, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in 2017, released an addendum to the E9 guideline (ICH E9 R1) putting forth the concept of Estimands and Sensitivity Analysis in Clinical Trials. This addendum addresses how these intercurrent events are to be handled using the Estimand concept, which is now expected to be detailed in a separate section of the study protocol. In this paper, we discuss what estimands are, and their likely impact on how regulatory trial protocols and their statistical analyses plans are written and implemented. We also look at the application of the concept of estimands to routine clinical practice.

Purpose: Clinical research in India has been besieged by controversies. While studies have addressed other stakeholders, few have addressed the patient. The present study was conducted to assess the extent of awareness and understanding about the nature and conduct of CR among people of Mumbai. Methods: Institutional Ethics Committee approval was taken (EC/OA-12/15) and written informed consent was obtained. Adults who were residents of Mumbai were enrolled. A prevalidated and published 48-item questionnaire based on six themes, namely awareness and participation, voluntariness and autonomy, compensation, confidentiality, safety, and involvement in CR were administered. Perception based on themes and association of variables such as age, gender, socioeconomic class, and education on this perception was assessed. Descriptive statistics along with Chi-square test/Chi-square test for trend and crude odds ratio (cOR) were assessed. Results: Of the 453 participants approached, 400 (age 32 [18–96]) consented. Only 210/400 (52.5%) were aware of CR and 194/400 (48.5%) said they needed permission for participation. Only 226/400 (56.5%) were aware of their rights and 111/400 (27.75%) felt that clinical trial participants received compensation. The socioeconomic class influenced awareness of CR (P < 0.00001; r2 = 0.495) as did the age (P < 0.0001; r2 = 0.82). Men were less likely to need permission to participate relative to women (cOR [95% confidence interval (CI)] 2.47 [1.6, 3.6] [P < 0.00001]). Those who had heard of CR were twice more willing to participate (cOR [95% CI] 1.72 (1.2, 2.6); P = 0.008). Conclusions: There is a greater need to improve awareness, especially about safety, compensation, and confidentiality in CR.

Introduction: The Clinical Trials Registry of India (CTRI) that initially permitted retrospective registration moved to mandatory prospective registration of studies with effect from April 1, 2018. The present study was an audit that compared registration 1 year post the rule versus a year prior to it. Materials and Methods: All studies registered with the CTRI from April 1, 2017, to March 31, 2018, and subsequently from April 1, 2018, to March 31, 2019, were included for the analysis. The extents of retrospective registration a year pre and a year post April 1, 2018, of all studies were evaluated. Results: A total of 4628 studies were registered prior to April 1, 2018, and 5438 post that. Pre April 1, 2018, 2687 / 4628 (58.06%) studies were retrospectively registered, while post that, 1100 / 5438 (20.23%) studies were retrospectively registered (cOR: 5.46 [5.0, 5.9], P < 0.001). Regardless of whether the studies were PG theses, regulatory studies, observational studies, or interventional studies, there was a statistically significant reduction in the number retrospectively registered post April 1, 2018, relative to the year predating it. Discussion and Conclusion: The success of CTRI's decision to move to prospective registration is seen in the overall reduction in the total number of retrospective registrations from nearly two-thirds in the year predating April 1, 2018, to just a quarter in the year post that, indicating significant inroads made by the CTRI with regard to raising awareness. Some regulatory studies continue to be retrospectively registered and this presents a significant ethical and regulatory breach. This could be potentially addressed by linking ethics committee approval with trial registration.

Background: The approval process of every drug regulatory agency differs, and hence, the time required for the approval of a new drug varies. This results in a drug lag and India is no exception to this phenomenon. A drug lag precludes Indian patients from accessing new medicines at the same time as they are approved elsewhere. Against this backdrop, we assessed the absolute and relative drug lags of the Indian regulator relative to three regulators in mature markets, namely United States (US), European Union (EU), and Japan. Methods: International nonproprietary names were used to identify new drugs. Their dates of approval (2004-2018) from the online database of four regulatory agencies were identified. Both absolute and relative drug lags were calculated for India as compared to US, EU, and Japan as well for all the agencies relative to the Indian regulator. Results: We identified a total of 453, 473, 424, and 472 new drugs approved over the study period in India, US, EU, and Japan, respectively. The absolute drug lag of Central Drugs Standard Control Organization (CDSCO) was 19 and 18 relative to the US Food and Drug Administration (FDA) and Japan Pharmaceuticals and Medical Devices Agency (PMDA), respectively. The relative drug lag for the CDSCO vis-a-vis the US FDA, European Medicines Agency, and PMDA was 43.2 (2.1–1287.8), 25.6 (0.03–1310.5), and 30.3 (1.2–1242) months, respectively. Conclusion: Our study shows a significant drug lag between India and other three developed nations (US, EU, and Japan). However, in some therapeutic areas, Indian regulator has proactively approved new drugs much before other agencies. The New Drugs and Clinical Trials Rule of 2019 has brought hope for reduction in drug lag in the near future.

Purpose: A committee chaired by Dr. Ranjit Roy Chaudhary suggested accreditation of investigators, sites and ethics committees to improve the quality of trial conduct in the country. Prior to accreditation, understanding the challenges faced at the sites by investigators could help define the extent of the problem and identify potential solutions. Hence, we conducted the present study. Methods: Institutional Ethics Committee approval and written informed consent was obtained prior to enrolment. A checklist and a questionnaire was used to assess compliance to Quality Council of India (QCI) standards and the challenges faced by the sites and investigators respectively. Mumbai based investigators listed in the Clinical Trial Registry of India (CTRI) were enrolled. The responses obtained were analysed descriptively. The responses to each question in the checklist were calculated as a proportion and response to each item in the questionnaire was calculated in frequency and percent frequency. All the analysis was done using Microsoft Excel version 2013. Results: A total of 30 investigators from 69 clinical trial sites agreed to participate. We found that over 80% of the sites complied with standards recommended by the QCI guideline. The most frequently reported issues at the site were lack of space for archival (25%), no System to evaluate adequacy of training (31.81%) and lack of understanding of the technical language of the informed consent form (39.02%). Conclusion: There is a need of coordinated effort between all the stakeholders to improve the clinical trial conduct at the site.

Background: Abnormal laboratory values are a common reason for the exclusion of participants in clinical studies, increasing the recruitment time and cost during conduct. The use of sample-specific reference intervals (RIs) may help to address this issue. Hence, the present study derived site-specific RIs using the department laboratory database and compare the proportion of “out of range” (OOR) values between the new and the old RIs used by the trial site. Methods: Institutional ethics committee approval was obtained. Data for hematology and biochemistry parameters were analyzed. Normality was assessed and RIs computed using nonparametric method. Data were partitioned for gender and descriptive statistics applied for demographics. The OOR values based on new RIs were compared with old RIs using Chi-squared tests. Between gender OOR proportions compared using Chi-squared test (significance at P < 0.05). Post hoc analysis was performed with Beasley's technique. Results: Data of 601 participants were analyzed. The median (Inter Quartile Range) age was 22 (47) years and 64.72% were male. New RIs for key parameters were: Haemoglobin (9.3–16.5 g/dl), alanine aminotransferase (11.4–47.74 U/I), aspartate aminotransferase (8.8–58 U/I), total bilirubin (0.27–1.4 mg/dl), and creatinine (0.59–1.36 mg/dl). Post partitioning, the RI for hemoglobin (g/dl) was lower (8.72–15.72) in females. The proportion of OOR values were lower with new RIs relative to old laboratory RIs (P < 0.0001). Conclusion: A reduction in the proportion of OORs and a change in the upper and lower bound laboratory intervals with new RIs emphasize the need for sample-specific ranges to prevent unnecessary exclusions of volunteers from trials.

Background: A conflict of interest (COI) in publication exists when the primary interest of publication is influenced by a secondary interest (financial or non-financial). International guidelines are available that can be used by journal editors to formulate their own COI policies. The present study was carried out with the objective of evaluating COI policies existing among Indian biomedical journals. Materials and Methods: MEDLINE/PubMed and MedIND/IndMed databases were searched. Inclusions were journals that were active and indexed. Outcome measures were proportion of journals: (a) mentioning COI disclosure statement for authors, reviewers, and editors, (b) adequately explaining COI, (c) referring to three international guidelines, and (d) the proportion of PubMed/other than PubMed indexed journals mentioning COI policy for authors, reviewers, and editors and providing an adequate explanation for COI. Apart from descriptive statistics, associations between indexing and COI Policy for all three stakeholders were evaluated. Results: A total of n = 106 journals formed the final sample. Among them, 82 (77%) were PubMed and 24 (23%) were MedIND/IndMed indexed. COI disclosure statement was mentioned in 93 (87.7%) journals for authors, 10 (9.4%) for reviewers, and 06 (5.6%) for editors. Only 35 (33%) journals adequately explained COI. A total of 61 (57.5%) journals endorsed all the three international guidelines. PubMed indexing was found to be associated with approximately 19 times the odds of COI policies being present on the journal's home page relative to the journals indexed with other indexing agencies (crude odds ratio - 18.8, 95% confidence interval [4.6, 77],P < 0.0001). Conclusion: Very few Indian biomedical journals have COI policies for reviewers and editors and most did not explain it adequately. Nearly, a fifth of the journals we evaluated did not follow any guideline for disclosing COI.

Introduction: A key determinant of the success of any study is the recruitment and subsequent retention of participants. Screen failure and dropouts impact both the scientific validity and financial viability of any study. We carried out this audit with the objective of evaluating the recruitment and retention of participants in clinical studies conducted over the last five years at our center. Methods: Studies completed between 2014 and 2018 at our center were included. Screening ledgers and study trackers were hand searched for screen failures and dropouts. Four pre-identified predictors were evaluated – risk as per the classification of Indian Council of Medical Research 2017 Ethical Guideline, nature of funding, study design, and nature of participants. Association of the predictors with screen failures and dropouts was determined using crude odds ratios along with 95% confidence intervals. All analyses were done at 5% significance using Microsoft Excel 2016. Results: A total of n = 19 completed studies had n = 2567 screened and n = 2442 enrolled participants with a screen failure and dropout rate of 5% and 4%, respectively. We found 59% screen failures due to abnormal laboratory values. The main reasons for dropouts were lost to follow-up 86 (88%). High-risk and interventional studies were the predictors for both screen failures and dropouts, but pharmaceutical industry-funded studies and healthy participants were predictors for only screen failures. Conclusion: Risk, funding, study design, and nature of participants are important to be considered while planning studies to minimize screen failures and dropouts.

The coronavirus disease-19 pandemic has affected all aspects of health care including clinical research, as the focus of health-care systems has shifted to maintaining essential care. The impact on clinical research has been profound. In this article, we have enlisted the multiple challenges faced by investigators and sites in carrying out clinical research activities during this crisis and the steps which can be taken by them to reduce the impact of this evolving pandemic on clinical research.

Drug development is a tedious and expensive procedure and it takes roughly 10 to 15 years to take a potential treatment from bench to bedside and costs the pharmaceutical companies as much as USD ~2 billion for the process. Delay in investigator-initiated studies can cause financial loss to grant providers (either public or private) and investigator's reputation may also be at stake. Participant recruitment and retention are two major bottlenecks in conducting clinical trials and contribute vastly to the delays. They are essential for both scientific validity of the clinical study and economic reasons. Thus, issues in recruitment and retention should be addressed and minimized. A proper recruitment and retention plan incorporating adequate communication between all stakeholders will eventually avoid the delays in drug development and make treatments available to the consumer at an earlier date and at a more affordable price. Awareness of challenges and reviewing strategies that can optimise recruitment and retention will facilitate drug development. The article gives a first-person perspective on challenges and proposed solutions from an experienced clinical study centre in a tertiary care hospital.

Background: In January 2015, the Drugs Controller General of India approved the formation of 25 Subject Expert Committees [SEC] to aid the office of the Central Drugs Standard Control Organization [CDSCO] with regards to decision making. The present study is an audit of the minutes of the meetings the SECs held over the past three years. Methods: All minutes during the period 1st July 2014 to 31st October 2017 were accessed from the CDSCO website. Applications were classified as those for clinical trials [CT] and those for marketing authorization [MA]. Each application was classified as being approved, amendment requested for or rejected. Results: A total of n = 317 meetings were held over a 40 month period with n = 2616 agenda items. The Oncology/Hematology SEC had the maximum number of meetings at n = 48 [15.1%]. Only n = 2030 [77.6%] were evaluable agenda items. There were 1082 [53%] applications for clinical trials, and 948 [47%] applications for MA with or without a request for a clinical trial waiver[CTW]. Applicants seeking CTW were 5 times more likely to be rejected [for the waiver] relative to those not seeking waivers (cOR 5 [3.8, 7], P

Background: The Clinical Trials Registry of India (CTRI) was launched in July 2007 and will enter its tenth year in 2017. While its mission is to encourage prospective trial registration, CTRI does permit retrospective trial registration. Against this backdrop, the present audit was carried out with the primary objective of assessing the nature and extent of trials retrospectively registered with CTRI. Methods: All studies registered in the year 2016 were searched within CTRI using the keyword “CTRI/2016.” The total number of trials registered in that year, their phase, the source of funding and their nature (Interventional or observational; whether postgraduate theses or otherwise, source of funding (pharmaceutical industry/Government of India/Institute Funded), whether prospectively or retrospectively registered were noted. We also tested for the association between the nature of the trial and retrospective registration using the Chi-square test and generated crude odds ratios with 95% confidence intervals. Results: A total of 1147 studies were registered in 2016, of which 719 (63%) were retrospectively registered. Interventional studies formed the majority of studies at n = 926 (81%), while postgraduate theses constituted half of the studies (384; 53%). Postgraduate theses (relative to all other studies) were twice as likely to be retrospectively registered (cOR 2.4 [1.8, 3.0], p < 0.0001). Studies funded by the pharmaceutical industry were four times more likely to be registered prospectively relative to nonindustry funded studies (cOR 4.4 [3.2, 5.9], p < 0.0001). Conclusion: Given that CTRI will be insisting on prospective registration effective April 1, 2018, and as trial registration is an ethical, scientific and moral imperative, prospective registration must always be done as prerequisite to participant protection.

Purpose: The Prof. Ranjit Roy Chaudhury committee report recommended the accreditation of Institutional Ethics Committees (IECs). Rule 122DD of the Drugs and Cosmetics Act (and Rules) mandates that only registered ECs can accord approval for regulatory studies. We evaluated the current status of registered, reregistered, and accredited ECs in the country to assess the impact of both the recommendation and rule. Materials and Methods: Websites of stakeholders-the Central Drugs Standard Control Organization (CDSCO), National Accreditation Board for Hospitals and Healthcare Providers (NABH) were assessed. Information on registration status was then compared with regulatory clinical trials in the Clinical Trials Registry of India, population demographics of all states, and the Medical Council of India recognized postgraduate medical colleges in the various states. Results: A total of 1268 ECs were registered with CDSCO. Of these, 1008 (79.5%) were institutional and 256 (20.18%) independent ECs. A total of 499/1268 (39.4%) ECs were reregistered. Of which 449/499 (90%) were institutional and 50/499 (10%) were independent. Institutional ECs were five times more likely to be reregistered with CDSCO relative to independent ECs (cOR 4.52 [3.12, 6.54], P < 0.0001). A total of 15/233 (7%) applications to NABH had received accreditation. A wide skew was seen in the distribution of ECs across various states as also their oversight of regulatory clinical trials. Conclusions: Registration and reregistration of ECs along with accreditation is not commensurate with the needs of the country at this time and must be vigorously promoted.

Purpose/Aim: The Adverse Drug Reaction [ADR] form is the source document for the Pharmacovigilance Programme of India [PvPI] and captures information first hand from the patient. The raw data from it then gets converted into an individual case safety report [ICSR] after entry into Vigiflow. The National Coordinating Centre [NCC] uses an instrument to assess quality of these ICSRs. We carried out the present study to assess whether the same instrument with minor modifications could be used to check the quality of ADR forms at our centre. Materials and Methods: ADR reports of three months from three consecutive years were selected randomly. The ADR form [18 fields] was matched with the NCC instrument [14 fields] as the latter is made from the former. A perfect ICSR would score 1. Three fields in the NCC instrument - case narrative, compliance with standard operating procedures [SOPs] and free text [5 components] were modified, while the rest were retained. Zero was given to the first two fields. In the third field, we retained only 3/5 components and changed the last two components [sender and reporter comments] to dechallenge and rechallenge while keeping the total score the same. Results: A total of 1008 ADR reports were analyzed. We found an overall completeness score of approximately 80% with the lowest completeness score being for the year 2015. The mandatory fields had close to 100% scores. Conclusion: The NCC instrument was found well suited to evaluate quality and completeness of ADR forms.

Monitoring and audits are two distinct processes that ensure that the rights and safety of the participants are protected, and data integrity is maintained. The present narrative summates authors' experiences with monitoring and audits by sponsor along with challenges faced by the site. It also offers potential solutions for challenges faced during the process of monitoring and audits. It is important to remember that no monitoring or audit can ever substitute for a well-designed and articulated protocol. In addition, a determined approach by the investigator and his/her team to ensure that all aspects of the protocol are adhered to in totality will go a long way in assuring quality.

Investigator-initiated studies (IISs) help by generating data on effectiveness and safety of a drug in the real-world setting and attempt to answer questions that clinicians face in their day-to-day practice. These are studies that are initiated and managed by a nonpharmaceutical company researcher/s who could be an individual investigator, an institution or a group of institutions, and a collaborative study group or a cooperative group. They are largely driven by questions that arise beyond the completion of Phase III studies that have not been studied during Phases I–III of drug development. The benefits of doing IISs are often offset by the myriad challenges posed by an IIS. These include finances, regulatory submissions, continuous oversight, training of study personnel, lack of expertise in statistics, data management, and medical writing Nonetheless, doing an IIS is extremely rewarding for the investigator and has the capacity to contribute to evidence and eventually impact policy. The present article presents both a brief literature review of IISs and a personal narrative of experience gained during the conduct several IISs in the last two decades. Challenges and potential solutions are described.

The quality of the written informed consent process is one of the most important aspects of clinical research, as it is the single tool that serves as a metric of autonomy. Several challenges have been identified with the informed consent process in developing countries the most important of which is the ability to assimilate and understand the information presented in the consent form. In India, a unique aspect of the informed consent process is the need for audio-video [AV] recording of the process for vulnerable populations and new chemical entities. The present narrative summates authors' experiences as investigators with A-V recording of the informed consent process as also providing a brief narrative review of relevant literature. It also offers potential solutions for challenges faced during this process.

Purpose: The International Committee of Medical Journal Editors mandates trial registration as a precondition for publication. Growing evidence indicates that information in registry may not correlate with eventual publication. The present study was carried out with the objective of comparing content of Randomized Controlled Trials (RCTs) published in one year in the Journal of the American Medical Association (JAMA), with the information contained in trial registries. Methods: All RCTs published in JAMA in 2013 were included. 11 data set items were matched for content between registry entry and published RCT: Title, Primary and Secondary Objectives, Study type, Inclusion and Exclusion Criteria, Treatment Age Group, Follow up, Sample Size, Primary and Secondary Outcomes. A fully correct match was scored 2, partially correct 1 and incorrect 0. Thus, maximum possible score for each paper was number of items multiplied by 2, i.e., 22. Results: The median [range] total score achieved by RCTs was 15. No RCT achieved a perfect score of 22. The largest proportion of RCTs reported secondary objectives, study type, treatment age group, follow up, sample size and primary outcomes fully correctly. However, only 13.5 %, 12 % and 13.5 % of RCTs were a perfect match with registry entries in terms of title, primary objective and secondary outcomes respectively. Almost three quarters did not match perfectly in selection criteria. Conclusion: There exist discrepancies between trial registration and published paper even in a high impact factor journal. Both authors and editors should adhere to CONSORT guidelines to ensure transparency of published research.

Background: India continues to contribute disproportionately to the global burden of disease and public health research output from India is also known to be not commensurate with her healthcare needs. We carried out the present study to assess if clinical trials were in line with the health care needs of the country by auditing the clinical trials registry of India. Materials and Methods: All the clinical studies registered in CTRI between July 20, 2007 and December 31, 2015 were searched in the “Trial Search” section. The total number of studies, their phases of development, and therapeutic areas were assessed. Trials in each therapeutic area was compared with the disease burden (DALYs) in that area taken from Global Health Estimates [2014] Summary Tables of the WHO. The number of trials conducted per state in India was also compared with the population of that state [Census 2011]. Results: A total of 6474 studies were registered of which 3325 (51.4%) were clinical trials. The state of Maharashtra had the highest number trials [16.4%] followed by Karnataka ( 11.6%) and Tamil Nadu (10%). Populous states like Uttar Pradesh (5.3%) and Bihar (1.4%) had far fewer trials. The largest number of trials was in the area of cancer (16.4%), followed by diabetes (12.1%) and cardiovascular diseases (10.1%). Infectious and parasitic diseases had the highest DALYs (82,681) and ranked first in disease burden but accounted for only 5% of the total trials and ranked 7th according to number of trials. Cancer ranked first in the number of trials (16.4%), but ranked 6th based on DALYs. Conclusion: Clinical trials conducted in India are not in consonance with her health care needs. Strengthening the capacity for conducting trials in the populous states and the north-eastern part of the country is necessary to allow a more equitable selection of participants. The government should introduce policies to encourage new drug development in areas where needed the most.

Cannabis is one of the world's oldest cultivated plants and the most commonly used recreational drug worldwide. The plant relevant for medicinal use is Cannabis sativa that has two pharmacologically active ingredients - delta-9-tetrahydrocannabinol that is psychoactive and cannabidiol that does not have psychotropic activity. The policy tapestry of Cannabis has undergone a significant change in the past few decades worldwide. Different countries have diverse policies, ranging from classifying use of Cannabis as illicit, to legalization of its use, both for medicinal and recreational purposes. Cannabis products are approved for use, for instance, in multiple sclerosis and Dravet syndrome (US Food Drug and Administration). Against this backdrop, we find that the knowledge foundations for use of Cannabis in clinical trials in India are still evolving. Conducting ethical research within a clinical trials framework is essential to understand dosing, formulation, shelf life, drug-drug interaction, tolerability, and safety before establishing its utility for various indications. In the absence of guidelines or a regulatory framework for conduct of these studies, the various Institutional Ethics Committees (IECs), which are responsible for reviewing projects related to Cannabis, face unique challenges with respect to the basic requirements. The principal investigators (PIs) are equally strained to find local guidance, recommendations, and literature in support of their application to the respective IEC, thus leading to an impasse and delay in initiating the proposed clinical studies with Cannabis. The present article addresses considerations, questions, and issues that affect the conduct of these clinical studies and recommends mandatory documents and some suggested guidelines for use by both PIs and IECs to take studies with Cannabis forward until such time that an interdisciplinary regulatory framework is firmed up by regulatory authority. [ABSTRACT FROM AUTHOR]

Aim: The present study is an audit of the communiquιs issued by the Drugs Controller General of India [DCGI] to Ethics Committees [ECs] for content and directives after the mandatory notification of registration of Ethics Committees issued on 8 th February 2013. Methods: All letters were downloaded from the website of the Central Drugs Standard Control Organization [CDSCO] and evaluated for the date of issue, number of directives, domains covered by the directives [general instructions, administrative requirements and quorum requirements], median time to approval for registration and time elapsed between date of application and issue of the approval letter. Results: There were a total of 1036 EC letters listed on the website, from which 854 [82.4%] could be downloaded. A working denominator of 841 was arrived at after discarding repeat letters and those that had an incorrect address. The state of Maharashtra had the highest number of ECs registered (209/841, 24.9%) followed by Gujarat [97/841, 11.5%) and Karnataka [96/841, 11.4%]. The number of directives within each letter ranged from 8-22. The overall time to approval was 77.5 [24-919] days and the time to approval between Institutional and Independent Ethics Committees was significantly different. Conclusions: The office of the DCGI had a very wide time range for approving registration of Ethics Committees that ranged from less than a month to more than two years. The quality and nature of the directives improved with time. As the country moves towards accreditation, letters issued by the DCGI should have uniformity. The large number of ECs in a single state and lack of even a single one in several others is something that needs to be addressed by policy makers.

Background: The 1983 US Orphan Drug Act provided impetus for the development of new therapies for rare diseases. Several studies focused on the number of orphan designations over time. However, very few focused on clinical trials that lead to their approval, particularly for infectious diseases. Materials and Methods: All new drug approvals (orphan and non-orphan) by the US Food and Drug Administration (FDA) from January 2010 to December 31, 2020, were identified and details of approvals were taken from the US-FDA labels and summary reports for each drug. The pivotal trials for each were characterized based on their design. We tested the association of the type of drug approval with respect to the characteristics of trial using Chi-square test and generated crude odds ratios with 95% confidence intervals. Results: From the total 1122 drugs approved, 84 were for infectious diseases, of which 18 were orphan drugs and 66 were nonorphan. A total of 35 pivotal trials supported 18 orphan drug approvals, while 115 pivotal trials supported 66 nonorphan drugs. The median number of participants enrolled/trial for orphan drugs was 89, while for nonorphan drugs, it was 452 (P < 0.0001). Blinding was done for 13/35 (37%) orphan drugs versus 69/115 (60%) nonorphan drugs (P = 0.029); randomization was done for 15/35 (42%) orphan drugs versus 100/115 (87%) nonorphan drugs (P < 0.0001) and 20/35 (57%) of the orphan drugs got approval in phase II versus 8/115 (6%) of nonorphan drugs (P < 0.00001). Conclusion: A significant number of orphan drugs get approval based on early phase, nonrandomized, and unblinded with a smaller sample size as compared to nonorphan drugs. [ABSTRACT FROM AUTHOR]

Introduction: The institutional ethics committees (IECs) raise queries following protocol reviews. The quality of these queries would be a useful metric to assess how well the IEC executes its fundamental role of protecting participants. Methods: Queries received after the initial review and replies sent by a single research department were evaluated. A content analysis was done to identify the domains and categories of queries. We categorized these queries as administrative, ethics related, and scientific. The impact of each query in improving the science or safeguarding the rights and safety of research participants (ethics) was evaluated by two authors of this manuscript: one affiliated and the other nonaffiliated to the institute. Kappa statistics were used to evaluate for agreement between the two. Results: A total of 13 studies (investigator-initiated studies [IISs]: 7 and pharmaceutical industry-sponsored studies [PSSs]: 6) formed the final sample size for analysis. The total number of queries was 364 (IIS: 106 and PSS: 258; P < 0.001). With regard to the categories, we found n = 42 (11.54%) to be irrelevant at that stage of the review process; n = 51 (14.01%) were about information already available which the IEC had missed; n = 67 (18.41%) queries where the IEC needed paraphrasing; n = 50 (13.74%) were entirely relevant with the need for further clarification; and n = 154 (42.31%) had been missed by the investigator during the initial submission. The overall agreement between the affiliated and unaffiliated investigators was just 12.9% (P < 0.001). Conclusions: We found that approximately 25% of the queries raised by the IEC were redundant. It is our opinion that this redundancy could have been channeled into greater focus on scientific and ethical aspects of the protocol. Ongoing dialog between investigators and ethics committees may help address this. Perspectives between the affiliated and the unaffiliated investigators with regard to the relevance of queries were grossly different. [ABSTRACT FROM AUTHOR]

Introduction: The Investigational New Drug (IND) committee advises the Drug Controller General of India on matters pertaining to clinical trials (CTs) of IND for clinical development. An audit of the minutes of this committee's meetings would shed light on the drug discovery in India. Methods: Minutes of the IND committee meetings available in the public domain (2-year period) were evaluated. The applications which were postponed were excluded from the study. Outcome measures were therapeutic areas of IND, purpose of the applications, status of registration with the CT Registry of India (CTRI), and the innovator country. Results: The minutes of N = 7 meetings were available in the public domain for the period January 2017–December 2018 with N = 45 agenda items. One agenda item was excluded, and n = 44 agenda items were finally analyzed. The total number of therapeutic agents discussed was N = 29, of which n = 7/29 and n = 6/29 belonged to infectious diseases (ID) and oncology, respectively. The total number of purposes of these applications was N = 46, of which n = 35/46 (76%) were to seek permission to conduct a CT, and n = 31/35 (88.6%) were found registered with CTRI as on April 01, 2019. Of the N = 46 purposes, n = 33/46 (71.7%) were approved. Of the n = 29 INDs discussed, n = 19/29 (65.52%) were of the Indian origin. Conclusions: Although a majority (65%) of INDs discussed in the meetings were of the Indian origin, the drug discovery was not in line to tackle the top ten causes of years of life lost prematurely (barring ID). [ABSTRACT FROM AUTHOR]

Background: Abnormal laboratory values are a common reason for the exclusion of participants in clinical studies, increasing the recruitment time and cost during conduct. The use of sample-specific reference intervals (RIs) may help to address this issue. Hence, the present study derived site-specific RIs using the department laboratory database and compare the proportion of "out of range" (OOR) values between the new and the old RIs used by the trial site. Methods: Institutional ethics committee approval was obtained. Data for hematology and biochemistry parameters were analyzed. Normality was assessed and RIs computed using nonparametric method. Data were partitioned for gender and descriptive statistics applied for demographics. The OOR values based on new RIs were compared with old RIs using Chi-squared tests. Between gender OOR proportions compared using Chi-squared test (significance at P < 0.05). Post hoc analysis was performed with Beasley's technique. Results: Data of 601 participants were analyzed. The median (Inter Quartile Range) age was 22 (47) years and 64.72% were male. New RIs for key parameters were: Haemoglobin (9.3–16.5 g/dl), alanine aminotransferase (11.4–47.74 U/I), aspartate aminotransferase (8.8–58 U/I), total bilirubin (0.27–1.4 mg/dl), and creatinine (0.59–1.36 mg/dl). Post partitioning, the RI for hemoglobin (g/dl) was lower (8.72–15.72) in females. The proportion of OOR values were lower with new RIs relative to old laboratory RIs (P < 0.0001). Conclusion: A reduction in the proportion of OORs and a change in the upper and lower bound laboratory intervals with new RIs emphasize the need for sample-specific ranges to prevent unnecessary exclusions of volunteers from trials. [ABSTRACT FROM AUTHOR]

Purpose: A committee chaired by Dr. Ranjit Roy Chaudhary suggested accreditation of investigators, sites and ethics committees to improve the quality of trial conduct in the country. Prior to accreditation, understanding the challenges faced at the sites by investigators could help define the extent of the problem and identify potential solutions. Hence, we conducted the present study. Methods: Institutional Ethics Committee approval and written informed consent was obtained prior to enrolment. A checklist and a questionnaire was used to assess compliance to Quality Council of India (QCI) standards and the challenges faced by the sites and investigators respectively. Mumbai based investigators listed in the Clinical Trial Registry of India (CTRI) were enrolled. The responses obtained were analysed descriptively. The responses to each question in the checklist were calculated as a proportion and response to each item in the questionnaire was calculated in frequency and percent frequency. All the analysis was done using Microsoft Excel version 2013. Results: A total of 30 investigators from 69 clinical trial sites agreed to participate. We found that over 80% of the sites complied with standards recommended by the QCI guideline. The most frequently reported issues at the site were lack of space for archival (25%), no System to evaluate adequacy of training (31.81%) and lack of understanding of the technical language of the informed consent form (39.02%). Conclusion: There is a need of coordinated effort between all the stakeholders to improve the clinical trial conduct at the site. [ABSTRACT FROM AUTHOR]

Background: The approval process of every drug regulatory agency differs, and hence, the time required for the approval of a new drug varies. This results in a drug lag and India is no exception to this phenomenon. A drug lag precludes Indian patients from accessing new medicines at the same time as they are approved elsewhere. Against this backdrop, we assessed the absolute and relative drug lags of the Indian regulator relative to three regulators in mature markets, namely United States (US), European Union (EU), and Japan. Methods: International nonproprietary names were used to identify new drugs. Their dates of approval (2004-2018) from the online database of four regulatory agencies were identified. Both absolute and relative drug lags were calculated for India as compared to US, EU, and Japan as well for all the agencies relative to the Indian regulator. Results: We identified a total of 453, 473, 424, and 472 new drugs approved over the study period in India, US, EU, and Japan, respectively. The absolute drug lag of Central Drugs Standard Control Organization (CDSCO) was 19 and 18 relative to the US Food and Drug Administration (FDA) and Japan Pharmaceuticals and Medical Devices Agency (PMDA), respectively. The relative drug lag for the CDSCO vis-a-vis the US FDA, European Medicines Agency, and PMDA was 43.2 (2.1–1287.8), 25.6 (0.03–1310.5), and 30.3 (1.2–1242) months, respectively. Conclusion: Our study shows a significant drug lag between India and other three developed nations (US, EU, and Japan). However, in some therapeutic areas, Indian regulator has proactively approved new drugs much before other agencies. The New Drugs and Clinical Trials Rule of 2019 has brought hope for reduction in drug lag in the near future. [ABSTRACT FROM AUTHOR]

Purpose: Clinical research in India has been besieged by controversies. While studies have addressed other stakeholders, few have addressed the patient. The present study was conducted to assess the extent of awareness and understanding about the nature and conduct of CR among people of Mumbai. Methods: Institutional Ethics Committee approval was taken (EC/OA-12/15) and written informed consent was obtained. Adults who were residents of Mumbai were enrolled. A prevalidated and published 48-item questionnaire based on six themes, namely awareness and participation, voluntariness and autonomy, compensation, confidentiality, safety, and involvement in CR were administered. Perception based on themes and association of variables such as age, gender, socioeconomic class, and education on this perception was assessed. Descriptive statistics along with Chi-square test/Chi-square test for trend and crude odds ratio (cOR) were assessed. Results: Of the 453 participants approached, 400 (age 32 [18–96]) consented. Only 210/400 (52.5%) were aware of CR and 194/400 (48.5%) said they needed permission for participation. Only 226/400 (56.5%) were aware of their rights and 111/400 (27.75%) felt that clinical trial participants received compensation. The socioeconomic class influenced awareness of CR (P < 0.00001; r2 = 0.495) as did the age (P < 0.0001; r2 = 0.82). Men were less likely to need permission to participate relative to women (cOR [95% confidence interval (CI)] 2.47 [1.6, 3.6] [P < 0.00001]). Those who had heard of CR were twice more willing to participate (cOR [95% CI] 1.72 (1.2, 2.6); P = 0.008). Conclusions: There is a greater need to improve awareness, especially about safety, compensation, and confidentiality in CR. [ABSTRACT FROM AUTHOR]