Clinical Trials In India Research Articles

Navigating investigator-initiated clinical trials: A call for guidelines & monitoring frameworks from an Indian context

Investigator-initiated clinical trials – also known as non-regulatory or academic clinical trials, are conducted by investigators from academia or research organizations. They usually aim to address scientific questions with insufficient commercial implications and generate real-world applicable solutions, unlike trials sponsored by the pharmaceutical industry which are primarily focused on marketing approval of products that have a commercial value. For the trial results to be credible, adhering to robust methodology and the highest quality standards is paramount. Currently, investigator-initiated clinical trials in India are beyond the purview of the national regulatory authority. They are guided mainly by the National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, 2017 published by Indian Council of Medical Research. They lack an accepted framework for review, conduct, monitoring, reporting of adverse events, and participant compensation. Considering this scenario, we discuss the challenges faced in an investigator initiated clinical trial and explore plausible solutions.

PreVenTB trial: protocol for evaluation of efficacy and safety of two vaccines VPM1002 and Immuvac (Mw) in preventing tuberculosis (TB) in healthy household contacts of newly diagnosed sputum smear-positive pulmonary TB patients: phase III, randomised, double-blind, three-arm placebo-controlled trial

IntroductionTuberculosis (TB) continues to be one of the deadliest infectious diseases over the centuries, killing more people worldwide than any other single infectious disease. There is an urgent need for...

Effectiveness and Safety of Varying Doses of Linezolid With Bedaquiline and Pretomanid in Treatment of Drug-Resistant Pulmonary Tuberculosis: Open-Label, Randomized Clinical Trial.

Treatment of drug-resistant tuberculosis with bedaquiline-pretomanid-linezolid regimen has demonstrated good treatment efficacy. Given linezolid's toxicity profile, prudence suggests reconsidering its dose and duration. We determined the effectiveness and safety of structured dose reduction of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant (pre-XDR) or treatment-intolerant/nonresponsive multidrug-resistant (MDRTI/NR) pulmonary tuberculosis. Adults with pre-XDR or MDRTI/NR pulmonary tuberculosis were enrolled in a multicenter, parallel-group, randomized clinical trial in India. Patients were randomized to 26 weeks of bedaquiline, pretomanid, and daily linezolid, at 600 mg for 26 weeks (arm 1); 600 mg for 9 weeks followed by 300 mg for 17 weeks (arm 2); or 600 mg for 13 weeks followed by 300 mg for 13 weeks (arm 3). Study end points included sustained cure, bacteriological failure, toxicity, and death. Of 403 patients enrolled, 255 (63%) were <30 years old, 273 (68%) had prior tuberculosis episodes, and 238 (59%) were malnourished. At the end of treatment, after excluding those with negative baseline cultures, cure was seen in 120 (93%), 117 (94%), and 115 (93%) in arms 1, 2, and 3 respectively. Myelosuppression seen in 85 patients each in arms 1 and 2 and 77 patients in arm 3, not significantly different. Peripheral neuropathy was noticed in 66 patients (30, 17, and 19 in arms 1, 2, and 3) at 10-26 weeks (P = .02). The linezolid dose was reduced because of toxicity in 13, 2, and 4 patients in arms 1, 2, and 3, respectively. In adults with pre-XDR or MDRTI/NR pulmonary tuberculosis, structured linezolid dose reduction to 300 mg/d is as effective as the standard 600-mg dose but with fewer cases of peripheral neuropathy when given with bedaquiline and pretomanid. Clinical Trial Registry of India (CTRI/2021/03/032189).

GLAD TIDINGS FOR INDIAN PHARMACEUTICAL INDUSTRY

Dear Reader, It is indeed heartening to note that the Indian Government has notified Rules for fast-track launch of new, breakthrough drugs including block-buster molecules, waiving or bypassing clinical trials in India under Chapter V of the Rules, where the relevant drug has already been approved in specified countries, such as the European Union, US, UK, Japan, Australia and Canada. This decision was announced through an executive order specifying the list of developed countries under Rule 101 of the New Drugs and Clinical Trials Rules (NCDT) 2019, issued by the DCGI, Dr. Rajeev Singh Raghuvanshi. For the time being, the list of drugs covered under the order for approval of new drugs, under Chapter X are restricted to those for treatment of orphan drugs (rare diseases), new drugs for special defence purposes and those used in pandemic diseases, gene and cellular therapy products. It is further to be noted that drugs having significant therapeutic advances over the standard care, are also covered under this notification waiving domestic clinical trials. Indirectly, this waiver will not only help State Government and other public procurement agencies such as DGHS and Ayushman Bharat to reduce expenditure in their budgets, but also do away with animal trials in India in line with Indian and global initiatives. This initiative to selectively waive clinical trials will be a boon to research-based Indian Pharma companies too, for introducing generic equivalents of these drugs having significant therapeutic benefits to patients.

Increased NGS testing and real-world clinical usage of targeted therapy: All dressed up, nowhere to go.

e13758 Background: National and International recommendations mandate panel- based biomarker testing for all advanced cases of NSCLC. However, analogous to uptake of many other state of the art cancer management strategies, the uptake of NGS based testing and subsequent targeted therapy varies greatly across socio-demographic groups, explained by awareness and economic restraints. This study investigates the potential differences in uptake of NGS based testing and precision medicine in advanced NSCLC patients from India. Methods: This is a single center non-interventional study where retrospective review of patient data of biomarker driven advanced NSCLC patients was carried out. The records were recovered from electronic health records of the hospital. Single gene testing for EGFR and ALK are performed using Roche Cobas V2 and D5F3 Ventana systems respectively. A machine learning algorithm: Classification and Regression Tree (CART) was employed. Results: A total of 5894 patients of advanced NSCLC were identified. Of these 33% received NGS based biomarker testing at diagnosis. The proportion of patients who received NGS tests increased over calendar time from 2014-2023, with an average increment of 15.8% every year, and peak increase in 2022 of 51%. NGS based testing yielded a positive result in 80% cases with a median turnaround time of 18.2+/-3 days. NGS detected 10.2% cases more in EGFR, 3.2% cases less in ALK, 3.1% more in ROS1. Overall NGS was able to detect 37.8% extra cases of biomarker driven cases. Among the biomarker driven, uptake of targeted therapy was 65% for MET, 83% for ROS1, 52% for RET, 17.6% for ERBB2, 63% for BRAF V600E, 75% for EGFR and 79% for ALK at any given point in the disease. None of the G12C KRAS received selective treatment owing to drug unavailability in the country. Applying the CART model, targeted therapy was received by patients younger than 68 years of age, male gender, with ECOG status 0-2, and absence of brain metastases at diagnosis. Patients with brain metastases at diagnosis, females and those &gt;69 years of age were less likely to opt for TKI(p&lt;0.02*). Conclusions: This is the largest cohort from India reporting real world uptake of NGS based biomarker testing and targeted therapy. There is a clear disparity in terms of gender and age group, possibly attributable to social stigmata and taboos prevailing in rural parts of the country. Despite increased detection rates, access to targeted therapy is still a concern owing to inaccessibility to drugs/ lack of global clinical trials in India as well as lack of patient support programs/groups.

Successful transport across continents of GMP-manufactured and cryopreserved culture-expanded human fetal liver-derived mesenchymal stem cells for use in a clinical trial

IntroductionCell therapy has been increasingly considered to treat diseases, but it has been proven difficult to manufacture the same product at multiple manufacturing sites. Thus, for a wider implementation an alternative is to have one manufacturing site with a wide distribution to clinical sites. To ensure administration of a good quality cell therapy product with maintained functional characteristics, several obstacles must be overcome, which includes for example transfer of knowledge, protocols and procedures, site assessment, transportation and preparation of the product. MethodsAs the preparatory work for a clinical trial in India using fetal mesenchymal stem cells (fMSCs) developed and manufactured in Sweden, we performed a site assessment of the receiving clinical site, transferred methods, developed procedures and provided training of operators for handling of the cell therapy product. We further developed a Pharmacy Manual to cover the management of the product, from ordering it from the manufacturer, through transport, reconstitution, testing and administration at the clinical site. Lastly, the effect of long-distance transport on survival and function of, as well as the correct handling of the cell therapy product, was evaluated according to the pre-determined and approved Product Specification. ResultsFour batches of cryopreserved human fetal liver-derived fMSCs manufactured according to Good Manufacturing Practice and tested according to predetermined release criteria in Sweden, were certified and transported in a dry shipper at −150 °C to the clinical site in India. The transport was temperature monitored and took three–seven days to complete. The thawed and reconstituted cells showed more than 80% viability up to 3 h post-thawing, the cell recovery was more than 94%, the cells displayed the same surface protein expression pattern, differentiated into bone, had stable chromosomes and were sterile, which conformed with the data from the manufacturing site in Sweden. ConclusionsOur study shows the feasibility of transferring necessary knowledge and technology to be able to carry out a clinical trial with a cell therapy product in distant country. It also shows that it is possible to transport a cryopreserved cell therapy product over long distances and borders with retained quality. This extends the use of cryopreserved cell therapy products in the future.

Real-World Experiences of Next-Generation Sequencing in Oncology: From an Indian Multicenter Registry and Collaborative Centers

Abstract Background The integration of next-generation sequencing (NGS) in guiding personalized therapy for oncology faces the challenges, primarily, of cost and drug accessibility. Limited data from Indian academic centers accentuate the need for comprehensive insights into the real-world applications of NGS in oncology. Methods The Network of Oncology Clinical Trials in India (NOCI), accessible at www.noci-india.com, compiled data on patients who underwent NGS for solid organ cancers from January 1, 2018, to December 31, 2021. This study aimed to elucidate the testing indications, sample types analyzed, and the resultant impact on patient care. Results Analysis of data from six centers included 278 subjects, with 24 specimens (9%) excluded due to quality test failure. Tissue constituted 59.7% of specimens, blood 38.5%, and both 1.8%. Predominantly, NGS was employed for identifying BRCA1/2 mutations (56%) and for targeted therapy in non-small-cell lung cancer (NSCLC; 28%). Only 41 (16%) patients with other cancers underwent multigene NGS panels in pursuit of targetable mutations. Among them, 13 exhibited targetable mutations, and 3 received treatment based on NGS findings. Conclusion This study underscores that the majority of NGS applications focused on screening for BRCA1/2 mutations and identifying targetable mutations in NSCLC. However, among those undergoing NGS for advanced cancers, only a limited number received personalized therapy. The findings underscore the challenges of utilizing NGS in off-label indications within resource-constrained settings.

Advancement, utilization, and future outlook of Artificial Intelligence for physiotherapy clinical trials in India: An overview

As healthcare landscapes evolve, Artificial intelligence (AI) has emerged as a transformative force in physiotherapy research in India. The integration of machine learning algorithms, computer vision, and natural language processing has significantly advanced the analysis of patient data, enabling the prediction of treatment outcomes and personalization of physiotherapy interventions. This overview delves into specific examples of successful AI integration in ongoing clinical trials within the Indian context, showcasing notable improvements in trial efficiency and positive impacts on patient outcomes. Challenges in implementing AI, including data security, ethical considerations, and the need for specialized training, are discussed. Proposed solutions encompass robust data encryption, ethical guidelines, interpretability of AI models, and targeted educational programs for healthcare professionals. Looking forward, the future outlook emphasizes personalized treatment plans, expanded tele physiotherapy using wearable technology, and the integration of augmented and virtual reality. Ethical and regulatory frameworks, continued advancements in robotic assistance, and interdisciplinary collaboration are highlighted as key factors shaping the trajectory of AI in physiotherapy clinical trials in India. The primary objectives of this manuscript are to explore the current state of AI in physiotherapy clinical trials in India, assess its utilization, and discuss the potential future developments in the field.

A Review on CDSCO: Central Drug Standard Control Organisation

India has been a hub for managing various multi centre trials the central drug standard control organisation (CDSCO), headed by the drug controller general of India (DCGI), drowsing the regulation for the manage of clinical trials in India the conduct of trails, regulations in India and quality of data generated may be the source for this evolution it is crucial that now all clinical trials conducted in India should as per the international conference of harmonization good clinical practice guidelines ( ICH- GCP) for clinical trials and follow the newly amended schedule Y of the drugs and cosmetic Act.

Towards inclusive trial design for vascular cognitive impairment in the diverse context of India

AbstractBackgroundThe burden of vascular contribution to cognitive impairment and dementia is substantially higher in low and middle‐income countries like India compared to the high‐income countries (HIC). Nearly 40% of 5.3 million people with dementia are estimated to be due to vascular aetiology. This high burden of vascular cognitive impairment (VCI) is due to a greater prevalence of vascular risk factors such as diabetes, hypertension and stroke as well as low awareness and a wide treatment gap. Lack of validated diagnostic instruments in various regional languages and availability brain imaging pose challenges to diagnosis of VCI. These factors pose unique challenges to reducing the burden of VCI in India. Novel clinical trials are being implemented to risk of progression of VCI, but these efforts are mainly restricted to HIC. The limited availability of evidence for effective treatment and preventive strategies in the context of diverse countries like India are major impediments to effective public health interventions to reduce burden.MethodWe present results from a large cohort of 2000 individuals from multiple centres across the country including individuals at high risk of developing VCI, patients with vascular mild cognitive impairment and vascular dementia. Languages spoken by patients included Kannada, Telugu, Hindi, Malayalam, Urdu, Bengali and English among others. A were illiterate and around 60% were bilingual.ResultsHarmonised cognitive and functional measures adapted to multiple Indian languages and educational variability were used to detect VCI in the diverse population. MRI imaging to detect vascular imaging biomarkers was performed to detect infarcts, cortical atrophy, microbleeds and white matter lesions, for accurate identification of vascular damage and neurodegeneration. Collaborations between multiple centres in a systematic manner are ongoing. Novel public health initiatives with support of policy makers are also being implemented to improve brain health by increasing awareness and reducing risk of stroke and dementia in the community.ConclusionsThese large‐scale efforts towards developing clinical‐trial readiness of VCI cohorts in the community across India will be crucial to fill research evidence gaps and implement clinical trials in India in concurrence with ongoing global efforts.

Landscape of cancer clinical trials in India – a comprehensive analysis of the Clinical Trial Registry-India

Cancer is one of the leading causes of morbidity and mortality in India. Clinical trials are critical for driving innovation in cancer therapy, diagnosis, and prevention. This study aims to depict the evolving landscape of cancer clinical trials in India by analysing the clinical trials registered in Clinical Trial Registry-India (CTRI). We identified cancer trials registered in CTRI (between 2007 and 2021) using search terms adapted from the cancer types defined by the National Cancer Institute (USA). We then collated and analysed the publicly available information from CTRI (cancer subtypes, type of trial, treatment intent, type of intervention, sponsor type, recruitment countries) and used descriptive statistics to illustrate the overall as well as year-to-year trend. In total, we identified 1988 cancer trials, the majority of which focused on treating cancer (63%) and rest of the trials aimed at optimising the operational aspects of surgery (19%), mitigating treatment-related toxicity (10.6%), or treating cancer-related symptoms (7.8%). Focusing on trials with the intent of treating cancer, we found that most were investigating solid tumours as opposed to haematological malignancies with the most prominent cancer subtypes being breast cancer (17%), head and neck cancer (9.8%), lung cancer (9.6%), and cervical cancer (6.6%). The number of trials conducted in a given cancer subtype from our analysis overall correlated to the incidence, mortality, and 5-year prevalence of the respective cancer subtype in India; however, head and neck cancer and cervical cancer were underrepresented in trials as compared with the disease burden. The most common type of intervention was investigational drugs. The most common sponsor types were global pharmaceutical industry (26%) and research institution and hospital (26%). Despite a relatively high cancer burden, the availability of cancer trials in the Northeastern states of India was limited. There is a pressing need for clinical cancer research in India to be better aligned with the nation's healthcare needs and disease burden, focusing on prevalent and deadly cancers while ensuring the availability of clinical trials across geographic regions and underserved populations. Pi Health USA, a fully owned subsidiary of BeiGene Ltd.

A Review Paper on : Clinical Trials

To assure the safety and effectiveness of any new treatment, clinical research is a crucial step in the drug discovery process. Clinical trials are essential in the worldwide scientific era of today for bringing new and improved medications to market. Human volunteers (subjects) are used in clinical trials to test prospective treatments to see whether they should be licensed for use in the general population. Due to a number of variables, India served as a global centre for clinical trials in the past. Clinical trials and clinical trials in India are discussed in this essay.

Attitude and perception toward clinical trials in India among patients and patient bystanders visiting the Indian Ophthalmology Clinical Trial Network: A multi-centric, cross-sectional survey.

Advances in patient treatment depend heavily on clinical trials (CTs). Patient volunteers for CT are tougher to recruit and retain. In order to administer CTs effectively, it is necessary to comprehend how the public views and perceives participating in them. The study assessed the perception and attitudes of patients and bystanders toward CTs in India. This was a multi-centric, cross-sectional study among patients and bystanders using a questionnaire that consisted of socio-demographic characteristics and questions on knowledge and attitude toward participation in CTs. The minimum sample size estimated for the survey was 750. A total of 1260 respondents (patients and bystanders) had participated in the survey. 42% of total respondents were aware about CTs. Unawareness regarding (i) voluntary power of an individual to participate in a CT (only 47%), (ii) entitled benefits of free treatment and medical insurance during enrolment in a CT (only 47%), and (iii) only 16% of the respondents knew involvement of human subjects in CT were the major highlights among those who had prior knowledge about CTs. Education was the most pervasive factor in shaping positive perception among the respondents. Occupation was another ubiquitous factor in shaping their perception regarding CTs. The majority of respondents were not aware of CTs. The major concerns observed were time consumption and harmful nature of CTs that influenced their unwillingness to participate in CTs. Initiatives such as awareness campaigns and survey assessments that would result in scientifically effective health service policies would be strategic methods to enhance CT participation.

Commentary on 'Attitude and perception toward clinical trials in India among patients and patient bystanders visiting Indian ophthalmology clinical trial network: A multicentric, cross-sectional survey'.

Commentary on 'Attitude and perception toward clinical trials in India among patients and patient bystanders visiting Indian ophthalmology clinical trial network: A multicentric, cross-sectional survey'.

REVIEW ON INDIAN REGULATORY REQUIREMENTS OF CLINICAL TRIALS ON COVID VACCINES

COVID-19 is an infectious disease caused by a coronavirus strain that was discovered in December 2019 in Wuhan city,China. Corona viruses are a type of virus that causes common colds, MERS (Middle East Respiratory Syndrome), SARS(Severe Acute Respiratory Syndrome) and other illnesses. After the United States and Brazil, India has risen to third placein the world in terms of the number of COVID-19 cases. To protect humans from the disease, a race among vaccinedevelopers around the world has begun, with hundreds of COVID-19 vaccine candidates in various stages of clinicaltrials. On January 16, 2021, India's government began offering free COVID-19 vaccinations, and as part of what isanticipated to be the world's largest immunization campaign, it is asking all of its residents to get vaccinated. FourCOVID-19 vaccines, out of the eight being tested in various phases of clinical trials in India, were created. The Indianmedicines regulator has given its approval. Covishield, the Oxford-AstraZeneca vaccine, and Covaxin, a locally producedvaccine made by Bharat Biotech, are only to be used in cases of extreme urgency. The capability of Indian producers tosupply the nation's anticipated future demand for COVID-19 vaccines has been confirmed. The initial immunisation of30 million healthcare workers can be completed with the help of the staff and cold-chain infrastructure in place prior tothe pandemic. The Indian government has acted quickly to increase the nation's capacity for vaccine production and hasalso created an effective digital system to handle and monitor all facets of vaccine administration.

High Intensity Statins in Acute Coronary Syndrome Part II: A comparison of Atorvastatin and Rosuvastatin for use in ACS, Clinical trials in India and Place for statins in current guidelines

High Intensity Statins in Acute Coronary Syndrome Part II: A comparison of Atorvastatin and Rosuvastatin for use in ACS, Clinical trials in India and Place for statins in current guidelines

Knowledge and perception of health-care professionals on clinical trials in India: A pan-Indian cross-sectional survey.

The purpose of the study was to evaluate the knowledge and perception of health-care professionals (HCPs), such as doctors/surgeons, pharmacists, nurses, optometrists, and lab technicians, on clinical trials (CTs) in India. The study was a pan-Indian cross-sectional survey initiated by the Indian Ophthalmology Clinical Trial Network (IOCTN) by using a previously validated questionnaire for three months of data collection. An online survey was used to record information regarding demographics, CT knowledge, and CT perception among HCPs. A total of 630 responses were recorded from HCPs: 207 doctors and surgeons, 159 pharmacists, and 264 laboratory technicians, nurses, and optometrists across India. Over 90% of HCPs had a clear knowledge on the purpose of CTs, the informed consent (IC) process, ethical approval by the Drugs Controller General of India (DCGI). About 80% and 90% were aware of confidentiality of patients, voluntariness of participation, and good clinical practice. Surprisingly, less than 50% had lesser knowledge regarding monetary incentives of CT participants (CTPs). A slightly positive perception was observed regarding the potential benefits of CTPs, compensation related to injury, and importance of obtaining IC. Less than 50% had a negative perception that monetary compensation to CTPs led to bias and deprivation of standard treatments. However, no significant difference was observed between other aspects of demographics and perception regarding CTs. We observed doctors and surgeons to be having the highest regarding CTs, followed by pharmacists. The survey highlighted the necessity of scheduling awareness programs among the HCPs, which would improve their misconceptions and perception of CTs while interacting with patients for CT enrollment.

Legislative Framework and Role of Judiciary in Clinical Trials in India

This research paper explores the legislative framework governing clinical trials in India and the role of the judiciary in ensuring their compliance. India has emerged as a preferred destination for clinical trials, primarily due to the country's large and diverse patient population. However, this has also brought to light several ethical and legal issues surrounding clinical trials. The paper begins by examining the regulatory framework for clinical trials in India, including the Drugs and Cosmetics Act, the Indian Council of Medical Research Guidelines, and the Clinical Trials Registry - India. The paper then delves into the role of the judiciary in overseeing clinical trials, particularly in cases of ethical violations and compensation claims. The research analyses landmark cases in the Indian legal system and their implications for clinical trial regulation.

Vitamin D as an adjunct to antibiotics for the treatment of acute childhood pneumonia.

Children with acute pneumonia may be vitamin D deficient. Clinical trials have found that prophylactic vitamin D supplementation decreases children's risk of developing pneumonia. Data on the therapeutic effects of vitamin D in acute childhood pneumonia are limited. This is an update of a Cochrane Review first published in 2018. To evaluate the efficacy and safety of vitamin D supplementation as an adjunct to antibiotics for the treatment of acute childhood pneumonia. We searched CENTRAL, MEDLINE, Embase, and two trial registries on 28 December 2021. We applied no language restrictions. We included randomised controlled trials (RCTs) that compared vitamin D supplementation with placebo in children (aged one month to five years) hospitalised with acute community-acquired pneumonia, as defined by the World Health Organization (WHO) acute respiratory infection guidelines. For this update, we reappraised eligible trials according to research integrity criteria, excluding RCTs published from April 2018 that were not prospectively registered in a trials registry according to WHO or Clinical Trials Registry - India (CTRI) guidelines (it was not mandatory to register clinical trials in India before April 2018). Two review authors independently assessed trials for inclusion and extracted data. For dichotomous data, we extracted the number of participants experiencing the outcome and the total number of participants in each treatment group. For continuous data, we used the arithmetic mean and standard deviation (SD) for each treatment group together with number of participants in each group. We used standard methodological procedures expected by Cochrane. In this update, we included three new trials involving 468 children, bringing the total number of trials to seven, with 1601 children (631 with pneumonia and 970 with severe or very severe pneumonia). We categorised three previously included studies and three new studies as 'awaiting classification' based on the research integrity screen. Five trials used a single bolus dose of vitamin D (300,000 IU in one trial and 100,000 IU in four trials) at the onset of illness or within 24 hours of hospital admission; one used a daily dose of oral vitamin D (1000 IU for children aged up to one year and 2000 IU for children aged over one year) for five days; and one used variable doses (on day 1, 20,000 IU in children younger than six months, 50,000 IU in children aged six to 12 months, and 100,000 IU in children aged 13 to 59 months; followed by 10,000 IU/day for four days or until discharge). Three trials performed microbiological diagnosis of pneumonia, radiological diagnosis of pneumonia, or both. Vitamin D probably has little or no effect on the time to resolution of acute illness (mean difference (MD) -1.28 hours, 95% confidence interval (CI) -5.47 to 2.91; 5 trials, 1188 children; moderate-certainty evidence). We do not know if vitamin D has an effect on the duration of hospitalisation (MD 4.96 hours, 95% CI -8.28 to 18.21; 5 trials, 1023 children; very low-certainty evidence). We do not know if vitamin D has an effect on mortality rate (risk ratio (RR) 0.69, 95% CI 0.44 to 1.07; 3 trials, 584 children; low-certainty evidence). The trials reported no major adverse events. According to GRADE criteria, the evidence was of very low-to-moderate certainty for all outcomes, owing to serious trial limitations, inconsistency, indirectness, and imprecision. Three trials received funding: one from the New Zealand Aid Corporation, one from an institutional grant, and one from multigovernment organisations (Bangladesh, Sweden, and UK). The remaining four trials were unfunded. Based on the available evidence, we are uncertain whether vitamin D supplementation has important effects on outcomes of acute pneumonia when used as an adjunct to antibiotics. The trials reported no major adverse events. Uncertainty in the evidence is due to imprecision, risk of bias, inconsistency, and indirectness.

Clinical studies with Cannabis in India - A need for guidelines for the investigators and ethics committees.

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.