Vitamin D deficiency in rheumatoid arthritis patients of India - a single-arm meta-analysis.

Background: Vitamin D deficiency is commonly seen in patients with rheumatoid arthritis (RA). Objectives: This meta-analysis is aimed to determine the prevalence of Vitamin D deficiency in RA patients in India and also to evaluate the association between vitamin D level and disease activity. Methods: The relevant works of literature were identified through multiple databases and data was extracted from eligible studies independently. A single-arm meta-analysis was performed to estimate the prevalence of Vitamin D deficiency in RA patients in an Indian setup and its association with disease activity. A total of 15 studies was included in the analyses. Results: The mean serum vitamin D level was 19.99 ng/ml [95% CI 16.49-24.23]. The proportion of patients with low vitamin D level was 0.80 [95% CI 0.65- 0.90], Vitamin D deficiency was 0.56 [95% CI 0.31-0.77] and vitamin D insufficiency was 0.20 [95% CI 0.12- 0.32]. A negative relationship was seen with serum vitamin D and disease activity score. Conclusions: The results demonstrate significant low levels of serum vitamin D levels in patients with RA and established a negative correlation of Vitamin D with RA disease activity. The current evidence suggests a rationale for Vitamin D supplementation in the management of RA.

Impact of sodium-glucose co-transporter 2 inhibitors on renal outcomes in patients of diabetes mellitus: A meta-analysis of landmark renal and cardiovascular outcome trials.

Sodium-glucose co-transporter 2 inhibitors (SGLT2is) are recommended as the next step therapy for the management of diabetes mellitus. The large clinical trials of SGLT2is demonstrated benefits on various renal endpoints. We conducted this meta-analysis of large trials on cardiovascular and renal safety trials to explore the renoprotective effect of this group of drugs. PubMed, Cochrane CENTRAL, and EMBASE databases were searched with specific keywords till January 19, 2021. Randomized trials of SGLT2is that evaluated the cardiovascular or renal composite outcome as a primary outcome measure were eligible. Random-effects model was used to calculate the overall risk ratios. The search yielded 716 studies and 10 studies were included. The SGLT2is reduced the risk of composite renal outcome (risk ratio [RR] = 0.64, 95% confidence interval [CI] = 0.58-0.72), decline in estimated glomerular filtration rate (eGFR) (RR = 0.62, 95% CI = 0.50-0.77), doubling of serum creatinine (RR = 0.67, 95% CI = 0.56-0.81), dialysis or renal replacement therapy (RR = 0.71, 95% CI = 0.59-0.86), sustained eGFR of <15 ml per min per 1.73 m2 for at least 30 days or more (RR = 0.66, 95% CI = 0.55-0.81), end-stage renal disease (RR = 0.70, 95% CI = 0.56-0.87), and acute kidney injury (RR = 0.79, 95% CI = 0.71-0.89). This analysis establishes the renoprotective effect of SGLT2is. This benefit is noted in patients who had eGFR of more or <60 ml per min per 1.73 m2. This benefit was uniform across all the SGLT2 inhibitors except ertugliflozin and sotagliflozin.

A comprehensive evaluation of the safety of ipilimumab, nivolumab and their combination therapy: A systematic review and network meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have changed the landscape of management of advanced cancers. It is imperative to evaluate the safety of nivolumab and ipilimumab based therapies. This study was aimed to assess the comparative safety profiles of ipilimumab, nivolumab and their combinations. MATERIALS AND METHODS: We searched PubMed, Embase, and the CENTRAL for randomised controlled trials of ipilimumab and nivolumab. The outcome measures were treatment-related adverse events [TRAEs], TRAEs of grade 3-5, treatment discontinuation due to TRAEs [TDTRAEs], TDTRAEs of grade 3-5, serious adverse events [SAEs] and SAEs of grades 3-5. We performed a network meta-analysis using the Bayesian approach in R version 4.0.3. RESULTS: We identified 42 RCTs for final analysis. The treatment ranking for TRAEs revealed that nivolumab 240 mg/week and nivolumab 3 mg/kg/week were safer (0.84 and 0.81 in SUCRA); for TRAEs of grade 3-5, nivolumab 3 mg/kg/week and nivolumab 240 mg/week were safer (0.83 and 0.75 in SUCRA); for TDTRAEs nivolumab 3 mg/kg/week and ipilimumab in combination with other drugs were safer (0.87 and 0.64 in SUCRA) and for TDTRAEs of grade 3-5, nivolumab 3 mg/kg/week was safer (0.85 in SUCRA). Nivolumab 3 mg/kg/week and nivolumab 240 mg/week were safer (0.79 and 0.76 in SUCRA) for SAEs and nivolumab 3 mg/kg/week was safer for SAEs of grade 3-5 (0.78 in SUCRA). CONCLUSION: Nivolumab 3 mg/kg biweekly, nivolumab 240 mg weekly and nivolumab 3 mg/kg plus ipilimumab 1 mg/kg triweekly could be preferred due to the relatively low risk of TRAEs, TDAEs and SAEs.

Efficacy and Safety of Liraglutide 3.0 mg in Patients with Overweight and Obese with or without Diabetes: A Systematic Review and Meta-Analysis.

Background: Liraglutide in a 3.0 mg subcutaneous dose daily is approved for weight reduction. Objectives: Objectives are to evaluate the efficacy and safety of liraglutide 3.0 mg in patients with overweight and obesity irrespective of diabetic status. Methods: We conducted an electronic database search in PubMed, Embase, and https://ClinicalTrial.gov to identify all randomized control trials (RCTs) that evaluated the efficacy and safety of liraglutide 3.0 mg dose compared to placebo in overweight (≥27 kg/m2) and obese (≥30 kg/m2) patients above 18 years of age. Results: We compared the pooled estimate of the study results between liraglutide 3.0 mg groups and placebo groups both in diabetic and nondiabetic patients. The efficacy outcomes that were found to be significant among respective studies involving nondiabetic patients vs. diabetic patients were mean change in body weight from baseline: 12 studies [MD = -5.04 kg (95% CI = -5.60, -4.49), P < 0.001, I 2 = 92.95%] vs. 2 studies [MD = -4.14 kg (95% CI = -4.95, -3.32), P < 0.001, I 2 = 0%], reduction in waist circumference from baseline: 8 studies [MD = -3.64 cm (95% CI = -4.43, -2.85), P < 0.001, I 2 = 96.5%] vs. 2 studies [MD = -3.11 cm (95% CI = -3.88, -2.34), P < 0.001, I 2 = 0%], BMI reduction from baseline: 5 studies [MD = -1.95 kg/m2 (95% CI = -2.22, -1.68) vs. 1 study [MD = -1.86 kg/m2 (95% CI = -2.14, -1.57), P < 0.001, I 2 = 0%, P < 0.001, I 2 = 95.6%], proportion of patients losing more than 5% of weight loss from baseline: 8 studies [RR = 2.21, (95% CI = 1.89, 2.58), P=0.03, I 2 = 59.02%] vs. 2 studies [RR = 2.34, (95% CI = 1.93, 2.85), P=0.39, I 2 = 0.00%], and 10% weight loss from baseline: 7 studies [RR = 3.36, (95% CI = 1.92, 5.91), P=0.00, I 2 = 87.03%] vs. 2 studies [RR = 3.64, (95% CI = 2.46, 5.40), P=0.81, I 2 = 0.00%]. Safety outcome assessment with use of liraglutide 3.0 mg compared with placebo in respective nondiabetic vs. diabetic patients revealed significant proportion of patients experiencing the adverse events: 9 studies [RR = 1.11, (95% CI = 1.04, 1.18), P=0.00I 2 = 79.15%] vs. 2 studies [RR = 1.06, (95% CI = 1.01, 1.11), P=0.42, I 2 = 0.03%] but similar risk of serious adverse events: 9 studies [RR = 1.03, (95% CI = 0.70, 1.51), P=0.26, I 2 = 18.54%] vs. 2 studies [RR = 1.11, (95% CI = 0.67, 1.84), P=0.25, I 2 = 23.77%] and TDAEs: 4 studies [RR = 0.89, (95% CI = 0.35, 2.28), P=0.03, I 2 = 61.89%] vs. 1 study [RR = 2.53, (95% CI = 1.00, 6.37)]. However, the pooled estimates irrespective of the glycaemic status were mean change in body weight from baseline: 14 RCT [MD = -4.91 kg (95% CI = -5.43, -4.39), P < 0.001, I 2 = 92.35%], reduction in waist circumference from baseline: 10 studies [MD = -3.55 cm, (95% CI = -4.21, -2.89), P < 0.001, I 2 = 94.99%], BMI reduction from baseline: 6 studies [MD = -1.86 kg/m2, (95% CI = -2.14, -1.57), P < 0.001, I 2 = 96.14%], and proportion of patients losing more than 5% and 10% of weight from baseline: [RR = 2.23, (95% CI = 1.98, 2.52), P < 0.001, I 2 = 48.87%] and [RR = 3.28, (95% CI = 2.23, 4.83), P < 0.001, I 2 = 78.98%], respectively. Also, the proportion of patients experiencing the adverse event was more with liraglutide 3.0 mg compared with placebo 11 study [RR = 1.09, (95% CI = 1.04, 1.15), P < 0.01, I 2 = 76.60%] and similar risk for both serious adverse events: 11 studies [RR = 1.09, (95% CI = 1.04, 1.15), P < 0.01, I 2 = 76.60%] and TDAEs: 5 studies [RR = 1.14, (95% CI = 0.50, 2.60), P < 0.01, I 2 = 64.93%] with liraglutide compared with placebo. Conclusions: Liraglutide in 3.0 mg subcutaneous dose demonstrated significant weight reduction with a reasonable safety profile for patients with overweight or obesity regardless of diabetic status compared to placebo.

An audit of US FDA warning letters issued to sponsors, institutional review boards and investigators over a six-year period.

The present audit was carried out with the objective of evaluating warning letters (WLs) issued to trial sponsors, clinical investigators and institutional review boards (IRBs) by the United States Food and Drug Administration during a six-year period and compare it with two similar earlier audits. WLs were reviewed and classified as per stakeholders and further categorised as per predefined violation themes. The chi-square test was performed for trend analysis of WLs. A total of 62 WLs were issued to the three stakeholders. The maximum number of WLs were issued to the clinical investigators (36/62, 58.06%), followed by sponsors (19/62, 30.64%), and least to the IRBs (7/62, 11.29%). Among sponsors, lack of standard operating procedures for the monitoring, receipt, evaluation and reporting of post-marketing adverse drug events was the most common violation theme (8/19, 42.1%). Among clinical investigators, deviation from investigational plan was the most common violation theme (31/36, 86.11%.). For IRBs, inadequate documentation was the most common violation theme (6/7, 85.71%). We saw an overall reduction in the number of WLs issued to the stakeholders. Thus, we identified multiple areas on which each stakeholder should work for improvement.

Impact of disease-modifying therapies on MRI outcomes in patients with relapsing -remitting multiple sclerosis: A systematic review and network meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disorder of the central nervous system. The clinical presentation supported by characteristic findings on MRI forms the backbone of the current diagnostic criteria. This study was aimed to investigate the efficacy based on MRI outcomes of FDA approved disease-modifying therapies (DMTs) for relapsing-remitting MS (RRMS). MATERIALS AND METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomised controlled trials (RCTs) of DMTs. The outcome measures were the mean number of T2 [new/enlarging lesions], new T1 [gadolinium-enhancing (Gd+) T1 and hypointense T1] lesions in brain MRI performed at 12 months or 24 months. We performed a network meta-analysis using the frequentist approach in STATA version 16.0. RESULTS: We identified 26 RCTs for final analysis. Interferon ß-1a and placebo were the most common comparison treatment. Ocrelizumab was more effective in reducing the number of Gd+T1 lesions. Dimethyl fumarate 480 mg was relatively better in reducing the number of new T2 lesions. The treatment ranking showed that ocrelizumab and dimethyl fumarate 480 mg were more efficacious (1 and 0.9 in SUCRA, respectively) for reducing the number of new Gd+T1/hypointense lesions; dimethyl fumarate 480 mg/720 mg and natalizumab were more efficacious (1.0, 0.9 and 0.8 in SUCRA, respectively) to reduce the number of new T2 lesions. CONCLUSION: Ocrelizumab, dimethyl fumarate 480/720 mg and natalizumab demonstrated favourable MRI outcomes in patients with the RRMS.

An Audit of Black Box Warnings (BBWs) in the United States Food and Drug Administration (US-FDA) Database - A Five-Year Analysis.

BACKGROUND: The Black-Box Warning (BBW) is the most serious warning that US-FDA can ask for on a drug's labelling. BBWs represent key safety concerns uncovered either during dossier review or post-approval. We have conducted the present study with the primary objective of assessing BBWs issued by the US-FDA. METHODS: BBWs were identified on US-FDA's website from 1st January 2015 to 31st December, 2019. Prescribing information was used to identify and characterize BBWs into new and minor/major updates on a previous BBW. The therapeutic class of the drug, nature [Biological/New Molecular entity (NME)], formulation type, expected duration of use, along with the year of first approval of the molecule with BBWs were evaluated. RESULTS: A total of n = 167 BBWs were issued by the FDA of which 53 (31.7%) had major updates, 57(34.1%) had minor updates and 57(34.1%) were new BBWs. A total of 137(82%) of BBWs were with NME's whereas 30(18%) were with biologics. Drugs for neurology 40(25.5%)had the highest number of BBWs, followed by oncology 38(24.2%). Among the type of BBWs, cardiovascular risk 31 (15%) were the highest. CONCLUSION: Practicing physicians need to understand that benefit-risk of a drug is dynamic and keep abreast of new data related to it.

A Meta-Analysis of Safety of Different Regimens of Remdesivir in COVID-19 Patients.

Remdesivir is an adenosine analogue drug that targets RNA-dependent RNA polymerase enzyme and inhibits viral replication. As of 22nd October, 2020, US FDA fully approved the drug Remdesivir for the treatment of COVID-19 patients who requires hospitalisation. Many clinical studies reported the derangement in hepatic and renal function tests, which is alarming considering the health conditions of the COVID-19 patients. In view of these results, the present study was envisaged to review the safety of Remdesivir in COVID-19 patients. The PubMed, Embase, and Cochrane databases were searched using the terms 'Remdesivir,' 'veklury,' 'SARS' and 'COVID' till 1st December, 2020. The studies included in this meta-analysis were either randomised or nonrandomised studies that evaluated Remdesivir for the treatment of COVID-19 against Placebo [standard of care]. The Adverse events [AEs], Serious adverse events [SAEs] and Treatment Discontinuation due to Adverse Events (TDAE) were used as primary outcome measures. The quality of studies was evaluated by using the Cochrane Collaboration's tool for the assessment of RoB. Data analysis was performed by two authors (MK & DB) using statistical software Review manager [Revman] version 5.3. The pooled Risk Ratios (RR) and 95% Confidence Intervals (CI) were calculated by using a random-effects model for both primary and secondary outcomes. A total of four RCTs were included for the meta-analysis. Out of the four included clinical trials accepted for its methodological quality, three were of excellent quality and one study was of moderate quality. The pooled estimates of the three studies showed that Remdesivir had a 24% lower risk of SAEs compared to the placebo arm. However, the pooled estimates of two studies showed that 10 days of Remdesivir had 56% higher risk of SAEs compared to 5 days of Remdesivir regimen. Similarly, the 10 days of Remdesivir had two times higher risk of TDAEs compared to 5 days Remdesivir regimen. In conclusion, our meta-analysis demonstrated that Remdesivir is a safe therapeutic option. Our metanalysis revealed 5 days' regimen have better safety profile than 10 days' regimen of drug Remdesivir with respect to SAEs and TDAEs. For hospitalized patients, a 5-day course could be preferable with fewer safety concerns and lower drug costs. PROSPERO Registration ID: CRD 42020224272.

A Systematic Review and Meta-Analysis of the Safety of Hydroxychloroquine in a Randomized Controlled Trial and Observational Studies.

INTRODUCTION: Hydroxychloroquine (HCQ) has recently become the focus of attention in the current COVID-19 pandemic. With an increase in the off-label use of HCQ, concern for the safety of HCQ has been raised. We, therefore, performed this systematic review to analyze the safety data of HCQ against placebo and active treatment in various disease conditions. METHODS: We searched PubMed, Embase, and Cochrane for Randomized Controlled Trials (RCTs) and Observational Studies (OSs) that evaluated HCQ for the treatment of any disease other than COVID19 in adult patients up to May 2020. We assessed the quality of the included studies using Risk of Bias 2 (for RCTs) and Newcastle-Ottawa Scale (for OSs). Data were analyzed with randomeffect meta-analysis. Sensitivity and subgroup analyses were performed to identify heterogeneity. RESULTS: A total of 6641 studies were screened, and 49 studies (40 RCTs and 9 OSs) with a total sample size of 35044 patients were included. The use of HCQ was associated with higher risks of TDAEs as compared to placebo/no active treatment [RR 1.47, 95%CI 1.03-2.08]. When HCQ was compared with active treatments, the risks of AEs [RR 0.74, 95% CI 0.63-0.86] and TDAEs were less in the HCQ arm [RR 0.57, 95% CI 0.39-0.81]. The outcomes did not differ in the sensitivity analysis. CONCLUSION: The results suggest that the use of HCQ was associated with a lower risk of AEs and TDAEs as compared to active treatment, whereas posing higher risk of TDAEs as compared to placebo.

Analysis of Robustness of the Landmark Cardiovascular Outcome Trials of Antidiabetic Drugs - A Systematic Review.

BACKGROUND: It is essential for randomized controlled trials (RCTs) to report results in a comprehensive manner. Hence, it is necessary to assess the robustness of the trials with statistically significant and as well as non-significant results. Robustness can be evaluated using fragility index (FI), while reverse fragility index (RFI) can be used for trials with statistically significant as well as non-significant results. The primary aim of this study was to calculate FI and RFI for cardiovascular outcome trials (CVOT). MATERIALS AND METHODS: PubMed/MEDLINE was searched to identify all RCTs of antidiabetic drugs where the primary objective was to evaluate the cardiovascular outcomes. We recorded the trial characteristics of each CVOT trial. The FI, RFI, fragility quotient (FQ), and reverse fragility quotient (RFQ) were calculated to evaluate the robustness of the trials. Spearman rank correlation test was used for correlation. FINDINGS: A total of 889 studies were identified and 24 RCTs were included. Among the 24 trials, 12 (50%) trials achieved statistical significance. The median FI and RFI were 29 (4-12) and 22.5 (1-37) for trials with statistically significant and non-significant results. The median FQ and RFQ were 0.0075 (0.002-0.013) and 0.0003 (0.0001-0.004) for trials with statistically significant and non-significant results. The hazard ratio, p-value, and NNT-B had a strong negative relationship with FI. INTERPRETATION: Our study showed that half of the trials showing the superiority of cardioprotective benefits have favourable FI. The trials that failed to show superiority also have a reasonable RFI indicating the robustness of these trials. However, the results of the trials where patients lost to follow- up exceed the FI of that trial demands caution during interpretation.

Evaluation of efficacy and safety of fosfomycin versus nitrofurantoin for the treatment of uncomplicated lower urinary tract infection (UTI) in women - A systematic review and meta-analysis.

Urinary tract infections (UTI) are among the most frequent medical conditions requiring outpatient treatment. Single dose oral fosfomycin (300 mg) and the older nitrofurantoin (100 mg for 5 days) have been found to be more effective than other first-line drugs in multiple studies. This systematic review and meta-analysis were carried out with the objective of evaluating their comparative efficacy and safety in the management of uncomplicated UTI. Two authors independently searched PubMed, Cochrane Central, Embase, and Google Scholar till Nov 2020 using MeSH terms and free text. Randomized controlled trials (RCTs) comparing both drugs for efficacy and safety in uncomplicated UTI in adult women were included. The primary outcome measures were microbiological and clinical cure rates. The search resulted in n = 663 studies out of which only four studies (three for treatment of uncomplicated UTI in women and one for asymptomatic bacteriuria in pregnancy) satisfied the selection criteria. No significant differences in clinical, (RR 0.95, 95% CI - 0.81, 1.12) and microbiological cure, (RR 0.96, 95% CI - 0.84, 1.08) were found within 4 weeks of treatment. The incidence of adverse events was found to be more in fosfomycin relative to the nitrofurantoin group (RR 1.05, 95% CI - 0.59, 1.87). Hence, single-dose fosfomycin presents a potentially useful and safe treatment option for the treatment of uncomplicated UTI in women and asymptomatic bacteriuria in pregnancy.

An Audit of Interim Analyses of Randomized Controlled Trials (RCTs) Published in Three High Impact Factor Medical Journals Over a Seven- year Period (2012-2018).

BACKGROUND: Interim analysis is an integral component of clinical research and drug development in particular and helps reduce 'time to market' for an intervention or stop further development of unsafe and ineffective interventions. In this audit, we evaluated the extent of use of interim analyses in published RCTs in three leading journals and their impact on regulatory approval. METHODOLOGY: RCTs published in JAMA, NEJM and Lancet in the year 2012 to 2018 were extracted. Each RCT was scrutinized using the filter term 'Interim'. Both descriptive and inferential statistics were used to analyze the data. The factors (therapeutic areas, nature of interventions, source of funding and phases of trials) associated with Interim analysis and its impact on drug approval were analyzed. RESULTS: The majority of RCTs with interim analysis belonged to oncology (27%) and cardiology (17.2%) and were related to drugs (70%). Majority of the RCTs were in phase 3 (56.3%) and funded exclusively by Pharmaceutical industry (36.2%). A total of 2% and 14% studies led to accelerated approval and normal regulatory approval. The choice of alpha spending function was not mentioned in 44.8% studies and 21% studies used O-Brien Fleming method. A total of 18.5% studies were stopped early. The oncology trials, drug as intervention and Phase 3 trials were associated with the conduct of interim analysis which was associated with significantly higher numbers of accelerated and routine regulatory approvals. CONCLUSION: Majority of the RCTs with interim analysis were from oncology and most did not report a stopping rule. Interventions that were drugs (rather than devices or surgical procedures). and phase 3 trials (relative to other phases of RCTs). were associated with significantly higher number of interim analyses which was also associated with significantly higher number of regulatory approvals.

Placing the results of the SOLIDARITY trial with regards to remdesivir in perspective.

Remdesivir, a repurposed antiviral, was first accorded approval by the US Food Drug Administration (FDA) for the treatment of COVID-19 which necessitates hospitalization. However, the interim data of SOLIDARITY trial revealed no benefits with remdesivir for COVID-19 patients which led immediate debates in social media and the press about the utility of the drug. Both preclinical and clinical data demonstrated its efficacy in COVID-19. The recently concluded ACTT-1 trial showed its efficacy in reducing the duration of hospital stay which is of utmost importance for a country like India where reduction in bed occupancy can save lives of many and eases the financial burden of patient and government. Our benefit-risk analysis of ACTT-1 trial also favored the use of remdesivir over standard of care. The SOLIDARITY trial was fundamentally different from other clinical trials on remdesivir with respect to its design, adaptive nature, and selection of endpoints. Moreover, the success of antiviral therapy also depends on the timing of initiation and combination with other drugs. Hence we believe that drugs like Remdesivir are very important for countries like India where soft end points such as time to recovery and clinical improvement and early discharge become extremely significant during a pandemic.

Factors influencing recruitment and retention of participants in clinical studies conducted at a tertiary referral center: A five-year audit.

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.

An audit of reporting of conflict of interest policies among three stakeholders in Indian biomedical journals.

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.

An audit of studies registered retrospectively with the Clinical Trials Registry of India: A one year analysis.

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.

Investigator-initiated studies: Challenges and solutions.

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.

Investigator preparedness for monitoring and audits.

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.