An audit of questions asked by participants during the informed consent process for a phase 2/3 COVID-19 vaccine regulatory study at a tertiary referral centre.

Objective: To evaluate questions asked during the informed consent process by adult participants in a COVID-19 vaccine regulatory study conducted at our center in 2020. Methods: After approval by the IEC, informed consent documents and consent narratives were evaluated. We collated the total number and nature of questions. We then looked at the association between education, gender, socio-economic status, employment status, the language of consent, and number of questions. Between-group comparison (female vs male, unemployed vs employed, primary school vs secondary school vs graduate vs post-graduates, upper vs upper-middle vs middle vs lower middle vs lower) for the number of questions asked was done using univariate analysis followed by multivariate regression analysis with post hoc Tukey's test. Independent variables were gender, employment status, education and socioeconomic status and the dependent variable was the number of questions asked by the participant. All analyses were done at 5% significance. Content analysis was done in addition by creating categories after evaluation and coding them. Results: A total of N = 129 consents from the same number of participants were evaluated. A total of N = 127/129 participants asked at least one question. Sixty-seven percent of participants asked questions related to the study procedure, followed by 44.9% of participants who asked questions related to the safety of vaccine or placebo. A total of N = 295 questions were asked by the 127 participants. In content analysis, 149/295 (50.5%) questions were on study-related procedures followed by one quarter 76/295 (25.8%) based on safety associated with Investigational Product. Very few participants [2.4%] asked about post-trial access as the regulatory trial was a placebo-controlled trial. None of the independent variables were found to be associated with the number of questions. Conclusion: The majority of the questions asked by the participants were about study-related procedures and vaccine safety. No association was found between any of the independent variables and the number of questions asked. However, there were differences in the demographics of the trial participants between the pandemic and pre-pandemic era.

An audit of safety reporting in randomized controlled trials over a five-year period in a high impact factor journal.

Background: Randomized controlled trials [RCTs] form the corner-stone of evidence-based medicine. RCTs published in high impact factor journals such as the New England Journal of Medicine [NEJM] are a key driver of clinical practice and policy decisions. RCTs are expected to report both efficacy and safety, however, safety reporting in many studies tends to be poor. The present audit was undertaken with the primary objective of evaluating safety reporting during a five-year period in all RCTs published in the NEJM. Methods: PubMed alone was searched for RCTs published in NEJM from 2013-17. Each RCT was searched for the following outcome measures -whether the trial was sponsored by pharmaceutical industry or investigator initiated, phase of trial, nature of intervention and therapeutic area in terms of reporting of safety outcomes [with 'P values' or '95% confidence interval']. Results: A total of n=623 articles reported safety outcomes of which 275/623 (44.1%) articles reported statistics for safety outcome. There was significant difference in reporting of safety statistics between investigator initiated studies and pharmaceutical industry sponsored studies, [cOR=4.0, 95% CI 2.8- 5.5 P < 0.001]; phase 3 and phase 4 trials, [cOR 0.67, 95% CI 0.5 - 0.9, P = 0.02]; trials involving drugs and surgery, [ cOR 2.07, 95% CI 1.2-3.5, P = 0.01] and in therapeutic areas, cardiovascular and oncology [cOR 0.26, 95% CI 0.1-0.4, P < 0.0001]. Conclusions: Safety reporting in RCTs continues to take a back seat relative to efficacy reporting and is worse for pharmaceutical industry funded studies. Safety reporting should be emphasized in the CONSORT guidelines.

A literature review of consent declines and consent withdrawals in randomized controlled trials conducted during the COVID-19 pandemic.

Objectives: We evaluated the extent of consent declines and consent withdrawals during the COVID-19 pandemic as seen in published randomized controlled trials (RCTs) and compared it with non-COVID-19 RCTs published at the same time and two historical controls. Methods: PubMed/Medline only was searched using key-word "COVID-19" and "RCTs" separately, and filtered for COVID-19 RCTs and non-COVID-19 RCTs respectively, published during a nine-month period (1 Feb - 1 Nov 2020). Exclusions were study protocols, observational studies, interim analysis of RCT data and RCTs with missing data. Primary outcome measures were the proportion of consent declines and consent withdrawals as percentage of total participants screened and randomized respectively in COVID-19 RCTs. We compared consent declines and consent withdrawals of COVID-19 RCTs with non-COVID-19 RCTs and two earlier studies on the same topic that served as historical controls (non-pandemic setting). Results: The search yielded a total of 111 COVID-19 RCTs and 49 non-COVID-19 RCTs. Of these, 39 (35.13%) COVID-19 RCTs and 11 (22.45%) non-COVID-19 RCTs were finally analysed. A total of 770/17759 (4.3%) consent declines and 100/7607 (1.31%) consent withdrawals were seen in 39 COVID-19 RCTs. A significant difference was observed in consent declines between COVID-19 vs non-COVID-19 RCTs [4.3% vs 11.9%, p < 0.0001] and between COVID-19 RCTs vs two historical controls [(4.3% vs 8.6%, p < 0.0001) and (4.3% vs 21.1%, p < 0.0001), respectively]. Conclusion: RCTs conducted during the COVID-19 pandemic appear to have significantly lower consent declines relative to non-COVID-19 RCTs during pandemic and RCTs conducted in non-pandemic settings.

Evaluation of pharmacokinetics of single-dose primaquine in undernourished versus normally nourished children diagnosed with Plasmodium vivax malaria in Mumbai.

BACKGROUND: The pharmacokinetics of primaquine [PQ] have been the subject of studies in both adults and healthy participants. However, there is no study on its pharmacokinetics in a setting of undernourishment. In India, there is evidence to show considerable malnourishment in children that in turn can affect drug pharmacokinetics. Given that the country is moving towards malaria elimination, the present study was planned with the objective of comparing pharmacokinetics of the drug in undernourished children relative to normally nourished children. MATERIALS AND METHODS: After Institutional Ethics Committee approval, children of either gender between the ages of 5 and 12 years and smear-positive for Plasmodium vivax malaria were included. Nourishment status was determined using the Indian Academy of Pediatrics classification of protein energy malnutrition based on Khadilkar's growth charts. Twelve children each were enrolled in the two groups. PQ was given in the dose of 0.3 mg/kg/d and blood collections were made at 0, 1, 2, 3, 4, 6, 8 and 24 hours post-dosing. Levels were estimated by high-performance liquid chromatography. Chloroquine in the dose of 25 mg/kg was given over three days along with supportive care. RESULTS: Of the 24 children, there were 17 boys and 7 girls. There was a statistically significant difference in the body weight between the undernourished and the normally nourished children [21.5 ± 5.52 vs. 28.8 ± 8.84, P < 0.05]. PQ levels showed wide inter-individual variation in both groups. No significant difference was seen in any pharmacokinetic parameter between the two groups. DISCUSSION: This study adds to the limited body of evidence on the pharmacokinetics of PQ in children with malaria and indicates that the dosing of primaquine could potentially be independent of the nourishment status.

Pharmacokinetics of isoniazid in Indian children with tuberculosis on daily treatment.

OBJECTIVE: To assess the pharmacokinetics of isoniazid (INH) at 10 mg/kg/day among Indian children. METHODS: INH levels were estimated using liquid chromatography-tandem mass spectroscopy in 35 children aged 1-15 years on daily anti-tuberculosis treatment. Blood samples were collected 0, 1, 2, 3, 6 and 24 h after INH administration. The maximum concentration (Cmax) and area under the curve (AUC0-24) were determined. The normal therapeutic range for Cmax is 3-5 µg/ml. An AUC of <10.52 µg•h/ml for INH is low. RESULTS: The mean Cmax was 8.3 ± 4.28 µg/ml and was attained in 1.22 ± 0.5 h, with a median time to Cmax (Tmax) of 1 h. The mean AUC for INH was 46.23 ± 34.82 µg•h/ml. Children aged 1-4.9 years, 5-10 years and >10 years had a mean Cmax of respectively 9.87 ± 5.75 µg/ml, 7.62 ± 3.37 µg/ml and 7.21 ± 2.50 µg/ml (P = 0.08) and a mean AUC of respectively 60.97 ± 49.90 µg•h/ml, 38.95 ± 22.28 µg•h/ml and 36.09 ± 13.56 µg•h/ml (P = 0.29). The mean Cmax in children taking fixed-drug combinations and individual drugs was respectively 9.07 ± 4.67 µg/ml and 7.43 ± 3.71 µg/ml (P = 0.26); the mean AUC was respectively 50.48 ± 38.38 µg•h/ml and 41.20 ± 30.52 µg•h/ml (P = 0.44). Two children had hepatitis. CONCLUSION: Most Indian children had higher than normal INH AUC and Cmax values. It is necessary to determine the ideal dose of INH in Indian children using the genotypic acetylator status of the patients and pharmacokinetic toxicity analysis.

A critical analysis of the COMPASS trial with respect to benefit-risk assessment using the numbers needed to treat: Applicability and relevance in Indian patients with stable cardiovascular disease.

The recently published Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial evaluated the hypothesis that rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary prevention. In India, stable cardiovascular disease occurs in a much younger age group relative to the rest of the world. Our critical analysis of COMPASS trial showed that the younger age group appeared to derive greater benefit from the rivaroxaban+aspirin combination (relative to aspirin alone) as seen with number needed to treat metrics as compared to the older age group.

A comparative study of the informed consent process with or without audiovisual recording.

BACKGROUND.: The Central Standard Drugs Control Organization (CDSCO) issued an administrative order in November 201 3 mandating audiovisual (AV) recording of the informed consent process for all regulatory studies. At this point, a phase 2/3 trial ongoing at our centre had recruited 45 participants using the written, informed consent process. Another 40 participants were recruited after the order and underwent AV recording of the consent process. We assessed the difference in participants' understanding between the two consenting processes as the trial fortuitously had both forms of consent. METHODS.: A 16-item questionnaire with six domains (purpose, study procedures, risks, benefits, payment for participation, and rights and confidentiality) was designed and validated. It was administered to the participants after approval of the institutional ethics committee and written informed consent. Answers given were matched with a template of model answers. The responses were scored as fully correct (3), partially correct (2), 'don't remember' (1 ), and incorrect (0) with a total possible score of 48. Between-group analysis was done for total scores and domain-specific scores. Domain-wise analysis was done for the proportion of all categories of responses. The impact of potential confounders on participants' understanding was also factored in. RESULTS.: A total of 38 respondents-21 in the AV consent group and 1 7 in the written consent group-agreed to participate. The total mean (SD) score of the AV consent group was significantly higher (40.3 [5.9]) compared to that of the written consent group (34.8 [7.94]; p = 0.01). Between the groups the score was significant in the domains of rights and confidentiality (p = 0.01). The proportion of participants who gave fully correct answers was statistically significant in the domain of purpose (p = 0.04). The time elapsed between the original consent and this study showed a weak inverse correlation (ρ = -0.3, p = 0.01). CONCLUSION.: AV recording of the informed consent process in a clinical trial appears to improve the understanding of participants relative to the written informed consent alone.