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Background In May 2020, WHO recognized the role of extensive immunization for interrupting the transmission of the SARS-CoV-2 virus. The development of such vaccines in clinical trials relies upon participants who are expected to be vested in the research process. Assessment of participant factors such as motivation and satisfaction are hence important to gauge perspective and ensure successful conduct and completion of these trials. Methods We administered a validated three-domain questionnaire to and documented the binary categorical responses (yes/no) of participants (after informed consent) who had taken both doses of COVOVAX™ in a phase 3 trial at our institute. Association of the dependent variables (participant responses) with the independent variables (participant demographics and socioeconomic strata) was computed using Chi-square test at 5% significance. In case of a significant association, Bonferroni post-hoc test was applied for multiple comparisons. Results Of the 78 participants who were administered the questionnaire, two-thirds were highly satisfied with their experience at our site. Gaining access to a new vaccine was a primary motivation overall (74%) and also in graduates (p=0.03) and middle-class population (p=0.002), whereas the lower-middle class population (p Conclusion Participants in a Covid-19 vaccine trial at Mumbai were largely satisfied with the care given to them though altruism did not feature as a primary reason for participation.

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.

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.

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.

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.

Background: The present case–control study evaluated the association of PON1 gene polymorphisms and enzyme activity in the western Indian population. Materials & methods: Angiographically proven coronary artery disease (CAD) formed the cases. PON1 polymorphisms (Q192R, L55M) and enzymatic activity (paraoxonase) were assessed. Results: A total of 502 participants (251 per group) were studied. PON1 Q192R and L55M polymorphisms were not associated with the risk of CAD. Notably, a weak association was observed between Q192R polymorphisms and the risk of CAD. CAD patients had significantly lower PON1 enzymatic activity (U/L) as compared with the controls regardless of the genotype. Conclusion: Low serum PON1 activity was confirmed to be an independent predictor for the risk of CAD.

An innovative intranasal aqua-triggered in-situ (ATIS) gel is a polymer-free in-situ gelling microemulsion which gels instantaneously on contact with minute quantities of water to form a mucoadhesive gel. The objective of the study was to develop ATIS diazepam (ATIS-diazepam) as an alternative to the injection for epileptic emergencies and evaluate its brain uptake and nose-to-brain targeting efficiency in rats. ATIS-diazepam (1 mg/100 µL) was prepared and characterized for in vitro formulation characteristics. An LC–MS/MS method was developed and validated for the bioanalysis of diazepam. In vivo studies for pharmacokinetics, brain uptake and nasal irritation of intranasal ATIS-diazepam were conducted in rats. Brain uptake was investigated with brain microdialysis, a highly sensitive technique enabling quantification of free drug, which correlates to efficacy. ATIS-diazepam exhibited globule size

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.

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.

The government guidance regarding COVID-19 vaccination lists food allergy, drug allergy and history of anaphylaxis as contraindications for receiving vaccination. This study was planned to evaluate such patients listed in the database of an allergy center and who took any COVID-19 vaccine.Data on n=255 patients was mined. Inclusions were those over 18 years, any allergic diathesis and receipt of at least one dose of any COVID-19 vaccine. Age, gender, nature of allergy and type of COVID vaccine taken along with outcome of interest [occurrence or otherwise of all allergic reaction post vaccination] was collated.Data of 227 patients were finally analysed. Eighty one took the first dose and 33 took both doses. None with food and/or drug allergy and/or a history of anaphylaxis developed any adverse event (AE) post vaccination. Three AEs were seen in those with other allergic diathesis. Two AEs [One to COVAXIN™ and one to COVISHIELD™] were only generalized itching that were self-limiting. A female patient had itching with palmar erythema [post COVISHIELD™] which subsided after a week's treatment with an antihistamine. She had a history of allergy to radiocontrast media containing polyethylene glycol/PEG] indicating possible allergy to polysorbate 80 [PEG related compound contained in COVISHIELD™].No patient fitting contraindications for COVID-19 vaccination laid down by the Indian government developed any allergic reaction post vaccination. The guidelines for vaccination may be revisited to make them more inclusive with appropriate training of the vaccination centre staff.

Predatory journals charge publication fees from authors and publish without an adequate peer review, and often do not provide editorial and/or publishing services. Our objective was to evaluate e-mail solicitations received by authors in a defined time period to identify attributes of these solicitations as a metric to identify legitimacy of the journal. All e-mails seeking article submission received between January 1 and September 30, 2019, were evaluated. Each e-mail along with its respective webpage was evaluated for the journal’s and publisher’s names, mention of peer review, any assurance of publication, a mention of article processing charges (APC), composite invites [in the e-mail] and mention of peer review, the presence and functionality of archives, presence of manuscript management tab, mention of APC [on the webpage]. Descriptive statistics were used for the analysis. Of the 135 e-mails screened, 100 were finally included in the analysis. We found that 72% of the journals and/ or publishers were included in Beall’s list. According to our criteria, a total of 85% of the solicitations were from journals that we identified as “presumed predatory”. Our study has identified assurance of publication, rapid turnaround time, ambiguous information in the email and webpage, false claims of indexing as some descriptors which may help young authors and researchers assess a journal’s legitimacy.

Background and rationale When deception is used, a conflict ensues between the need to use it to answer a research question scientifically whilst protecting the participants’ autonomy simultaneously. Authorized deception (where participants are told they will be deceived) is a method that has been proposed to address the traditional “non-authorized” deception. Our study evaluated authorized versus non-authorized deception in a pain model of third molar extraction. Methods Adult patients requiring surgery for third molar extraction were enrolled after consent and randomized to either the authorized or “non-authorized” deception group. Within each group, they were further randomized to receiving either an “expensive” or an “inexpensive” painkiller. All participants actually received the same painkiller. The primary outcome measure was pain, while the proportion of patients taking rescue medication was the secondary outcome measure. All patients were debriefed at study completion. Results The median peak pain score was not significantly different between the groups. A little over 21% patients in the authorized deception group relative to 32.4% patients in the non-authorized group took rescue medication (p = 0.09). In the non-authorized deception group, 30% patients in the “inexpensive” group relative to 34.5% patients in the “expensive” group took rescue medication (p > 0.05). In the authorized deception group, 12.5% patients who received “expensive” relative to 30.4% who received the “inexpensive” painkiller took rescue medication (p = 0.04). Conclusions While our study showed equivalence of the two deception modalities, authorized deception may not be truly sterile.

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.

Purpose: In pharmaceutical industry funded clinical studies (PIS), there is rigorous monitoring to ensure adequate and accurate data documentation. In comparison, the investigator-initiated studies (IIS) often lack in resources and may not follow such quality checks. At present, very limited data on the existing deficiencies in documentation for IIS are available. Hence, the present study assessed data quality in IIS relative to those funded by the industry to identify and address issues in data documentation. Materials and Methods: We evaluated records of 1276 participants in 13 studies (5 – industry sponsored and 8 – investigator initiated) conducted during 2009–2015 using a prevalidated checklist. The percentage total scores for overall documentation and general trial-related and patient-specific documents were calculated. The percentage total scores within the patient-specific documents were also calculated and compared. Between-group score analysis was done by Student's t-test using GraphPad InStat version 5.0. Results: The mean (standard deviation [SD]) percentage total score for the IIS was 80.96 (13.26) and that for PIS was 98.77 (1.84) (P = 0.01). For IIS, the total percentage scores ranged from 63% to 100% while it was above 95% for all PIS. For general trial-related documents, the mean (SD) percentage total score for IIS was 90.39 (13.26) while that for PIS was 97.38 (0.92) (P > 0.05). In the patient-specific documents, IIS scored 80.52 [14.41] versus 98.95 (1.98) for PIS (P = 0.016). The scores for IIS versus PIS (70.22 [21.6] and 99.36 [1.43]) within patient-specific documents were significant only for admission criteria (P = 0.016). Conclusion: Quality of IIS needs to be addressed by greater oversight and periodic quality control assessments.

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.

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.

Background: ChAdOx1 nCoV-19 Corona Virus Vaccine (Recombinant) (SII-ChAdOx1 nCoV-19), manufactured in India at Serum Institute of India Pvt Ltd (SIIPL) after technology transfer from AstraZeneca, was evaluated in this phase 2/3 immunobridging study. Methods: This observer-blind study randomised participants 3:1 to SII-ChAdOx1 nCoV-19 or AZD1222 (ChAdOx1 nCoV-19) (immunogenicity/reactogenicity cohort) and 3:1 to SII-ChAdOx1 nCoV-19 or placebo (safety cohort). Two doses of vaccine (5 × 10¹⁰ viral particles) or placebo were given at 4-week intervals (+2-week window). Primary objectives were to demonstrate non-inferiority of SII-ChAdOx1 nCoV-19 to AZD1222 in terms of geometric mean titre (GMT) ratio of anti-SARS-CoV-2 spike immunoglobulin G (IgG) antibodies 28 days after second dose (defined as lower 95% CI >0·67) and to determine the incidence of serious adverse events (SAEs) causally related to SII-ChAdOx1 nCoV-19. Anti-spike IgG response was assessed using a validated multiplexed electrochemiluminescence-based immunoassay. Safety follow-up continued until 6 months after first dose. Findings: Between August 25 and October 31, 2020, n=1601 participants were enrolled: n=401 to the immunogenicity/reactogenicity cohort and n=1200 to the safety cohort. After two doses of SII-ChAdOx1 nCoV-19 or AZD1222, seroconversion rates for anti-spike IgG antibodies were 98·0% and 98·9%, respectively, with anti-spike IgG GMTs of 30 245·6 AU/mL (95% CI 26 794·0–34 141·8) and 28 558·3 AU/mL (23 479·3–34 735·8); SII-ChAdOx1 nCoV-19 was non-inferior to AZD1222 (GMT ratio 0·98; 95% CI 0·79–1·23). SAEs were reported in 15/1200 (1·3%, 95% CI 0·7–2·1), 2/300 (0·7%, 0·1–2·4) and 2/100 (2·0%, 0·2–7·0) participants who received SII-ChAdOx1 nCoV-19, placebo and AZD1222, respectively; none were causally related. SARS-CoV-2 infections were observed in 1·9% (n=22), 3·4% (n=10) and 2·0% (n=2) of the SII-ChAdOx1 nCoV-19, placebo and AZD1222 groups, respectively; none were severe. Interpretation: SII-ChAdOx1 nCoV-19 has a non-inferior immune response compared to AZD1222 and an acceptable safety/reactogenicity profile. Trial Registration: This study was registered with number CTRI/2020/08/027170 Funding: SIIPL, Indian Council of Medical Research, AstraZeneca. Declaration of Interest: PSK, CB, AD, MG, US, DK, and BG are employees of SIIPL. JV and EJK are employees of AstraZeneca. All other authors declare no competing interests. Ethical Approval: The study was approved by the Drugs Controller General of India (DCGI) and the ethics committees of each study site.

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.

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 quadrivalent split-virion inactivated influenza vaccine (IIV4; Fluzone® Quadrivalent, Sanofi Pasteur) has been available in the US since 2013 for individuals aged ≥ 6 months. Here, we describe the results of an open-label, multicenter trial (WHO Universal Trial Number U1111-1143–8370) evaluating the immunogenicity and safety of IIV4 in Indian children aged 6–35 months and 3–8 years, adolescents aged 9–17 years, and adults aged ≥ 18 years (n = 100 per group). Post-vaccination hemagglutination inhibition titers for all strains in all age groups were ≥ 8 fold higher than at baseline (range, 8–51). At least 70% of participants in all age groups seroconverted or had a significant increase in titer for each strain. The most common solicited reactions were injection-site pain and tenderness, plus fever in participants 6–23 months and myalgia in older children and adolescents. All injection-site reactions and most systemic reactions were grade 1 or 2 and resolved within 3 days. Only three vaccine-related unsolicited adverse events were reported, all of which were grade 1 or 2 and transient. No immediate adverse events, adverse events leading to study discontinuation, adverse events of special interest, or serious adverse events were reported. This study showed that IIV4 was well tolerated and highly immunogenic in all age groups. This adds important data on the safety, tolerability, and immunogenicity of influenza vaccines in India.

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

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.

Rationale Vancomycin remains the standard of care for gram-positive bacterial infections, though there are significant developments in newer antibacterial agents. Efficacy can be improved by linking pharmacokinetic with pharmacodynamic principles, thus leading to optimum antibiotic exposure. There is scarcity of pharmacokinetic data in Indian intensive care unit (ICU) population. Materials and methods Fifteen subjects with suspected or proven gram-positive bacterial infection of either gender between 18 years and 65 years of age were enrolled. Vancomycin at the dose of 1 g every 12 hours was administered over 1-hour period and pharmacokinetic assessments performed on blood samples collected on days 1 and 3. Vancomycin concentrations were measured on validated liquid chromatography mass spectrometry method. Pharmacokinetic parameters were calculated using Winnonlin (Version 6.3; Pharsight, St. Louis, MO). Results The mean C max, elimination half-life, AUC0-12hours, volume of distribution, and clearance of single dose were 36.46 μg/mL (±14.87), 3.98 hours (±1.31), 113.51 μg/mL (±49.51), 52.01 L (±31.31), and 8.90 mL/minute (±3.29), respectively, and at steady state were 40.87 μg/mL (±19.29), 6.27 hours (±3.39), 147.94 μg/mL (±72.89), 56.39 L (±42.13), and 6.98 mL/minute (±4.48), respectively. The elimination half-life increased almost two-fold at steady state. The steady state mean AUC0-24 was 295.89 µg/mL (±153.82). Out of 45 trough levels, 32 (71.11%) concentrations were below recommended range. Conclusion Recommended AUC0-24hours and trough concentrations were not achieved in majority of patients with current dosing, suggesting reevaluation of current vancomycin dosing. Individualized treatment based on close monitoring of vancomycin serum concentrations in critically ill patients is imperative. How to cite this article Mali NB, Deshpande SP, Wandalkar PP, Gupta VA, Karnik ND, Gogtay NJ, et al. Single-dose and Steady-state Pharmacokinetics of Vancomycin in Critically Ill Patients Admitted to Medical Intensive Care Unit of India. IJCCM 2019;23(11):513-517.

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 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.

Aims and objectives Vancomycin is a drug of choice for various gram-positive bacterial (GPB) infections and is largely prescribed to pediatric intensive care unit (PICU) patients. Despite the different pathophysiology of these patients, limited data are available on pharmacokinetics of vancomycin. There are lack of data for critically ill Indian children; hence, study was conducted to assess the steady-state pharmacokinetics in children admitted to PICU. Materials and methods Twelve subjects (seven males, five females) aged 1-12 years were enrolled. Vancomycin (dose of 20 mg/kg per 8 hours) was infused for over 1 hour and steady-state pharmacokinetics was performed on day 3. Vancomycin concentrations were measured by the validated liquid chromatography mass spectrometry method. Pharmacokinetic parameters were calculated using Winnonlin (Version 6.3; Pharsight, St. Louis, MO). Results The steady-state mean C ssmax was 40.94 μg/mL (±15.07), and mean AUC0-8 hours was 124.15 μg/mL (±51.27). The mean t 1/2 was 4.82 hours (±2.71), Vd was 12.48 L (±4.43), and Cl was 2.08 mL/minute (±0.89). The mean AUC0-24 among 12 subjects was 372.44 μg/mL (±153.82). Among 35 measured trough concentrations, 23 (65.71%) were below, 11 (31.43%) were within, and 1 (2.86%) was above the recommended range. Conclusion The pharmacokinetic parameters of vancomycin were comparable with previously reported studies. However, recommended trough levels (10-20 μg/mL) were not achievable with current recommended dosing of 60 mg/kg/day. How to cite this article Mali NB, Tullu MS, Wandalkar PP, Deshpande SP, Ingale VC, Deshmukh CT, et al. Steady-state Pharmacokinetics of Vancomycin in Children Admitted to Pediatric Intensive Care Unit of a Tertiary Referral Center. IJCCM 2019;23(11):497-502.