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.

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.

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 analysis of invitations for article submission received via emails.

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.

A two-year evaluation of the minutes of Investigational New Drug committee meetings.

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

An evaluation of drug lag for new drugs approved by the Indian regulator relative to the United States, European Union, and Japanese regulatory agencies: A 15-year analysis (2004-2018).

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

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.

Evaluation of vanillin as a probe drug for aldehyde oxidase and phenotyping for its activity in a Western Indian Cohort.

BACKGROUND: Aldehyde oxidase (AO), a molybdoflavoenzyme, is emerging as a key player in drug discovery and metabolism. Despite having several known substrates, there are no validated probes reported for studying the activity of AO in vivo. Vanillin (4-hydroxy 3-methoxy benzaldehyde) is an excellent substrate of AO, in vitro. In the present study, vanillin has been validated as an in vivo probe for AO. Subsequently, a phenotyping study was carried out using vanillin in a subset of Indian population with 100 human volunteers. METHODS: For the purposes of in vitro probe validation, initially the metabolism of vanillin was characterized in partially purified guinea pig AO fraction. Further, vanillin was incubated with partially purified xanthine oxidase fraction and AO fractions, and liver microsomes obtained from different species (in presence and absence of specific inhibitors). For the phenotyping study, an oral dose of 500 mg of vanillin was administered to the participants in the study and cumulative urine samples were obtained up to 8 h after giving the dose. The samples were analyzed by high-performance liquid chromatography and metabolic ratios were calculated as peak area ratio of vanillic acid/vanillin. RESULTS: (a) The results of the in vitro validation studies clearly indicated that vanillin is preferentially metabolized by AO. (b) Normal distribution tests and probit analysis revealed that AO activity was not normally distributed and that 73.72% of the participants were fast metabolizers, 24.28% intermediate metabolizers, and 2% were slow metabolizers. CONCLUSIONS: Data of the phenotyping study suggest the existence of AO polymorphism, in a Western Indian cohort.

Has mandatory prospective registration of all studies brought about a change? A 1-year audit of studies registered in the Clinical Trials Registry of India [CTRI] before and after April 1, 2018.

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.

Nose-to-Brain Delivery of Diazepam from an Intranasal Aqua-Triggered In-Situ (ATIS) Gelling Microemulsion: Monitoring Brain Uptake by Microdialysis.

BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: ATIS-diazepam exhibited globule size < 200 nm, low viscosity, negative zeta potential and good stability. A significant increase in mucoadhesion was exhibited by ATIS-diazepam following the addition of a small quantity of water. ATIS-diazepam showed burst release in pH 6.4 with 50% diazepam release in ~ 10 min, which was sustained over 1 h. The absolute bioavailability was ~ 50% with both intranasal free-diazepam and ATIS-diazepam. Intranasal administration of ATIS-diazepam revealed immediate absorption with rapid and high brain extracellular fluid concentration compared to intravenous free-diazepam solution. The estimated direct transport potential and drug targeting efficiency of intranasal ATIS-diazepam was significantly higher (2-fold) than intranasal free-diazepam solution, which was attributed to the mucoadhesive and microemulsion properties of ATIS-diazepam. The nasal irritation study revealed the safety of ATIS-diazepam compared to free-diazepam solution. CONCLUSION: Intranasal ATIS-diazepam showed promise of higher direct nose-to-brain targeting, better safety and hence has an immense implication in the treatment of epileptic emergencies.

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.

Recruitment and retention of the participants in clinical trials: Challenges and solutions.

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.

A comparative study to evaluate quality of data documentation between investigator-initiated and pharmaceutical industry-sponsored studies.

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.

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.

Current status of standardized, quality and ethical oversight of clinical research in the country: An audit of the Central Drugs Standard Control Organization (registration of ethics committees) and national accreditation board for hospital and healthcare providers (accreditation) databases.

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.

An audit of minutes of Subject Expert Committee meetings as a metric to assess the clinical research roadmap of 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 <0.001). CTW applications for Oncology were 6.5 times more likely to be granted a waiver (cOR 6.5 [3.5, 11.7], P <0.001). Considerable variability was seen in the minutes. CONCLUSION: A vast majority of CT applications in the country receive approval, as do a majority of marketing authorization applications. Oncology, vaccine and opthalmology division predominate the approvals. There exists considerable heterogeneity in the minutes. Standardization of these minutes across committees will help add to the existing transparency and give greater insights into the decision-making process.

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.

Steady-state Pharmacokinetics of Vancomycin in Children Admitted to Pediatric Intensive Care Unit of a Tertiary Referral Center.

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.

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.