Strategy for COVID-19 vaccination in India: the country with the second highest population and number of cases

Free vaccination against COVID-19 commenced in India on January 16, 2021, and the government is urging all of its citizens to be immunized, in what is expected to be the largest vaccination program in the world. Out of the eight COVID-19 vaccines that are currently under various stages of clinical trials in India, four were developed in the country. India’s drug regulator has approved restricted emergency use of Covishield (the name employed in India for the Oxford-AstraZeneca vaccine) and Covaxin, the home-grown vaccine produced by Bharat Biotech. Indian manufacturers have stated that they have the capacity to meet the country’s future needs for COVID-19 vaccines. The manpower and cold-chain infrastructure established before the pandemic are sufficient for the initial vaccination of 30 million healthcare workers. The Indian government has taken urgent measures to expand the country’s vaccine manufacturing capacity and has also developed an efficient digital system to address and monitor all the aspects of vaccine administration.

Supporting Drug Regulators Through Simple Rapid Cycle Analyses

IntroductionDrug regulators require timely, relevant information to address questions about the safety of prescribed medicines. Some questions can be informed by initial rapid and simple analyses of linked exposure/outcome data. These analyses will establish how many individuals have received the drug, their characteristics, the availability of follow up time and the frequency of the event of interest in the exposed cohort. This approach does not enable causal inferences but establishes the need for, and feasibility of, more complex controlled analyses. Discovery that the exposure or outcome are uncommon can allay initial fears about the extent of a problem. Objectives and ApproachA pilot network to support the Australian drug regulator (TGA, Department of Health) was established among three research institutions in Australia and Canada. Initial queries were identified and prioritised by staff at the TGA. Academic staff at the partner institutions performed a rapid feasibility assessment based on existing knowledge and expertise. Following this, initial exposure/outcome analyses were undertaken on selected queries using routinely collected data from Canada and Australia. Updates were provided to the TGA at each stage to ensure that decision-makers were fully informed and participated in decision making. ResultsTo date, the network has assessed 20 queries. Seven were deemed infeasible and 4 queries were being addressed by studies that were already planned or underway; in these cases, arrangements were made to provide early results directly to the regulator. The final four queries progressed to an initial exposure/outcome analysis, and one such study was expanded to a fully adjusted controlled analysis. Conclusion / ImplicationsThis framework has proven to be agile and responsive and has strengthened the relationship between academia and the TGA. It may serve as a model for others who wish to engage more closely with governments or other decision makers.

Current Translational Insights into MGMT Methylation Regulating Temozolomide Sensitivity and Resistance in Glioblastoma Multiforme

Background: Temozolomide is used as frontline chemotherapy in the management of glioblastoma multiforme (GBM); however, its clinical utility is limited by the occurrence of significant resistance, majorly caused due to direct DNA repair. O6- methylguanine-DNA-methyltransferase (MGMT), a DNA repair protein, mediates this direct repair pathway and reverses the activity of temozolomide. Methods: We characterize and underscore the functional relevance and molecular aspects of MGMT in the development of sensitivity/resistance to temozolomide treatment. We review early translational, as well as clinical, evidence for the role of MGMT in mediating temozolomide resistance in vitro in cell lines, in vivo in small animals as well as in GBM patients. Results: Various approaches have been delineated to mitigate MGMT-induced temozolomide resistance. The most promising means in discovery biology appears to be the co-administration of MGMT inhibitors such as O6 benzyl guanine or lomeguatrib. Surprisingly, the validation of these pharmacologic inhibitors to assess the reversal of chemoresistance by appropriately designed safety and efficacy trials in combination with temozolomide is yet to be demonstrated. Conclusions: Taken together, given the regulation of temozolomide resistance by MGMT, intermediate and late discovery groups may focus their efforts on pharmacologic inhibition of MGMT, singly or in combination with radiotherapy or immunotherapy, to combat temozolomide resistance in GBM patients. In addition, one may speculate that the combined clinical use of temozolomide with a drug regulator-approved MGMT inhibitor as well as an immune checkpoint inhibitor such as nivolumab may prove beneficial. Future studies may also investigate any inter-ethnic variability in population pharmacogenetics of MGMT and pharmacometric approaches to optimize cancer precision medicine.