The reliability and integrity of overall survival data based on follow-up records only and potential solutions to the challenges

Summary Overall survival (OS) is considered the standard clinical endpoint to support effectiveness claims in new drug applications globally, particularly for lethal conditions such as cancer. However, the source and reliability of OS in the setting of clinical trials have seldom been doubted and discussed. This study first raised the common issue that data integrity and reliability are doubtful when we collect OS information or other time-to-event endpoints based solely on simple follow-up records by investigators without supporting material, especially since the 2019 COVID-19 pandemic. Then, two rounds of discussions with 30 Chinese experts were held and 12 potential source scenarios of three methods for obtaining the time of death of participants, including death certificate, death record and follow-up record, were sorted out and analysed. With a comprehensive assessment of the 12 scenarios by legitimacy, data reliability, data acquisition efficiency, difficulty of data acquisition, and coverage of participants, both short-term and long-term recommended sources, overall strategies and detailed measures for improving the integrity and reliability of death date are presented. In the short term, we suggest integrated sources such as public security systems made available to drug inspection centres appropriately as soon as possible to strengthen supervision. Death certificates provided by participants’ family members and detailed standard follow-up records are recommended to investigators as the two channels of mutual compensation, and the acquisition of supporting materials is encouraged as long as it is not prohibited legally. Moreover, we expect that the sharing of electronic medical records and the legal disclosure of death records in established health registries can be realized with the joint efforts of the whole industry in the long-term. The above proposed solutions are mainly based on the context of China and can also provide reference for other countries in the world.

Structural and physiological changes of the human body upon SARS-CoV-2 infection.

Since December 2019, the novel coronavirus (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) has spread to many countries around the world, developing into a global pandemic with increasing numbers of deaths reported worldwide. To data, although some vaccines have been developed, there are no ideal drugs to treat novel coronavirus pneumonia (coronavirus disease 2019 (COVID-19)). By examining the structure of the coronavirus and briefly describing its possible pathogenesis based on recent autopsy reports conducted by various teams worldwide, this review analyzes the possible structural and functional changes of the human body upon infection with SARS-CoV-2. We observed that the most prominent pathological changes in COVID-19 patients are diffuse alveolar damage (DAD) of the lungs and microthrombus formation, resulting in an imbalance of the ventilation/perfusion ratio and respiratory failure. Although direct evidence of viral infection can also be found in other organs and tissues, the viral load is relatively small. The conclusion that the injuries of the extra-pulmonary organs are directly caused by the virus needs further investigation.

Efficacy and safety of tocilizumab in COVID-19 patients: A Meta-Analysis (preprint)

The therapeutic effect of tocilizumab remains controversial. We aimed to evaluate whether tocilizumab might be beneficial in COVID-19 patients. We searched PubMed, Embase and Cochrane library from inception to June 23, 2020. Summary estimates of overall response rate (ORR) and all-cause death rate in all patients were analyzed. This study was registered with PROSPERO (CRD42020191313). We included data from 28 articles including 991 COVID-19 patients who underwent tocilizumab administration. The pooled ORR was 72% (95% CI, 66-79%) and pooled all-cause death rate was 16% (95% CI, 11-22%). The optimal timing of administration was the 7.15 day from the symptom onset and with the lowest death rate of 13.11%. 562 patients were defined as with severe infection, and the pooled ORR was 78% (95% CI, 70-85%). The pooled ORR of 56 organ transplantation recipients was 53% (95% CI, 26-78%), which was lower than non-transplant patients [75% (95% CI, 69-81%)]. Nearly all studies confirmed the safety of tocilizumab administration. Tocilizumab improves the clinical outcome of COVID-19 patients, especially in severe cases, and the optimal timing of administration may provide the guidance for management. However, tocilizumab may be used with caution in solid transplant recipients for the suboptimal efficacy.