ETHICAL ISSUES IN RANDOMIZED CONTROL TRIALS: A REVIEW

Randomized Control Trials (RCTs) are scientific experiments that are used to investigate the effectiveness of various interventions in the field of Medicine and public health. As a result of complexity of the process, even the competent individuals are not able to understand the process of randomization with anticipated consequences associated with it. There is rise in trend of research and conduct of RCTs in developing countries; hence, there is a need to review all ethical issues confronted by the researchers during conduct of such trials. An Online literature search was carried out in April 2015 to May 2015 from Google Scholar, BioMed Central Ethics and PubMed using the key term “Trials”, “Randomized Control Trials”, “Ethical issues” and various synonymous terms from the titles of the articles. This resulted in 25 articles. Following, which these articles were scrolled down, and all articles with ethical issues encountered with different type of trials, were included. Avoiding the duplication of issues, 13 articles were finally selected for review. From the review narrates that ethical issues of patient autonomy, informed consent, therapeutic misconceptions, state of equipoise for individuals, clinicians and researchers, controversies between placebo and active control orthodoxies, design biases, role of gate keepers, benefit verses risk assessment and protection of vulnerable groups are the important ethical issues highlighted by various researchers. There can be issues related to some surgeries, early cessation of RCTs due to some apparent benefits and conduct of trials in third world countries. It is imperative that institutional review boards should consider all such issues during ethical assessment of such trials. Keywords:Benefit verses risk assessment Institutional review board (IRB), Randomized Control Trials (RCTs), vulnerable groups

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation

HEALTHCARE IN PAKISTAN–A SYSTEMS PERSPECTIVE

Health system in Pakistan has witnessed evolution and dates back to the medieval, traditional health care, health for all approach, primary health care approach and health systems strengthening approach for better health outcomes. The main objectives of health system are improvement in health, fairness in distribution of risk and finances and responsiveness to the non medical needs of the population. With decreasing expenditure on health care, booming private health sector and flourishing pharmaceutical industry, government can only reduce catastrophic health expenditures by the poor and impoverished through an efficient, effective, accessible and responsive public health system. Inter sectoral collaboration, community participation, social protection, equitable distribution of resources, people centric health policy, health work force development, evidence based health information system and quality assurance of essential medicines will strengthen health system in Pakistan