A non-inferiority (NI) trial is intended to show that the effect of a new treatment is not worse than the comparator. We conducted a review to identify how NI trials were conducted and reported, and whether the standard requirements from the guidelines were followed. From 300 randomly selected articles on NI trials registered in PubMed at 5 February 2009, we included 227 NI articles that referred to 232 trials. We excluded studies on bioequivalence, trials on healthy volunteers, non-drug trials, and articles of which the full-text version could not be retrieved. A large proportion of trials (34.0%) did not use blinding. The NI margin was reported in 97.8% of the trials, but only 45.7% of the trials reported the method to determine the margin. Most of the trials used either intention to treat (ITT) (34.9%) or per-protocol (PP) analysis (19.4%), while 41.8% of the trials used both methods. Less than 10% of the trials included a placebo arm to confirm the efficacy of the new drug and active comparator against placebo, and less than 5.0% were reporting the similarity of the current trial with the previous comparator's trials. In general, no difference was seen in the quality of reporting before and after the release of the CONSORT statement extension 2006 or between the high-impact and low-impact journals. The conduct and reporting of NI trials can be improved, particularly in terms of maximizing the use of blinding, the use of both ITT and PP analysis, reporting the similarity with the previous comparator's trials to guarantee a valid constancy assumption, and most importantly reporting the method to determine the NI margin.

Since 2010, Indonesian government has initiated a chronic disease management program, Prolanis (Program Pengendalian Penyakit Kronis) targeted for diabetes and hypertension. The program is continued at the commencement of universal health coverage (UHC) in 2014. “This study aimed to report the utilization and cost of the implementation of Prolanis in Indonesia from 2014 to 2016, or two years since the commencement of Indonesian universal health coverage.” Secondary data analysis was performed using publicly available data and data obtained from the national health insurance agency (BPJS); while data on disease prevalence were collected from basic national health survey. There was an increase trend of Prolanis participants, from around 11,000 participants in 2014 to more than 250,000 in 2016. More than 70% of participants were adults living in Java, however, the acceptance rate was very low in other area. Across different activities in Prolanis, physical activity was the most participated ones. In comparison to other regions, regions in Java were the most active area. The total expenditure for Prolanis program in 2016 increased almost triple from the annual cost in 2014. However, the cost per person was actually decreased more than 50%. Within two years of UHC implementation, there were increase covered participants and total costs, but cost per individual was decreased and there was significant difference in of cost between Java and outside Java. Further study and routine monitoring-evaluation process by health authority is needed to assess whether the cost difference would affect the service quality.

A randomized controlled trial (RCT) can have either a superiority design or a noninferiority design. A superiority design aims to show that a new drug is better than placebo or an active comparator, whereas a noninferiority design aims to show that a new drug is not worse than its comparator, which

The active-controlled trial with a non-inferiority design has gained popularity in recent years. However, non-inferiority trials present some methodological challenges, especially in determining the non-inferiority margin. Regulatory guidelines provide some general statements on how a non-inferiority trial should be conducted. Moreover, in a scientific advice procedure, regulators give companies the opportunity to discuss critical trial issues prior to the start of the trial. The aim of this study was to identify potential issues that may benefit from more explicit guidance by regulators. To achieve this, we collected and analyzed questions about non-inferiority trials posed by applicants for scientific advice in Europe in 2008 and 2009, as well as the responses given by the European Medicines Agency (EMA). In our analysis we included 156 final letters of advice from 2008 and 2009, addressed to 94 different applicants (manufacturers). Our analysis yielded two major findings: (1) applicants frequently asked questions ‘whether’ and ‘how’ to conduct a non-inferiority trial, 26% and 74%, respectively, and (2) the EMA regulators seem mainly concerned about the choice of the non-inferiority margin in non-inferiority trials (36% of total regulatory answers). In 40% of the answers, the EMA recommended using a stricter margin, and in 10% of the answers regarding non-inferiority margins, the EMA questioned the justification of the proposed non-inferiority margin. We conclude that there are still difficulties in selecting the appropriate methodology for non-inferiority trials. Straightforward and harmonized guidance regarding non-inferiority trials is required, for example on whether it is necessary to conduct such a trial and how the non-inferiority margin is determined. It is unlikely that regulatory guidelines can cover all therapeutic areas; therefore, in some cases regulatory scientific advice may be used as an opportunity for tailored advice.