Improving the efficiency of clinical trials in multiple sclerosis.

BACKGROUND: Phase 3 clinical trials for disease-modifying therapies in relapsing-remitting multiple sclerosis (RRMS) have utilized a limited number of conventional designs with a high degree of success. However, these designs limit the types of questions that can be addressed, and the time and cost required. Moreover, trials involving people with progressive multiple sclerosis (MS) have been less successful. OBJECTIVE: The objective of this paper is to discuss complex innovative trial designs, intermediate and composite outcomes and to improve the efficiency of trial design in MS and broaden questions that can be addressed, particularly as applied to progressive MS. METHODS: We held an international workshop with experts in clinical trial design. RESULTS: Recommendations include increasing the use of complex innovative designs, developing biomarkers to enrich progressive MS trial populations, prioritize intermediate outcomes for further development that target therapeutic mechanisms of action other than peripherally mediated inflammation, investigate acceptability to people with MS of data linkage for studying long-term outcomes of clinical trials, use Bayesian designs to potentially reduce sample sizes required for pediatric trials, and provide sustained funding for platform trials and registries that can support pragmatic trials. CONCLUSION: Novel trial designs and further development of intermediate outcomes may improve clinical trial efficiency in MS and address novel therapeutic questions.

Prevalence and incidence of HIV among female sex workers and their clients: modelling the potential effects of intervention in Rwanda.

BACKGROUND: Rwanda has identified several targeted HIV prevention strategies, such as promotion of condom use and provision of antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) for female sex workers (FSWs). Given this country's limited resources, understanding how the HIV epidemic will be affected by these strategies is crucial. METHODS: We developed a Markov model to estimate the effects of targeted strategies to FSWs on the HIV prevalence/incidence in Rwanda from 2017 to 2027. Our model consists of the six states: HIV-; HIV+ undiagnosed/diagnosed pre-ART; HIV+ diagnosed with/without ART; and death. We considered three populations: FSWs, sex clients and the general population. For the period 2017-2027, the HIV epidemic among each of these population was estimated using Rwanda's demographic, sexual risk behaviour and HIV-associated morbidity and mortality data. RESULTS: Between 2017 and 2027, with no changes in the current condom and ART use, the overall number of people living with HIV is expected to increase from 344,971 to 402,451. HIV incidence will also decrease from 1.36 to 1.20 100 person-years. By 2027, a 30% improvement in consistent condom use among FSWs will result in absolute reduction of HIV prevalence among FSWs, sex clients and the general population by 7.86%, 5.97% and 0.17%, respectively. While recurring HIV testing and improving the ART coverage mildly reduced the prevalence/incidence among FSWs and sex clients, worsening the two (shown by our worst-case scenario) will result in an increase in the HIV prevalence/incidence among FSWs and sex clients. Introduction of PrEP to FSWs in 2019 will reduce the HIV incidence among FSWs by 1.28%. CONCLUSIONS: Continued efforts toward improving condom and ART use will be critical for Rwanda to continue their HIV epidemic control. Implementing a targeted intervention strategy in PrEP for FSWs will reduce the HIV epidemic in this high-risk population.

Mobile phone short message service for adherence support and care of patients with tuberculosis infection: Evidence and opportunity.

To attain the Global End Tuberculosis (TB) goals, the treatment of persons with TB requires advancements in coordinated approaches that are low-cost and highly accessible. Treating TB successfully requires prolonged medication regimens with good adherence, which in turn requires patients to be adequately supported. Furthermore, TB care-providers often wish to monitor treatment-taking by patients in order to track the success of their programs and ensure adequate completion of therapies by individuals. The standard-of-care for treatment monitoring in TB programs often includes directly observed therapy (DOT). Video observed therapy (VOT) has emerged as a method to mimic in-person visits or observations, especially in the smartphone era with internet data connections, but remains simply inaccessible to patients in areas where TB is most endemic. Both approaches may be considered more intensive than necessary for many patients, leaving an opportunity for more affordable and acceptable approaches. The rapid increase in mobile phone penetration provides an opportunity to reach patients between clinical visits. Short message services (SMS) are available on almost every mobile phone and are supported by first generation cellular communication networks, thus providing the farthest reach and penetration globally. Evidence from non-TB conditions suggests SMS, used in a variety of ways, may support outpatients for better medication adherence and quality of care but the evidence in TB remains limited. In this paper, we discuss how basic mobile phones and SMS-related services may be used in supporting global care of persons with TB, with a focus on patient-centered approaches.

Effects of biomarker diagnostic accuracy on biomarker-guided phase 2 trials.

Recent advancements in genomics have attracted attention towards biomarker-guided trials. These trials aim to identify therapies that target diseases based on their genetic profile, and are especially common in cancer research. Careful incorporation of biomarkers in phase II studies is critical to the selection of candidates for further phase III investigation. This short communication focuses on problems of biomarker test accuracy in biomarker-guided trials. We assessed how diagnostic accuracy of biomarker tests affects type I error rate, statistical power, and sample size requirements of single-arm biomarker-guided trials. In particular, we report how false positive rates (FPRs) of biomarker tests reduce statistical power and type I error for Simon's two-stage design, and the degree of sample size correction required to achieve pre-specified power and type I error with varying FPRs. This was done using a case study based on a previous biomarker-guided single-arm trial that was designed with an assumed tumor response rate of 10% under the null hypothesis and 40% for the alternative hypothesis for the mutant group for 5% type I error and 90% power. With varying FPRs of biomarker tests, we considered two scenarios in which the response rate for the wild-type group was assumed to be lower than the response rate for the mutant group at 5% and 10%. We also developed a simple open-source online trial planner for future investigators to use for their biomarker-guided phase II trials (https://mtek.shinyapps.io/Biomarker_Trial_Planner/).

Reporting of master protocols towards a standardized approach: A systematic review.

BACKGROUND: In September 2018 the FDA provided a draft guidance on master protocols reflecting an increased interest in these designs by industry. Master protocols refer to a single overarching protocol developed to evaluate multiple hypotheses and may be further categorized as basket, umbrella, and platform trials. However, inconsistencies in reporting persist in the literature. We conducted a systematic review to describe master protocol reporting with the goal of facilitating the further development and spread of these innovative trial designs. METHODS: We searched MEDLINE, EMBASE, and CENTRAL from inception to April 25, 2019 for English articles on master protocols. This was supplemented by hand searches of trial registries and of the bibliographies of published reviews. We used the FDA's definitions of master protocols as references and compared them to self-reported master protocols. RESULTS: We identified 278 master protocol publications, consisting of 228 protocols and 50 reviews. Sixty-six records provided unique definitions of master protocol types. We observed considerable heterogeneity in definitions of master protocols, and over half (54%) used oncology-specific language. The majority of self-classified master protocols (57%) were consistent with the FDA's definitions of master protocols. CONCLUSION: The terms 'master protocol', 'basket trial', 'umbrella trial', and 'platform trial' are inconsistently described. Careful treatment of these terms and adherence to the definitions set forth by the FDA will facilitate better understanding of these trial designs and allow them to be used broadly and to their full potential in clinical research. We encourage trial methodologists to use these trial designations when applicable.

Critical concepts in adaptive clinical trials.

Adaptive clinical trials are an innovative trial design aimed at reducing resources, decreasing time to completion and number of patients exposed to inferior interventions, and improving the likelihood of detecting treatment effects. The last decade has seen an increasing use of adaptive designs, particularly in drug development. They frequently differ importantly from conventional clinical trials as they allow modifications to key trial design components during the trial, as data is being collected, using preplanned decision rules. Adaptive designs have increased likelihood of complexity and also potential bias, so it is important to understand the common types of adaptive designs. Many clinicians and investigators may be unfamiliar with the design considerations for adaptive designs. Given their complexities, adaptive trials require an understanding of design features and sources of bias. Herein, we introduce some common adaptive design elements and biases and specifically address response adaptive randomization, sample size reassessment, Bayesian methods for adaptive trials, seamless trials, and adaptive enrichment using real examples.

Use of peers to improve adherence to antiretroviral therapy: a global network meta-analysis.

INTRODUCTION: It is unclear whether using peers can improve adherence to antiretroviral therapy (ART). To construct the World Health Organization's global guidance on adherence interventions, we conducted a systematic review and network meta-analysis to determine the effectiveness of using peers for achieving adequate adherence and viral suppression. METHODS: We searched for randomized clinical trials of peer-based interventions to promote adherence to ART in HIV populations. We searched six electronic databases from inception to July 2015 and major conference abstracts within the last three years. We examined the outcomes of adherence and viral suppression among trials done worldwide and those specific to low- and middle-income countries (LMIC) using pairwise and network meta-analyses. RESULTS AND DISCUSSION: Twenty-two trials met the inclusion criteria. We found similar results between pairwise and network meta-analyses, and between the global and LMIC settings. Peer supporter+Telephone was superior in improving adherence than standard-of-care in both the global network (odds-ratio [OR]=4.79, 95% credible intervals [CrI]: 1.02, 23.57) and the LMIC settings (OR=4.83, 95% CrI: 1.88, 13.55). Peer support alone, however, did not lead to improvement in ART adherence in both settings. For viral suppression, we found no difference of effects among interventions due to limited trials. CONCLUSIONS: Our analysis showed that peer support leads to modest improvement in adherence. These modest effects may be due to the fact that in many settings, particularly in LMICs, programmes already include peer supporters, adherence clubs and family disclosures for treatment support. Rather than introducing new interventions, a focus on improving the quality in the delivery of existing services may be a more practical and effective way to improve adherence to ART.