Vaccines for COVID-19: learning from ten phase II trials to inform clinical and public health vaccination programmes.
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ABSTRACT:
SUBMITTER: Bhopal SS
PROVIDER: S-EPMC7846205 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundIf multiple Phase II randomized trials exist then meta-analysis is favorable to increase statistical power and summarize the existing evidence about an intervention's effect in order to help inform Phase III decisions. We consider some statistical issues for meta-analysis of Phase II trials for this purpose, as motivated by a real example involving nine Phase II trials of bolus thrombolytic therapy in acute myocardial infarction with binary outcomes.MethodsWe propose that a Bayesian random effects logistic regression model is most suitable as it models the binomial distribution of the data, helps avoid continuity corrections, accounts for between-trial heterogeneity, and incorporates parameter uncertainty when making inferences. The model also allows predictions that inform Phase III decisions, and we show how to derive: (i) the probability that the intervention will be truly beneficial in a new trial, and (ii) the probability that, in a new trial with a given sample size, the 95% credible interval for the odds ratio will be entirely in favor of the intervention. As Phase II trials are potentially optimistic due to bias in design and reporting, we also discuss how skeptical prior distributions can reduce this optimism to make more realistic predictions.ResultsIn the example, the model identifies heterogeneity in intervention effect missed by an I-squared of 0%. Prediction intervals accounting for this heterogeneity are shown to support subsequent Phase III trials. The probability of success in Phase III trials increases as the sample size increases, up to 0.82 for intracranial hemorrhage and 0.79 for reinfarction outcomes.ConclusionsThe choice of meta-analysis methods can influence the decision about whether a trial should proceed to Phase III and thus need to be clearly documented and investigated whenever a Phase II meta-analysis is performed.
| S-EPMC4162965 | biostudies-literature
Project description:More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease.
| S-EPMC5177991 | biostudies-literature
Project description:After a long period of stagnation, traditionally explained by the voluntary nature of the programme, a considerable increase in routine measles vaccine uptake has been recently observed in Italy after a set of public interventions aiming to promote MMR immunization, whilst retaining its voluntary aspect. To account for this take-off in coverage we propose a simple SIR transmission model with vaccination choice, where, unlike similar works, vaccinating behaviour spreads not only through the diffusion of "private" information spontaneously circulating among parents of children to be vaccinated, which we call imitation, but also through public information communicated by the public health authorities. We show that public intervention has a stabilising role which is able to reduce the strength of imitation-induced oscillations, to allow disease elimination, and to even make the disease-free equilibrium where everyone is vaccinated globally attractive. The available Italian data are used to evaluate the main behavioural parameters, showing that the proposed model seems to provide a much more plausible behavioural explanation of the observed take-off of uptake of vaccine against measles than models based on pure imitation alone.
| S-EPMC3462214 | biostudies-literature
Project description:BACKGROUND:Decisions regarding which vaccines are funded in the United Kingdom (UK) are increasingly informed by cost-effectiveness analyses. Such analyses use Quality Adjusted Life Years (QALYs) as a measure of effectiveness and assume that QALYs are equal regardless of where and in whom they occur in the population. However, there is increasing debate about whether this QALY approach is appropriate and whether societal preferences for childhood vaccinations should be used to help inform childhood immunisation policy. OBJECTIVE:To gauge the general public's preferences for prioritising certain characteristics of childhood vaccination, to help inform future policy making decisions in the UK. DESIGN:Qualitative design using individual face-to-face interviews, with data analysed using an inductive thematic framework approach. SETTING:Two counties in England, UK. POPULATION:Adult members of the general public were recruited using the Bristol and South Gloucestershire open electoral registers, using gender and deprivation quotas for each area. PARTICIPANTS:21 members of the public participated in qualitative interviews. RESULTS:The qualitative research identified three major themes and several key attributes that influences participant's opinions about priority setting for childhood vaccinations: (1) population segment (i.e. age group, carer impact and social group), (2) vaccine preventable diseases preferences (i.e. disease severity, disease incidence and declining infection) and (3) risks and benefits associated with childhood vaccinations (i.e. vaccine associated side-effects, herd protection and peace of mind). CONCLUSION:Evidence from this qualitative study suggests that some members of the UK general public have more nuanced views than the health-maximisation approach when considering how childhood vaccines should be prioritised. This is not necessarily captured by the current economic approaches for assessing the benefits from childhood vaccinations in the UK, but is an important area for future research to ensure appropriate decision making.
| S-EPMC5999095 | biostudies-literature
Project description:Influenza B strains represent on average 23% of all circulating strains in Europe and when there is a vaccine mismatch on B strains, additional influenza-related hospitalizations and deaths as well as substantial additional costs are observed. The objective was to estimate the public health and economic impact of seasonal influenza vaccination with quadrivalent influenza vaccines (QIV) compared to trivalent influenza vaccines (TIV) in Europe (EU). Based on data from 5 EU countries (France, Germany, Italy, Spain and UK) during 10 influenza seasons from 2002 to 2013, epidemiological and associated economic outcomes were estimated for each season for the actual scenario where the TIV was used, and for a hypothetical scenario where QIV could have been used instead. By using QIV, this study estimated that for the 5 EU countries, an additional 1.03 million (327.9/100,000 inhabitants) influenza cases, 453,000 (143.9/100,000) general practitioners consultations, 672,000 (213.1/100,000) workdays lost, 24,000 (7.7/100,000) hospitalizations and 10,000 (3.1/100,000) deaths could have been avoided compared to the use of TIV over the 10-seasons-period. This study estimates that QIV can be of economic value since from a societal perspective 15 million Euros would have been saved on general practitioners consultations (14 million Euros from third-party payer perspective), 77 million on hospitalizations (74 million Euros from third-party payer perspective) and 150 million Euros on workdays lost, across the 5 EU countries. In conclusion, the present study estimates that, compared to TIV, QIV may result in a substantial decrease in epidemiological burden and in influenza-related costs.
| S-EPMC5027718 | biostudies-literature
Project description:Most phase II screening designs available in the literature consider one treatment at a time. Each study is considered in isolation. We propose a more systematic decision-making approach to the phase II screening process. The sequential design allows for more efficiency and greater learning about treatments. The approach incorporates a Bayesian hierarchical model that allows combining information across several related studies in a formal way and improves estimation in small data sets by borrowing strength from other treatments. The design incorporates a utility function that includes sampling costs and possible future payoff. Computer simulations show that this method has high probability of discarding treatments with low success rates and moving treatments with high success rates to phase III trial.
| S-EPMC3075947 | biostudies-literature
Project description:Background: Drug combinations are the standard of care in cancer treatment. Identifying effective cancer drug combinations has become more challenging because of the increasing number of drugs. However, a substantial number of cancer drugs stumble at Phase III clinical trials despite exhibiting favourable efficacy in the earlier Phase. Methods: We analysed recent Phase II cancer trials comprising 2165 response rates to uncover trends in cancer therapies and used a null model of non-interacting agents to infer synergistic and antagonistic drug combinations. We compared our latest efficacy dataset with a previous dataset to assess the progress of cancer therapy. Results: Targeted therapies reach higher response rates when used in combination with cytotoxic drugs. We identify four synergistic and 10 antagonistic combinations based on the observed and expected response rates. We demonstrate that recent targeted agents have not significantly increased the response rates. Conclusions: We conclude that either we are not making progress or response rate measured by tumour shrinkage is not a reliable surrogate endpoint for the targeted agents.
| S-EPMC7825663 | biostudies-literature
Project description: Not available
| S-EPMC7906739 | biostudies-literature
Project description:Introduction: Systemic sclerosis (SSc) is an autoimmune connective tissue disease that is characterized by excessive collagen deposition, vascular dysfunction, and fibrosis of cutaneous and visceral organs. Current therapeutic options are limited and provide only modest benefit.Areas covered: This review summarizes investigational agents in recent Phase I and II clinical trials evaluated for the treatment of SSc with a focus on skin in patients with early diffuse disease and interstitial lung disease. We performed a search on Pubmed and https://clinicaltrials.gov with keywords systemic sclerosis, Phase I clinical trial, and Phase II clinical trial to identify relevant studies from 2015 to 2019.Expert opinion: Therapeutic interventions in SSc should be guided by the level of disease activity and the degree of organ involvement. While most novel agents have failed to meet the primary endpoints of reducing skin thickening as measured by the modified Rodnan skin score, some have shown promise in improving the Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis (CRISS), reducing lung function decline, or improving patient-reported outcomes. However, most of the current evidence is based on small or open-label clinical trials. Well-designed, large, randomized, Phase III clinical trials are necessary to define the roles of investigational agents in treating SSc.
| S-EPMC7174094 | biostudies-literature
Project description:Phase II cancer clinical trial designs commonly incorporate an interim analysis for lack of efficacy. To strictly and ethically implement such designs, one should suspend accrual in cases where pending patient outcomes can affect early termination decisions. This article aims to evaluate various options for accrual suspension and illustrate how the suspension strategy affects operating characteristics of the trial.We define a strict suspension strategy for determining whether one should continue, suspend, or restart accrual at any point within the trial. The strategy is compared to a naive implementation of suspension and a strategy of no suspension. We evaluate the methods' operating characteristics by simulation.The suspension strategy has little effect on type I error, power, and early termination probability. Methods that involve stricter suspension policies generally lead to smaller but longer trials. Differences across strategies are substantial when the ratio of enrollment rate to outcome availability rate is high.The suspension strategy is most relevant in trials that accrue rapidly and require lengthy observation of each subject. The choice of suspension strategy involves a tradeoff between the cost of implementing a potentially complex suspension algorithm in real time versus the cost of enrolling more patients and exposing them to a potentially toxic and ineffective treatment regimen.
| S-EPMC4355337 | biostudies-literature