Assessment of cognitive safety in clinical drug development

Cognitive impairment is increasingly recognised as an important potential adverse effect of medication. However, many drug development programmes do not incorporate sensitive cognitive measurements. Here, we review the rationale for cognitive safety assessment, and explain several basic methodological principles for measuring cognition during clinical drug development, including study design and statistical analysis, from Phase I through to postmarketing. The crucial issue of how cognition should be assessed is emphasized, especially the sensitivity of measurement. We also consider how best to interpret the magnitude of any identified effects, including comparison with benchmarks. We conclude by discussing strategies for the effective communication of cognitive risks

AplusB: A Web Application for Investigating A plus B Designs for Phase I Cancer Clinical Trials

In phase I cancer clinical trials, the maximum tolerated dose of a new drug is often found by a dose-escalation method known as the A + B design. We have developed an interactive web application, AplusB, which computes and returns exact operating characteristics of A + B trial designs. The application has a graphical user interface (GUI), requires no programming knowledge and is free to access and use on any device that can open an internet browser. A customised report is available for download for each design that contains tabulated operating characteristics and informative plots, which can then be compared with other dose-escalation methods. We present a step-by-step guide on how to use this application and provide several illustrative examples of its capabilities

Toxicity-dependent feasibility bounds for the escalation with overdose control approach in phase I cancer trials

Phase I trials of anti-cancer therapies aim to identify a maximum tolerated dose (MTD), defined as the dose that causes unacceptable toxicity in a target proportion of patients. Both rule-based and model-based methods have been proposed for MTD recommendation. The escalation with overdose control (EWOC) approach is a model-based design where the dose assigned to the next patient is one that, given all available data, has a posterior probability of exceeding the MTD equal to a pre-specified value known as the feasibility bound. The aim is to conservatively dose-escalate and approach the MTD, avoiding severe overdosing early on in a trial. The EWOC approach has been applied in practice with the feasibility bound either fixed or varying throughout a trial, yet some of the methods may recommend incoherent dose-escalation, that is, an increase in dose after observing severe toxicity at the current dose. We present examples where varying feasibility bounds have been used in practice, and propose a toxicity-dependent feasibility bound approach that guarantees coherent dose-escalation and incorporates the desirable features of other EWOC approaches. We show via detailed simulation studies that the toxicity-dependent feasibility bound approach provides improved MTD recommendation properties to the original EWOC approach for both discrete and continuous doses across most dose-toxicity scenarios, with comparable performance to other approaches without recommending incoherent dose escalation.G. M. Wheeler and A. P. Mander are supported by the UK Medical Research Council (grant number G0800860). M. J. Sweeting is supported by a European Research Council Advanced Investigator Award: EPIC-Heart (grant number 268834), the UK Medical Research Council (grant number MR/L003120/1), the British Heart Foundation and the Cambridge National Institute for Health Research Biomedical Research Centre

Exact group sequential designs for two-arm experiments with Poisson distributed outcome variables

We describe and compare two methods for the group sequential design of two-arm experiments with Poisson distributed data, which are based on a normal approximation and exact calculations respectively. A framework to determine near-optimal stopping boundaries is also presented. Using this framework, for a considered example, we demonstrate that a group sequential design could reduce the expected sample size under the null hypothesis by as much as 44% compared to a fixed sample approach. We conclude with a discussion of the advantages and disadvantages of the two presented procedures.This work was supported by the Medical Research Council under Grant MC_UU_00002/3 to M.J.G. and A.P.M., and Grant MC_UU_00002/6 to J.M.S.W

Stepped wedge cluster randomized controlled trial designs: a review of reporting quality and design features

Background The stepped wedge (SW) cluster randomized controlled trial (CRCT) design is being used with increasing frequency. However, there is limited published research on the quality of reporting of SW-CRCTs. We address this issue by conducting a literature review. Methods Medline, Ovid, Web of Knowledge, the Cochrane Library, PsycINFO, the ISRCTN registry, and ClinicalTrials.gov were searched to identify investigations employing the SW-CRCT design up to February 2015. For each included completed study, information was extracted on a selection of criteria, based on the CONSORT extension to CRCTs, to assess the quality of reporting. Results A total of 123 studies were included in our review, of which 39 were completed trial reports. The standard of reporting of SW-CRCTs varied in quality. The percentage of trials reporting each criterion varied to as low as 15.4%, with a median of 66.7%. Conclusions There is much room for improvement in the quality of reporting of SW-CRCTs. This is consistent with recent findings for CRCTs. A CONSORT extension for SW-CRCTs is warranted to standardize the reporting of SW-CRCTs.This work was supported by the Wellcome Trust (grant number 099770/Z/12/Z to MJG); the Medical Research Council (grant number MC_UP_1302/2 to APM) and the National Institute for Health Research Cambridge Biomedical Research Centre (MC_UP_1302/4 to JMSW)

Bioprospecting the African Renaissance: The new value of muthi in South Africa

This article gives an overview of anthropological research on bioprospecting in general and of available literature related to bioprospecting particularly in South Africa. It points out how new insights on value regimes concerning plant-based medicines may be gained through further research and is meant to contribute to a critical discussion about the ethics of Access and Benefit Sharing (ABS). In South Africa, traditional healers, plant gatherers, petty traders, researchers and private investors are assembled around the issues of standardization and commercialization of knowledge about plants. This coincides with a nation-building project which promotes the revitalization of local knowledge within the so called African Renaissance. A social science analysis of the transformation of so called Traditional Medicine (TM) may shed light onto this renaissance by tracing social arenas in which different regimes of value are brought into conflict. When medicinal plants turn into assets in a national and global economy, they seem to be manipulated and transformed in relation to their capacity to promote health, their market value, and their potential to construct new ethics of development. In this context, the translation of socially and culturally situated local knowledge about muthi into global pharmaceuticals creates new forms of agency as well as new power differentials between the different actors involved

Objectively Measured Physical Activity and Fat Mass in Children: A Bias-Adjusted Meta-Analysis of Prospective Studies

Background: Studies investigating the prevention of weight gain differ considerably in design and quality, which impedes pooling them in conventional meta-analyses, the basis for evidence-based policy making. This study is aimed at quantifying the prospective association between measured physical activity and fat mass in children, using a meta-analysis method that allows inclusion of heterogeneous studies by adjusting for differences through eliciting and incorporating expert opinion. Methods:Studies on prevention of weight gain using objectively measured exposure and outcome were eligible; they were adopted from a recently published systematic review. Differences in study quality and design were considered as internal and external biases and captured in checklists. Study results were converted to correlation coefficients and biases were considered either additive or proportional on this scale. The extent and uncertainty of biases in each study were elicited in a formal process by six quantitatively-trained assessors and five subject-matter specialists. Biases for each study were combined across assessors using median pooling. Results were combined across studies by random-effects meta-analysis. Results The combined correlation of the unadjusted results from the six studies was −0.04 (95%CI: −0.22, 0.14) with considerable heterogeneity (I2 = 78%), which makes it difficult to interpret the result. After bias-adjustment the pooled correlation was −0.01 (95%CI: −0.18, 0.16) with apparent study compatibility (I2 = 0%). Conclusion:By using this method the prospective association between physical activity and fat mass could be quantitatively synthesized; the result suggests no association. Objectively measured physical activity may not be the key determinant of unhealthy weight gain in children

A personalized and systematically designed adherence intervention improves photoprotection in adults with xeroderma pigmentosum (XP): results of the XPAND randomized controlled trial

\ua9 The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.Background Poor adherence to photoprotection in xeroderma pigmentosum (XP) increases morbidity and shortens lifespan due to skin cancers. Objectives To test a highly personalized intervention (XPAND) to reduce the dose of ultraviolet radiation (UVR) reaching the face in adults with XP, designed using known psychosocial determinants of poor photoprotection. Methods A two-arm parallel group randomized controlled trial, including patients with suboptimal photoprotection to receive XPAND or a delayed-intervention control arm that received XPAND the following year. XPAND comprises seven 1 : 1 sessions targeting photoprotection barriers (e.g. misconceptions about UVR) supported by personalized text messages, activity sheets and educational materials incorporating behaviour change techniques. The primary outcome, mean daily UVR dose to face across 21 days in June–July 2018, was calculated by combining UVR exposure at the wrist with a face photoprotection activity diary. Secondary outcomes were UVR dose to face across 21 days in August 2018, time spent outside, photoprotective measures used outside, mood, automaticity and confidence to photoprotect. Financial costs and quality-adjusted life years (QALYs) were calculated. Results Sixteen patients were randomized; 13 provided sufficient data for primary outcome analysis. The XPAND group (n = 8) had lower mean daily UVR dose to face [0.03 standard error of difference (SED) (SD 0.02)] compared with controls (n = 7) [0.43 SED (SD 0.17)] (adjusted difference = –0.25, P < 0.001, Hedge’s g = 2.21) at the June 2018 assessment. No significant between-group differences were observed in time spent outside, photoprotection outside, mood or confidence. The delayed-intervention control showed improvements in UVR dose to face (adjusted difference = –0.05; Hedge’s g = –0.1), time outside (adjusted difference = –69.9; Hedge’s g = –0.28) and photoprotection (adjusted difference = –0.23, Hedge’s g = 0.45) after receiving XPAND (June 2019 assessment). XPAND was associated with lower treatment costs [–\ua32642; 95% confidence interval (CI) –\ua38715 to \ua33873] and fewer QALYs (–0.0141; 95% CI –0.0369 to 0.0028). Conclusions XPAND was associated with a lower UVR dose to face in patients with XP and was cost-effective

The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes

Background. Type 1 diabetes (T1D) results from loss of immune regulation, leading to the development of autoimmunity to pancreatic β cells, involving autoreactive T effector cells (Teffs). Tregs, which prevent autoimmunity, require IL-2 for maintenance of immunosuppressive functions. Using a response-adaptive design, we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of Teffs. Methods. DILfrequency is a nonrandomized, open-label, response-adaptive study of participants, aged 18–70 years, with T1D. The initial learning phase allocated 12 participants to 6 different predefined regimens. Then, 3 cohorts of 8 participants were sequentially allocated dose frequencies, based on repeated interim analyses of all accumulated trial data. The coprimary endpoints were percentage change in Tregs and Teffs and CD25 (α subunit of the IL-2 receptor) expression by Tregs, from baseline to steady state. Results. Thirty-eight participants were enrolled, with thirty-six completing treatment. The optimal regimen to maintain a steady-state increase in Tregs of 30% and CD25 expression of 25% without Teff expansion is 0.26 × 106 IU/m2 (95% CI –0.007 to 0.485) every 3 days. Tregs and CD25 were dose-frequency responsive, Teffs were not. The commonest adverse event was injection site reaction (464 of 694 events). Conclusions. Using a response-adaptive design, aldesleukin treatment can be optimized. Our methodology can generally be employed to immediately access proof of mechanism, thereby leading to more efficient and safe drug development

To add or not to add a new treatment arm to a multiarm study: A decision-theoretic framework.

Multiarm clinical trials, which compare several experimental treatments against control, are frequently recommended due to their efficiency gain. In practise, all potential treatments may not be ready to be tested in a phase II/III trial at the same time. It has become appealing to allow new treatment arms to be added into on-going clinical trials using a "platform" trial approach. To the best of our knowledge, many aspects of when to add arms to an existing trial have not been explored in the literature. Most works on adding arm(s) assume that a new arm is opened whenever a new treatment becomes available. This strategy may prolong the overall duration of a study or cause reduction in marginal power for each hypothesis if the adaptation is not well accommodated. Within a two-stage trial setting, we propose a decision-theoretic framework to investigate when to add or not to add a new treatment arm based on the observed stage one treatment responses. To account for different prospect of multiarm studies, we define utility in two different ways; one for a trial that aims to maximise the number of rejected hypotheses; the other for a trial that would declare a success when at least one hypothesis is rejected from the study. Our framework shows that it is not always optimal to add a new treatment arm to an existing trial. We illustrate a case study by considering a completed trial on knee osteoarthritis