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The article presents the advantages and limitations of adaptive clinical trials for assessing the effectiveness of medical interventions and specifies the conditions that contributed to their development and implementation in clinical practice. I advance two arguments by discussing different cases of adaptive trials. The normative argument is that responsible adaptation should be taken seriously as a new way of doing clinical research insofar as a valid justification, sufficient understanding, and adequate operational conditions are provided. The second argument is historical. The development of adaptive trials can be related to lessons learned from research in cases of urgency and to the decades-long efforts to end the productivity crisis of pharmaceutical research, which led to the emergence of translational, personalized, and, recently, precision medicine movements.

Costs and staffing resource requirements for adaptive clinical trials: quantitative and qualitative results from the Costing Adaptive Trials project

Background Adaptive designs offer great promise in improving the efficiency and patient-benefit of clinical trials. An important barrier to further increased use is a lack of understanding about which additional resources are required to conduct a high-quality adaptive clinical trial, compared to a traditional fixed design. The Costing Adaptive Trials (CAT) project investigated which additional resources may be required to support adaptive trials. Methods We conducted a mock costing exercise amongst seven Clinical Trials Units (CTUs) in the UK. Five scenarios were developed, derived from funded clinical trials, where a non-adaptive version and an adaptive version were described. Each scenario represented a different type of adaptive design. CTU staff were asked to provide the costs and staff time they estimated would be needed to support the trial, categorised into specified areas (e.g. statistics, data management, trial management). This was calculated separately for the non-adaptive and adaptive version of the trial, allowing paired comparisons. Interviews with 10 CTU staff who had completed the costing exercise were conducted by qualitative researchers to explore reasons for similarities and differences. Results Estimated resources associated with conducting an adaptive trial were always (moderately) higher than for the non-adaptive equivalent. The median increase was between 2 and 4% for all scenarios, except for sample size re-estimation which was 26.5% (as the adaptive design could lead to a lengthened study period). The highest increase was for statistical staff, with lower increases for data management and trial management staff. The percentage increase in resources varied across different CTUs. The interviews identified possible explanations for differences, including (1) experience in adaptive trials, (2) the complexity of the non-adaptive and adaptive design, and (3) the extent of non-trial specific core infrastructure funding the CTU had. Conclusions This work sheds light on additional resources required to adequately support a high-quality adaptive trial. The percentage increase in costs for supporting an adaptive trial was generally modest and should not be a barrier to adaptive designs being cost-effective to use in practice. Informed by the results of this research, guidance for investigators and funders will be developed on appropriately resourcing adaptive trials.

“Ready for What?”: Timing and Speculation in Alzheimer’s Disease Drug Development

“Readiness cohorts” are an innovation in clinical trial design to tackle the scarcity of time and people in drug studies. This has emerged in response to the challenges of recruiting the “right” research participants at the “right time” in the context of precision medicine. In this paper, we consider how the achievement of “readiness” aligns temporalities, biologies, and market processes of pharmaceutical innovation: how the promise of “willing bodies” in research emerges in relation to intertwined economic and biological time imperatives. Drawing on long-term engagement with the field of Alzheimer’s disease prevention and interviews with researchers from academia and the pharmaceutical industry, we describe the discursive construction and practical arrangement of readiness. This paper contributes to understandings of temporal specificity, or “timing,” within prevention research and casts critical light on the way this specificity—the threshold for “trial readiness”—relates to an opaque and highly speculative drug development pipeline. Extending the study of biomedical potential, as that which holds promise but may not yet exist, we consider how absences operate in adaptive trials. By highlighting these absences (“ready for what?”), we outline an opportunity for socio-ethical research to intervene in the speculative gaps of drug development.

The Bayesian Design of Adaptive Clinical Trials

This paper presents a brief overview of the recent literature on adaptive design of clinical trials from a Bayesian perspective for statistically not so sophisticated readers. Adaptive designs are attracting a keen interest in several disciplines, from a theoretical viewpoint and also—potentially—from a practical one, and Bayesian adaptive designs, in particular, have raised high expectations in clinical trials. The main conceptual tools are highlighted here, with a mention of several trial designs proposed in the literature that use these methods, including some of the registered Bayesian adaptive trials to this date. This review aims at complementing the existing ones on this topic, pointing at further interesting reading material.

Adding flexibility to clinical trial designs: an example-based guide to the practical use of adaptive designs

Adaptive designs for clinical trials permit alterations to a study in response to accumulating data in order to make trials more flexible, ethical, and efficient. These benefits are achieved while preserving the integrity and validity of the trial, through the pre-specification and proper adjustment for the possible alterations during the course of the trial. Despite much research in the statistical literature highlighting the potential advantages of adaptive designs over traditional fixed designs, the uptake of such methods in clinical research has been slow. One major reason for this is that different adaptations to trial designs, as well as their advantages and limitations, remain unfamiliar to large parts of the clinical community. The aim of this paper is to clarify where adaptive designs can be used to address specific questions of scientific interest; we introduce the main features of adaptive designs and commonly used terminology, highlighting their utility and pitfalls, and illustrate their use through case studies of adaptive trials ranging from early-phase dose escalation to confirmatory phase III studies.

Occurrence and Severity of Physiological Disorders of Oil Palm (Elaeis guineensis Jacq. L.) in Uganda

In Africa, oil palm is grown in 25 countries supported by corporate investors. In Uganda, commercial oil palm cultivation began in 2005 in Bugala Islands. Seedlings were imported from countries with established breeding programs. These seedlings were grown in areas with different environmental conditions which have resulted in a number of physiological disorders. The aim of this research was to determine the major physiological disorders in oil palm fruit bunches in Uganda. The study was carried out in the adaptive trials in Kagadi, Bugiri, Buvuma and Masaka Districts and in the different smallholder farmer blocks in Kalangala District. Data was collected on bunch rot, bunch failure and uneven ripening. Sampling was carried out in oil palm plantations above five years of age. Three fields were selected from each unit and three units from each block by the help of the Agricultural Extension Officers (AEOs). Palms were randomly sampled and assessed for presence of bunch rot, bunch failure and uneven ripening symptoms. The incidence was expressed as a percentage of the total number of palms sampled while the severity of bunch rot disease was scored on a scale of 0-4. From the results, the differences in bunch rot and bunch failure in adaptive trials were statistically significant as well as across seasons (P < 0.05). Uneven ripening was not statistically significant and severity of bunch rot in the different farmer blocks in Kalangala was statistically significant (P = 0.03). Uneven ripening was high across smallholder farmer blocks in Kalangala and was statistically significant (P = 0.05) even across seasons (P < 0.05). These results are important for sensitization of farmers on management of oil palm disorders and essential for guiding policy makers and investors as the oil palm industrial sector is being developed in Uganda. This study calls for determination of water deficit at the various ecological zones and its relationship to physiological disorders as a guide for further oil palm estate development.