Innovations In Clinical Neuroscience

ISCTM Supplement 2015

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 2 , N U M B E R 3 – 4 , S U P P L E M E N T A , M A R C H – A P R I L 2 0 1 5 ] 18S information related to a drug candidate is obtained. This includes 1) likelihood of showing an effect with FDA- accepted endpoints, 2) information for d esigning pivotal trials such as dose, and 3) likelihood of commercial potential. However, Phase IIa trials are frequently underpowered, and the usual clinical endpoints are too variable to test efficacy potential in a Phase IIa study with sufficient power at limited cost. As a result, Phase IIa trial results are vulnerable to bias problems and represent a risky basis for making go/no-go decisions. Diagnostic issues. Prevailing diagnostic systems are based on consensus and uses clinician observation and patient symptom reports that are phenomenological based. The current diagnostics 1) are not based on science, 2) do not incorporate recent scientific developments, 3) fail to align with neuroscience and genetic findings, 4) are not predictive of treatment response, 5) are unable to capture fundamental underlying mechanisms, and 6) are deficient in aiding in development of new treatment targets to underlying pathophysiological mechanisms. There is reason to believe that current diagnostics may actually be slowing developmental progression of novel treatments and in part contribute to study failure. Specifically, current diagnostics are unlikely to be successful in developing a drug for a condition that 1) does not have a unique pathophysiology and 2) cannot be reliably distinguished from other conditions. It is for these reasons that attention is now being turned to objective neurobiological targets for developing and testing new treatments of interest. Fundamental misconception. It is becoming increasingly clear that trial failure may stem from not establishing proof of concept (POC) and target engagement for the drug doses studied. Those that go to Phase III prior to establishing POC in terms of efficacy/safety profile in Phase I–II are at risk of a failed trial. Studying dosages that have not been demonstrated to robustly engage the target of interest is problematic. If the results are negative, there is uncertainty as to whether the dose was sufficient. The result is that m ultiple unnecessary trials are carried out because it is not possible to conclude that engaging the target does not achieve the desired effect with a single negative study. Another problem is the failure to test specific a priori hypotheses about an agent. The usual focus has been to determine whether a treatment has a therapeutic effect. This results in vulnerability to nonspecific effects and bias. A treatment can appear to have a therapeutic effect for many reasons, some of which are not because the treatment actually improves the condition being treated (e.g., there was an unequal distribution of placebo responders in the treatment groups). As a result, proceeding to Phase III on the basis of a study that only tested the hypothesis of whether there is evidence of a beneficial effect is a setup for failing to replicate. Proposed solution using quick- win/fast-fail approach. The focus is on designing early phase studies that achieve POC early through employment of biomarkers and surrogate endpoints. Once a dose is established and robustly engages the target, studies can be carried out that rigorously test the hypothesis of whether engaging the target achieves a hypothesized effect as a means of establishing POC. Objective biomarkers are likely closer to pathophysiology and therapeutic mechanism than clinical endpoints while possessing less variability and greater power. As a result, a smaller trial with less variability and cost can be carried out to determine POC. Furthermore, since the vast majority of drug candidates fail, this methodology provides a means to allow treatments that should not be further developed to fail more quickly and at less cost. This, however, requires a shift of R&D investment from later to earlier stages of drug development. It is proposed that designing Phase I/IIa studies to definitively indicate therapeutic potential is critical to success. Such studies must establish POC using biomarkers/surrogate endpoints early on as a basis for d etermining whether a treatment that engages a target achieves the desired effect on physiology or objectively measureable behavior. This strategy is not only less costly overall, it also makes it more likely that Phase III studies that are carried out will be more likely to replicate, as some of the sources of bias that create false positive Phase IIa results will have been eliminated. However, for this type of work to be possible, it is necessary to develop reliable biomarkers of both efficacy and safety for a variety of conditions, and this will require a substantial effort. Research Domain Criteria (RDoC) framework. RDoC is a new framework that incorporates reseach on pathophysiology, including emerging findings from genomics/neuroscience research. As RDoC is based on research findings, it is more likely to be useful than prior approaches for identifying promising new treatment targets, detecting key subgroups, and developing valid outcome assessments. It is also more likely to achieve correspondence between animal models and human conditions of interest. RDoC-defined "constructs" are key dimensions of function that are important for neuropsychiatric function. They are defined by research studies related to that dimension of function, and they are subject to continual refinement based on advances in science. This includes studies identifying relevant associated genes, molecules, cells, circuits, physiology, behavior, self-report, and experimental paradigms. Related constructs are grouped into five major domains of functioning: 1) Negative Valence Systems (i.e., systems for aversive motivation), 2) Positive Valence Systems, 3) Cognitive Systems, 4) Systems for Social Processes, and 5) Arousal Regulatory Systems. Recently, the NIMH established networks for carrying out early phase

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