Innovations In Clinical Neuroscience

ISCTM Supplement 2015

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

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Page 29 of 41

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 ] 30S cluster, that is part of a defined DSM syndrome (e.g., hallucinations in schizophrenia). Attempting to target a claim for a DSM syndrome in the c ontext of some comorbid condition (e.g., depression with cardiovascular disease, post-stroke patients, or in Parkinson's disease) might also be considered pseudospecific. Similarly, targeting a subgroup of some recognized DSM entity that is arbitrarily defined by some biomarker would also likely be considered pseudospecific. In the absence of strong argument and evidence to the contrary, regulators will likely default to the position that the requested claim is pseudospecific. However an agency's initial rejection of claim as pseudospecific might well represent a "straw man" position. In other words, the objection may be overcome with arguments and data to show validity and value of targeting a particular domain or biomarker-defined subgroup. For a claim targeting a particular domain, an approach to overcoming regulatory concern of pseudospecificity is to produce evidence that available drug treatments in the class do not address the domain in question. For some conditions, this might be accomplished by demonstrating that there is a residual phase of illness with persistence of symptoms in this domain, or perhaps evidence for a subtype of the disorder, with prominence of symptoms in this domain, and that is not responsive to available treatments. One noteworthy example of successful establishment of a domain within the schizophrenic syndrome is CIAS. This is a well-established aspect of schizophrenia that is not well addressed by available treatments. CIAS has a different time course than positive symptoms of schizophrenia, often being present even before the onset of psychosis and persisting into the "residual" phase of the illness. Both the FDA and the European Medicines Agency (EMA) have endorsed CIAS as a legitimate target for drug development. Other domains within DSM-defined syndromes that FDA has accepted as legitimate targets for drug development include negative symptoms of schizophrenia, suicidal i deation and behavior in schizophrenia, agitation in schizophrenia and bipolar disorder, irritability of autism, impulsive aggression in attention deficit hyperactivity disorder (ADHD), and agitation/aggression in dementia. Another pathway for overcoming a regulatory concern for pseudospecificity that should work for either a domain or a biomarker-defined subgroup would be to show drug response specificity for that domain or subgroup. One way to accomplish this would be to show that the drug works only for that domain or only for the biomarker-defined subgroup. Alternatively, a company might try to show that its drug is superior to another drug in the class on this domain or in this biomarker-defined subgroup. The question of validation (or qualification) of biomarkers often comes up in the context of these discussions, and there is much confusion about what this means. It is useful to distinguish between analytical validation of a biomarker and clinical validation. Analytical validation concerns the performance of the biomarker assay in accurately identifying patients who are marker positive (M+) and marker negative (M-). So this involves determining sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the assay with regard only to marker status. Clinical validation (also known as qualification) has a broader meaning with regard to what clinical outcomes the marker can predict. How this is accomplished depends on the particular use of the marker in question. This discussion is focused mostly on predictive biomarkers, and for this purpose, a clinical trial is the mechanism for demonstrating whether or not a particular biomarker has clinical predictive value. It is important to note that, for this limited purpose, a biomarker only needs to be validated for a particular drug of interest. Importantly, a marker that was identified in exploratory datasets needs to be confirmed in a pre- specified way in confirmatory studies. F or prognostic and surrogate markers, the process of validation is broader and not specific to any particular drug. Ultimately, companies are interested in understanding what is needed to get a biomarker into the labeling for a particular drug product. The way to accomplish this is to design a coherent hypothesis testing strategy. Assuming the focus is on an accepted DSM diagnostic category, e.g., schizophrenia, the ideal approach from regulatory perspective would be as follows. A valid and reliable biomarker assay would have been developed before the start of phase 3. This would provide the capability to establish biomarker status for all patients prior to randomization. Then during the phase 3 program, one would conduct stratified randomization (M+/M-) and have a clear plan for hypothesis testing that includes marker status (+/-) as well as adjustment for all other parameters of interest (e.g., dose, primary and key secondary endpoints). The decision on the role of a biomarker in a development program will drive the hypothesis testing strategy. If the sponsor wants broad claim in the population of patients with the disorder, but would also like to claim as added benefit in M+ patients, hierarchical testing would likely begin in the broad population and then proceed to marker subgroups. Alternatively, the sponsor may recognize that a biomarker may "salvage" a program that might otherwise fail. In this case the testing hierarchy might reasonably begin testing with M+ patients and then move to M-. In summary, regulatory agencies are not fundamentally opposed to considering alternative approaches to carving up the psychiatric illness space. However, there is a need to come prepared with strong arguments and data to support an alternative approach to diagnosing psychiatric illness. It is also helpful to have some

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