A biomarker is a characteristic that is measured objectively as an index of a pathogenic process or a response to treatment. We would argue that in evaluating the utility of a biomarker, the issues are similar to those involving the development of cognitive measures such as those considered during the first phase of CNTRICS discussed above (which can of themselves serve as biomarker measures). These issues are: 1) validity, that is the degree to which a measure reflects the neural substrates of particular cognitive mechanisms; and 2) reliability, that is to say the measurement properties of the measure. A third issue relevant to use in treatment development involves practicalities of administration and this can be a major issue for imaging biomarkers depending upon the imaging technology involved. A fourth issue is relationship between functional brain measures and symptoms and measures of functioning.
With the development and widespread use of non invasive imaging methodologies such as fMRI, EEG and MEG, the notion of using functional imaging based measures as markers of altered neural activity associated with cognitive and emotional processing in schizophrenia, and its modulation as a function of intervention, has obvious appeal. Pharmacological fMRI, for example, has become its own field, and it has become widely used as a tool to investigate the mechanisms by which CNS acting drugs exert their effects in the brain (2
). Indeed, the potential utility of imaging biomarkers seems quite self-evident. Using methods that have been well worked out in basic cognitive and affective neuroscience leverages over 50 years of progress in these fields and in related areas of neurobiology and neuropharmacology. This approach allows us to conceptualize and measure the target of an intervention as a discrete neural system supporting the impaired cognitive and emotional processes that we seek to remediate, bypassing the obvious limitations imposed on treatment studies that seek to impact categorically based diagnoses that may actually be highly heterogeneous neurobiologically (4
There are a number of different ways in which imaging biomarker measures may be used in the treatment development process, with the purpose to which they are put potentially differing as a function of the phase of development. For example, in phase 1 clinical studies, the use of imaging biomarkers may provide initial evidence for pharmacodynamic effects in the neural systems being targeted to achieve cognitive remediation. In doing so it may be possible to establish proof of mechanism of action in the human brain. For example based upon recent pharmacological and fMRI data from both animal models and humans, it has been hypothesized that a final common pathway for stimulant effects in the brain is mediated by changes in the functional state of the locus coeruleus norepinephrine system (5
A related strategy is the use of imaging markers in the context of normal volunteer models of cognitive impairment – for example, sleep deprivation or acute nicotine withdrawal in chronic smokers. Drugs which can mitigate the brain functional changes associated with cognitive impairment in these and other phase 1 models of neuropsychiatric disorders might be more likely to succeed therapeutically in later studies involving patients. Another potential application in early clinical studies will be to evaluate pharmacokinetic-pharmacodynamic relationships. In this context, one might explore the relationship between drug plasma levels or brain receptor occupancy determined with PET or SPECT and its effects on brain function as measured by fMRI or EEG/ERPs. In general the early clinical use of fMRI or EEG/ERPs to support evaluation of the dose-response properties of centrally-acting drugs, and to inform rational dose selection, is a potentially important area of future application of imaging biomarkers.
It was also noted that the opportunity to measure brain function in animal models using fMRI provided a new opportunity for a “translational bridge” between pre-clinical and clinical phases of drug development, which might help to reduce the high levels of attrition often ascribed to the poor predictive utility of traditional animal models of cognitive impairment and other psychiatric syndromes. In later (e.g. phase II) stages of the treatment development process, pharmaco imaging measures might be used to predict treatment effects on cognition prior to the onset of measurable changes in behavioral task performance. They might also be used to predict individual differences in response to a specific treatment within the context of a personalized medicine approach.
The potential of fMRI markers to predict treatment response would naturally be of particular interest in the development of centrally acting drugs which were expected to require several weeks or months of treatment to demonstrate clinical benefits by more established outcome measures or endpoints. For example, one can imagine using imaging biomarkers in future clinical trials to screen patients for a brain functional profile that is likely to predict a good therapeutic response to disease-modifying treatment of neurodegenerative disorders. Such imaging-based strategies for sample enrichment might be expected to reduce the cost and improve that statistical power of clinical studies, while also limiting the unnecessary treatment of patients unlikely to derive much therapeutic benefit from the drug.
Overall, the greatest value of imaging to the process of commercial drug development is likely to reside in its capacity to reduce the inherent risks of progressing a drug from preclinical through early clinical and proof-of-concept studies to large and expensive late stage clinical trials. Despite the potential appeal and opportunities for neuroscientifically-based risk mitigation described above, the use of non-invasive imaging biomarkers in treatment development has been limited (though growing) to date.
The cautious approach taken by the pharmaceutical industry and others to the use of imaging biomarkers is arguably based upon a number of fundamental conceptual and methodological concerns, which were the focus of the meeting described in this issue. Thus, we started work on addressing these concerns prior to the meeting by identifying which criteria the field felt were most important in selecting useful imaging biomarkers.
The development of criteria to evaluate the utility of different imaging biomarker methods
As with our efforts to identify valid cognitive constructs in the first series of CNTRICs meetings, the CNTRICS executive committee developed an initial list of potential criteria for evaluating the utility of different imaging biomarkers for use in cognition-enhancing treatment development and evaluation (see ). Like our prior surveys and meetings, we felt it important to involve as many individuals as possible in the process, as the FDA and the NIMH are more likely to benefit from the consensus views of a large group than the opinions of only a small subset of the field. We used a web-based survey to ask individuals from a wide range of expertise domains to rank the criteria in terms of their relevance for deciding whether or not to utilize an imaging biomarker in the treatment development and evaluation process. These domains of expertise included over 200 individuals from academia and industry (pharmaceutical, biotech and cognitive testing), from the basic and clinical sciences whose research focus was on measuring of brain function during cognitive and affective processing, as well as individuals with experience in clinical trials of medications and cognitive rehabilitation in schizophrenia. We used several methods to generate the list of individuals asked to participate in the survey, including: 1) the names of those individuals that were involved in the prior CNTRICS meetings; 2) individuals serving on the editorial boards of basic and clinical psychopharmacology, cognitive science, cognitive neuroscience, neuroimaging, and schizophrenia related journals; 3) individuals from as many small and large industry organizations as could be identified by the CNTRICS steering committee.
Importance Ratings of Initial Criteria for Evaluating Imaging Biomarkers
We asked these individuals to rank each potential criterion on a 5-point scale, ranging from 0 (Not Important) to 4 (Very Essential). A total of 121 individuals completed this survey, and shows the results for the total sample as well as separately for those individuals from academia and industry. As can be seen in , academic and industry participants rated many of the same criteria highly, including conceptual and validity criteria such as demonstrated sensitivity to manipulations of cognitive/affective processing and directness of interpretation, and methodological criteria such as test-retest reliability, clear quality assurance protocols, patient tolerance and standardization of administration and analysis protocols. However, one interesting divergence was that the industry respondents rated demonstrated sensitivity to pharmacological manipulations more highly than academic respondents. This may reflect the more exclusive focus of industry respondents on pharmacological approaches to cognitive enhancement, while the academic respondents included those who also use behavioral interventions to modify cognition. Sensitivity to treatment effects is, however, a critical property for any biomarker measure that will inform treatment development.