SBIR-STTR Award

An indication for the improvement of cognition in patients with schizophrenia is likely to require demonstration not only of improvement on cognitive tests, but also demonstration that these cognitive changes are clinically meaningful (Buchanan et al., 2005). Real-world functional change is considered to be too high a threshold for registration since outcomes such as employment, independent living, and social relationships are likely to require more time to change than the duration of a typical clinical trial. Further, real-world functional change appears to be dependent upon a variety of circumstances unrelated to treatment, such as whether a patient is receiving disability payments (Rosenheck et al, 2005). For these reasons, FDA representatives have stated that the meaningfulness of cognitive change can be demonstrated with the use of co-primary measures such as tests of functional capacity. However, there are no standard measures of functional capacity. In fact, the recent MATRICS Project concluded that while some available measures held promise as co-primary measures, there were not sufficient data to support the recommendation of any single instrument, and that all currently available instruments had considerable weaknesses (Green et al, in press). Therefore, we propose an SBIR project devoted to the development and validation of computer-based, virtual-reality measures of functional capacity that would be used as co-primary measures in clinical trials of cognitive enhancement in schizophrenia. These measures will assess cognitive function using realistic environments that simulate daily activities. Examples of these activities are presented in the scenario described within the document, along with the respective domains of cognitive function. Measures of cognitive function will be primarily based on error rates and times to completion for each of the assessment activities. All data regarding cognitive scores will be transferred to a central Web server, using standards compliant with both HIPAA and FDA regulations. A library with different scenarios and difficulty levels will be available so that learning effects as well as ceiling and floor effects are diminished. Finally, the measure will be culturally sensitive, allowing for use not only with minority subjects in the United States whose first language is not English, but also with study subjects from other countries participating in international trials.

Public Health Relevance:
Schizophrenia is characterized by a diverse array of symptoms, including cognitive deficits which usually accompany (Saykin et al. 1994) or precede (Fuller et al. 2002; Hawkins et al. 2004) the onset of psychosis, and remain throughout the course of illness (Green and Braff 2001; Heinrichs and Zakzanis 1998; Bilder et al. 2000). Unfortunately, while current antipsychotic treatments control the delusions and hallucinations found in people with schizophrenia, these drugs are unable to provide more than minimal cognitive benefit (Harvey and Keefe 2001; Keefe et al. 1999; Woodward et al. 2005; Keefe et al. 2007). A computerized interactive assessment of functional skills, as proposed here, promises to provide pharmaceutical companies with better information regarding patients' real-world functioning so that compounds targeting this improvement can be developed.

Public Health Relevance Statement:
Project Narrative Schizophrenia is characterized by a diverse array of symptoms, including cognitive deficits which usually accompany (Saykin et al. 1994) or precede (Fuller et al. 2002; Hawkins et al. 2004) the onset of psychosis, and remain throughout the course of illness (Green and Braff 2001; Heinrichs and Zakzanis 1998; Bilder et al. 2000). Unfortunately, while current antipsychotic treatments control the delusions and hallucinations found in people with schizophrenia, these drugs are unable to provide more than minimal cognitive benefit (Harvey and Keefe 2001; Keefe et al. 1999; Woodward et al. 2005; Keefe et al. 2007). A computerized interactive assessment of functional skills, as proposed here, promises to provide pharmaceutical companies with better information regarding patients' real-world functioning so that compounds targeting this improvement can be developed.

Project Terms:
Activities of Daily Living; Activities of everyday life; Affect; Antipsychotic Agents; Antipsychotic Drugs; Antipsychotics; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Cognition; Cognitive; Cognitive Science; Cognitive deficits; Computer Programs; Computer software; Computers; Confidentiality; Country; Data; Data Set; Dataset; Delusions; Development; Diagnosis; Disease; Disorder; Drugs; Employment; Ensure; Environment; FDA; Face; Floor; Food and Drug Administration; Food and Drug Administration (U.S.); Goals; Grant; HIPAA; Hallucinations; Health Insurance Portability and Accountability Act; Independent Living; International; Internet; Kennedy Kassebaum Act; Language; Learning; Libraries; Living, Independent; Major Tranquilizers; Measures; Medication; Mental Health; Mental Hygiene; Neuroleptic Agents; Neuroleptic Drugs; Neuroleptics; Outcome; PL 104-191; PL104-191; Paper; Patients; Performance; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phase; Privacy; Programs (PT); Programs [Publication Type]; Psychological Health; Psychoses; Psychotic Disorders; Public Law 104-191; Recommendation; Regulation; Research; SBIR; SBIRS (R43/44); Schizophrenia; Schizophrenic Disorders; Simulate; Small Business Innovation Research; Small Business Innovation Research Grant; Software; Study Subject; Symptoms; Technology; Testing; Time; Tranquilizing Agents, Major; Treatment Efficacy; USFDA; United States; United States Food and Drug Administration; United States Health Insurance Portability and Accountability Act; Validation; WWW; base; clinical investigation; cognitive change; cognitive enhancement; cognitive function; cognitive psychology; computer program/software; computerized; daily living functionality; dementia praecox; design; designing; disability check; disability claim; disability money; disability payment; disability refund; disease/disorder; drug/agent; facial; functional ability; functional capacity; improved; instrument; minority subjects; prevent; preventing; privacy of information; programs; public health relevance; schizophrenic; simulation; skills; social; standard measure; therapeutic efficacy; therapeutically effective; treatment trial; usability; virtual reality; web; world wide web

Schizophrenia is a devastating and costly mental illness with direct and unemployment costs approaching $95 billion per year. Cognitive impairments affect the majority of patients with schizophrenia. These impairments are strongly associated with poor long-term psychosocial outcomes and reflect a large and significant unmet clinical need. FDA approval of new drugs for cognitive impairment in patients with schizophrenia requires pharmaceutical companies to demonstrate not only improvements on cognitive tests, but also clear evidence that these cognitive changes lead to clinically meaningful improvements in functional capacity. Measures of functional capacity, known as co-primary measures, indicate the degree to which individuals have changed their potential to alter real-world behavior. At present, there are no standard measures of functional capacity, and existing data do not support the recommendation of any single instrument. The Virtual Reality Functional Capacity Assessment Tool (VRFCAT Copyright (c) 2011) is a novel computer based virtual-reality measure of functional capacity that relies on a realistic simulated environment to recreate routine activities of daily living. We designed it initially for use in domestic schizophrenia drug trials and were successful at developing and pilot testing it in the NIMH SBIR Phase 1 project. Findings on VRFCAT's reliability were encouraging and indicated that it may be superior to the most commonly used measure of functional capacity, the UPSA-2. In this Phase 2 SBIR application, we propose to further evaluate and establish the VRFCAT's sensitivity, reliability, validity and practicality, and prepare to commercialize it through NeuroCog Trials'existing sales and operational infrastructure. This application has 5 specific aims: 1) Examine VRFCAT's ability to measure changes in functional capacity by comparing it to the UPSA-2 in patients with schizophrenia and healthy controls;2) Examine and compare the test-retest reliabilities of the VRFCAT and UPSA-2;3) Determine the association between performance on the VRFCAT and performance on the standard measure of cognition, the MATRICS Consensus Cognitive Battery (MCCB);4) Examine the relative strength of the relationship of the VRFCAT and the UPSA-2 with a measure of real-world functioning outcomes, the Specific Levels of Functioning (SLOF);5) Assess the usability and practicality of the VRFCAT for both patients and research staff in multiple clinical trial settings. In Phase 1 we showed the VRFCAT to be a reliable measure. Phase 2 will allow us to further develop and commercialize the VRFCAT. This new and superior measure of functional capacity could improve clinical trials and facilitate approval for drugs to treat cognitive impairment in patients suffering from schizophrenia. The VRFCAT has the potential to fulfill the FDA's requirement of a reliable co- primary measure, and will help determine which new drugs have a meaningful impact on cognition and on the lives of schizophrenia patients.

Public Health Relevance:
Schizophrenia is a serious mental illness that affects approximately three million Americans and costs about $100 billion a year for direct treatment, community services, and lost wages. While the most obvious symptoms such as hallucinations and bizarre beliefs can be minimized with treatment, there is no currently available treatment for the underlying cognitive disturbances such as memory and attention impairment that are the prime cause of functional disability. Because one of the greatest current challenges of drug development in schizophrenia is to find the best tools for measuring changes in cognition and functioning, this research aims to provide the field with a valid measure of changes in functionally relevant cognition.