Cognitive Assessment in Schizophrenia Clinical Trials: MATRICS and Beyond Michael F. Green, PhD Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine at UCLA UCLA Semel Institute Department of Veterans Affairs, VISN 22 Mental Illness, Research, Education and Clinical Center (MIRECC) March 5 th 2009 ASENT / ISCTM Washington D.C.

MATRICS: Measurement and Treatment Research to Improve Cognition in Schizophrenia Steve Marder, M.D., P.I. Michael Green, Ph.D., Co-P.I. NIMH Project Officer: Wayne Fenton, M.D. NIMH Division Director, DMDBA: Ellen Stover, Ph.D.

Wayne Fenton Science That Matters

MATRICS: Background and Rationale Increasing evidence that cognitive deficits are core features of schizophrenia Increasing support for relationships between cognition and functional outcome in schizophrenia Increasing research focus on the basic studies of neuropharmacology of cognition

Targeting Cognition in Schizophrenia: Why the Bottleneck? l Lack of consensus regarding cognitive targets. l No widely accepted endpoint. l Ambiguity regarding optimal clinical trial design. l No path to FDA approval and labeling (not a DSM entity).

l FDA registration targets DSM disorders l “No fundamental objection to syndrome- based clinical targets (fever, pain, agitation)” l “We will not accept a new clinical endpoint for the convenience of any drug company” l NIMH can use its convening authority as independent scientific entity to define new and valid clinical endpoints FDA Processes Focus Industry Efforts

NIMH – MATRICS Goals and Products l Create Standardized Measure for use in Clinical Trials l Define Optimal Experimental Designs l Establish path to FDA Approval l Attract large pharmaceutical companies to focus efforts on this important clinical target l Success required involvement of: NIMH, FDA, pharmaceutical industry, and academia

Alzheimer’s Dementia compared with Schizophrenia Neuropsychological Deficit Scores From Heaton et al. (1994) Alzheimer’s Disease: substantial impairment in memory retention relative to schizophrenia

MATRICS Principles for Developing Consensus l Consensus should be as broad as possible l Transparency of process l Inclusion of academia, NIMH, industry, FDA, consumer representatives l A priori development of a path to consensus (e.g., RAND Panel, a modified Delphi process) l Management of conflicts of interest

Steps to MATRICS Consensus Cognitive Battery Subgroup of NCC* & survey of experts NCC, based on survey of experts Survey of experts NCC MATRICS Team RAND Panelists NCC, based on ratings of Panelists *NCC: MATRICS Neurocognition Committee **PASS: MATRICS Psychometric and Standardization Study 1. Identify cognitive domains 2. Select key criteria for test selection 3. Solicit nominations for cognitive tests 4. Narrow tests to 6 or less per domain 5. Create data base on criteria for candidate tests 6. Evaluate tests on criteria with RAND Method 7. Select 2-5 tests per domain for beta battery PASS** group NCC and PASS group 8. Psychometric study with beta battery 9. Final battery of 1-3 tests per domain 10. Co-norming of tests on community sample PASS group

Essential Criteria for Consensus Cognitive Battery for Clinical Trials in Schizophrenia Battery: Inclusion of the seven cognitive domains Valid assessment of cognition at the level of all individual major cognitive domains Individual Tests: High test-retest reliability High utility as a repeated measure Demonstrated relationship to functional outcome Demonstrated tolerability and practicality

MATRICS Consensus Cognitive Battery Estimated administration time – 63.5 min Speed of Processing Category Fluency BACS Symbol Coding Trial Making A Attention / Vigilance Continuous Performance Test - Identical Pairs version Working Memory Maryland Letter Number Span WMS Spatial Span Verbal Learning Hopkins Verbal Learning Test Visual Learning Brief Visuospatial Memory Test Reasoning and Problem Solving NAB Mazes Social Cognition MSCEIT Managing Emotions

MATRICS Consensus Cognitive Battery (MCCB) Distributed by: Pearson - Harcourt Assessment, Inc Multi-Health Systems (MHS) Psychological Assessment Resources (PAR)

Norms from MATRICS-Psychometric and Standardization Study (PASS) Kern et al. Am J. Psychiat. 2008

Co-primary (Intermediate) Measure in Addition to Cognitive Performance: “The current position of the FDA is that concurrent change on a co- primary measure of functional outcome will be required for approval of a neurocognitive drug for schizophrenia.” Buchanan et al. Schizophrenia bulletin 2005 Arguments for Community Status as Co-primary: Increase face validity for consumers and clinicians Increase acceptance by consumers and clinicians The ultimate goal is better community functioning Arguments against Community Status Co-primary: Measurement challenges Distance from biological systems (sensitivity to cognitive-enhancing drugs; likely length of time to change) Intervening variables / level of psychosocial support Arguments by analogy (e.g., not needed for hallucinations, depression, Parkinson’s tremor)

Key Linkages for Cognition and Functional Outcome Cognitive Performance Measures Functional Capacity Interview-based Cognitive Assessment Community Outcome Assessment Environment Laboratory Community Clinic Proximal Distal Within individual Interpersonal Less sensitive More sensitive Sensitivity to cognitive drug effects Intermediate

Follow up Activities to MATRICS 1) TURNS: NIMH Sponsored: Clinical trials network for cognition enhancing drugs; TENETS Network (Treatment and Evaluation Network for Trials in Schizophrenia) 2) Negative Symptoms Initiative New negative symptom scale 3) CNTRICS: NIMH Initiative for cognitive neuroscience measures in clinical trials 4) MATRICS-CT: Translation and Co-primary: Industry / Academic Consortium Translation and co-norming of MCCB into other languages for international trials Evaluation of co-primary measures

TURNS Research Sites Sites Columbia University Duke University Harvard / Mass General Nathan Kline Institute University of Maryland UCLA Washington University *

1. Merck (MK-0777) l 4-week trial l GABA A (α2, α3) partial agonist 2. Allon (AL-108) l 8-week trial l 8 amino acid peptide fragment l promotes assembly of microtubles l potentially neuroprotective 3. Novartis (AQW051) l single dose cross-over study l 2-week parallel group study l α7 nicotinic agonist NIMH-TURNS / TENETS Ongoing Clinical Trials

Identify set of cognitive systems and component processes as targets for treatment development in schizophrenia. Delineate psychometric and pragmatic issues relevant to the development of tasks that measure these cognitive systems. Develop specific measures of target cognitive processes that can be implemented as behavioral tasks, as well as non- invasive functional neuroimaging studies.

MATRICS-CT Scientific Board Representation by: NIMH NIH Foundation Academia Consumer Perspective Pharmaceutical Industry AstraZeneca Bristol-Myers Squibb Eli Lilly GlaxoSmithKline Lundbeck Johnson & Johnson Pfizer Merck Roche, Sanofi-Aventis Wyeth

MATRICS – CT Translation of the MCCB Jun ‘07 Aug ‘07 Oct ‘07 Dec ‘07 Feb ‘08 Apr ‘08 Jun ‘08 Aug ‘08 Oct ‘08 Dec ‘08 Feb ‘09 Apr ‘09 Jun ‘09 Aug ‘09 Forward / Backward Translations for MATRICS- CT Languages Establish Procedures for MCCB Academic Translations Test Owner Review and Approval Collection of Norms Page composition, Printing of MCCB Translated Components Final Reconciliation, Cultural Adaptation 1 st Tier Languages: Chinese, German, Hindi, Russian, Spanish (plus dialects for South and Central America) Obtain Legal Permission, Licensing

Validation of Intermediate Measures (VIM) Study: Key Dependent Measures Performance-based measures 1. Test of Adaptive Behavior in Schizophrenia (TABS) 2. UCSD Performance-based Skills Assessment (UPSA) 3. Independent Living Scales (ILS) Each of these performance-based assessments will be administered so that short forms can be compared with long forms. Interview-based measures 1. Semi-structured: Cognitive Assessment Interview (CAI) 2. Global assessment (1-100 pt scale): Global Assessment of Function from CAI 3. Clinical impression (1-7 pt scale): CGI for Cognitive Impairment

MATRICS – CT Validation of Intermediate Measures ( ) Jun ‘07 Aug ‘07 Oct ‘07 Dec ‘07 Feb ‘08 Apr ‘08 Jun ‘08 Aug ‘08 Oct ‘08 Dec ‘08 Feb ‘09 Apr ‘09 Jun ‘09 Selection Criteria Group Proposal Meeting #1: Approval of Selection Criteria UCLA Staff Solicit Nominations & Create Database Meeting #2: RAND Panel to Evaluate Instruments VIM Committee Selects & Invites Panelists Validation Study Data Collection VIM Committee Analyzes Data; Makes Recom- mendations Meeting #3: Review of Recommendations Valid. Study Start up / Training Aug ‘09 VIM Committee Selects Measures, Designs Trial, w/ input from Scientific Board

What we did not anticipate in MATRICS l Role of co-primary (intermediate) measures l Importance of norms l Intellectual property issues for tests selected for MCCB l Challenges for inclusion of tests from cognitive neuroscience l Limits of an English-only battery