1	FDA View of Cognitive Deficits in Schizophrenia as a Target for Drug Development Thomas Laughren, M.D. Team Leader, Psychiatric Drug Products Food and Drug Administration
2	Topics Covered Overview of current approach to drug claims in psychopharmacology Current regulatory approach to schizophrenia Pseudospecificity: Regulatory basis for critical examination of proposal to focus on cognitive deficits in schizophrenia as a distinct target Criteria for establishing cognitive deficits in schizophrenia as a unique aspect of this illness for drug development Practical issues in implementing a development program for cognitive deficits in schizophrenia
3	Clinical Targets for Drug Claims Diseases/Syndromes e.g., schizophrenia Symptoms/Symptom Clusters Specific to disease/syndrome e.g., agitation in schizophrenia e.g., suicidality in schizophrenia Nonspecific symptoms e.g., pain or fever
4	Evolution in Psychiatric Drug Claims over Past 15 Years Previous approach: Broad claims (mostly anxiety, depression, psychosis) Current approach: Specific diseases/syndromes Specific symptoms or symptom clusters Nonspecific symptoms Note: Pseudospecificity still a concern
5	Why Focus on Cognitive Impairment in Schizophrenia? Abundance of data showing Substantial CI in schizophrenia (1-2 SD below expected levels in normal controls) CI predictor of poor outcome NIMH MATRICS Program Pharmaceutical companies are interested in targeting CI in schizophrenia
6	Current Regulatory Approach to Schizophrenia Schizophrenia viewed as single clinical target New antipsychotics approved for the “treatment of schizophrenia” Cognitive deficits acknowledged as one aspect of the schizophrenic syndrome, but not teased apart as a distinct target (Note: not part of DSM-IV criteria) Assessment focus is on positive symptoms (but with some attention to “negative symptoms”) Trial Designs 4-6 week acute studies Randomized withdrawal studies for longer-term efficacy
7	Pseudospecificity: Regulatory Basis for Critical Examination of Proposal to Focus on Cognitive Deficits in Schizophrenia as a Distinct Target Definition of pseudospecificity Problems with pseudospecific claim Pseudospecificity as preliminary judgement Examples of pseudospecificity
8	Definition of Pseudospecificity Proposed claim is considered pseudospecific if found to be artifically narrow Claim focused on: Subgroup/subset within an ill population Particular aspect of illness (e.g., symptom) One model of nonspecific symptom Lack of empirical evidence to support such a narrow focus
9	Problems with Pseudospecific Claim Serves only promotional purpose Implied advantage over other drugs in class regarding subgroup/symptom Misleading (since no evidence to support)
10	Pseudospecificity as Preliminary Judgement Subject to being disproven Evidence needed to justify narrow claim: Superiority over other drugs in class regarding subgroup/symptom Effectiveness limited to particular subgroup/symptom FDA Position: Pseudospecific until proven otherwise Burden is on sponsor to provide evidence
11	Examples of Pseudospecificity Subgroup of recognized syndrome Demographic subgroup e.g., MDD in women Subgroup with particular comorbidity e.g., MDD in patients with cardiovascular disease Symptom of recognized syndrome e.g., hallucinations in schizophrenia e.g., insomnia of GERD Claiming specific benefit in single disease model for recognized nonspecific symptom e.g., dental pain
12	Questions to Ask in Attempting to Establish Cognitive Deficits in Schizophrenia as a Unique Aspect of this Illness for Drug Development Can cognitive deficits be clearly distinguished phenomenologically from other aspects of the illness? Do cognitive deficits in schizophrenia have a distinguishable course compared to other schizophrenic symptoms? Are cognitive deficits recognized in the diagnostic nomenclature as a distinct aspect of schizophrenia? Do schizophrenia experts recognize cognitive deficits as a unique feature of the illness? May ask advice of Psychopharmacological Drugs Advisory Committee Do cognitive deficits respond differently to treatment than other aspects of this illness? Are cognitive deficits understood at a mechanistic level, and do they have a unique pathophysiology?
13	Related Question: Are the cognitive deficits in schizophrenia nonspecific, i.e., not necessarily unique to schizophrenia? Can ask similar questions as those used in establishing cognitive deficits as unique aspect of schizophrenia, except comparison would be with cognitive deficits associated with other illnesses (Alzheimer’s disease, Huntington’s disease, etc.) FDA would likely consider the cognitive deficits of schizophrenia unique to schizophrenia (if shown to be distinct from other schizophrenic symptoms), unless advocates of nonspecificity could make very strong case for nonspecificity
14	Practical Issues in Implementing a Development Program for Cognitive Deficits in Schizophrenia Defining cognitive impairment in schizophrenia Identifying population to study Trial design Assessments Selecting primary and secondary endpoints
15	Issues to Address in Defining Cognitive Impairment in Schizophrenia One domain vs multiple domains Variability in profile and severity of deficits across patients Pattern of deficits over time Overall for schizophrenia Individual patient profiles
16	Issues to Address in Identifying Population to Study for Cognitive Impairment in Schizophrenia All schizophrenic patients or some subgroup? If subgroup: What measures to use for selecting patients What threshold for defining minimal impairment What phase of illness? Acute, residual, prodromal? Status of other schizophrenic symptoms, e.g., “positive” Might require some threshold level of control of positive symptoms
17	Key Issues to Address in Developing Trial Designs for Cognitive Impairment in Schizophrenia Acute vs residual phase Duration of trials Monotherapy vs Add-On Dose response
18	Trial Design for Cognitive Impairment in Schizophrenia (Acute vs Residual Phase) Acute phase trials (patients with positive symptoms and cognitive impairment) Would positive symptoms interfere with assessment of cognitive function? Would effective treatment of “positive symptoms” lead to secondary “improvement” in cognition? Residual phase trials (patients on standard antipsychotic drugs with positive symptoms below some threshold, but who have cognitive impairment) “All comers” vs single standard drug for positive symptom control?
19	Trial Design for Cognitive Impairment in Schizophrenia (Duration of Trials) Cognitive impairment is persistent throughout the course of illness Studies should be long-term At least 6 months Long-term, placebo controlled monotherapy trials not feasible
20	Trial Design for Cognitive Impairment in Schizophrenia (Monotherapy vs Add-On) Add-on may be optimal design, since many patients will need standard antipsychotic therapy for control of positive symptoms Feasible only if different pharmacology than standard drug Add-on new drug or placebo Could be long-term, residual phase study Monotherapy design would be alternative for drug active in both positive symptoms and cognitive impairment Optimal design unclear: May need 2 designs Acute phase (for positive symptom claim) Short-term; placebo control Need to show new drug > placebo on positive symptoms Residual phase (for cognition claim) Long-term; active control Need to show new drug > active standard on cognitive symptoms Problem: Interpretation of difference difficult without placebo Caution: Need to examine fairness of comparison
21	Trial Design for Cognitive Impairment in Schizophrenia (Dose response) Minimum effective dose Dose plateau for effectiveness Maximum tolerated dose
22	Issues to Address in Developing and Selecting Assessments for Cognitive Impairment in Schizophrenia What specific tests address the cognitive domains of interest? What are the functional consequences of cognitive impairment, and how can these be measured?
23	Selecting Primary Endpoints for Cognitive Impairment in Schizophrenia Cognitive endpoints: separate domains vs summary scores? Functional improvement endpoints Likely requirement as co-primary endpoint Current standard for Alzheimer’s disease Many unresolved issues Proxy vs real-world measures Time needed for measurable functional change Other ingredients needed (psychosocial therapy) Patient distress measures
24	Summary Comments FDA open to arguments for targeting cognitive impairment in schizophrenia as a distinct aspect of the syndrome Many issues to resolve, including: What population to study What endpoints to focus on Optimal trial designs Need to consider whether or not a similar effort is needed to target negative symptoms