Guidelines from the FDA-NIMH-MATRICS Workshop on Clinical Trial Designs for Neurocognitive Drugs for Schizophrenia

Held April 23, 2004

Note: These suggested guidelines are intended to represent reasonable starting points for the trial design of cognitive enhancing drugs, with the understanding that there may be deviations in any particular trial, but that any deviations will need to be explained by either drawing upon new data, subsequent findings, or other methodological considerations.

Inclusion Criteria for Clinical Trials of Potential Cognitive Enhancer Medication

Q1: Among the major psychotic disorders, what is the evidence that schizophrenia and related disorders (i.e., schizoaffective disorder, schizophreniform disorder) are characterized by a unique pattern of cognitive impairments?

Suggested Guidelines:

The pattern of cognitive deficits in schizophrenia and schizoaffective disorder is very similar and is distinctive from the patterns in major depression, bipolar disorder, and Alzheimer’s dementia. Therefore, neurocognitive impairment in schizophrenia and schizoaffective disorder is a unique and appropriate target for drug development.
However, because the current approach of the FDA to approval/labeling reflects greater diagnostic specificity of the targeted population, studies of potential cognitive enhancers should initially include only patients with schizophrenia.

Q2: What is the optimal phase of illness for patient inclusion?

Suggested Guidelines:

Adjunctive/Co-Treatment Agents (i.e., Cognition is primary indication)
- Phase of Illness: Include subjects who have been clinically-stable and in the residual (non-acute) phase of their illness for a specified period of time (e.g. 8 –12 weeks).
- Maintained on current antipsychotic and other concomitant psychotropic medications for a specified period of time sufficient to minimize potential complications of assessment of cognitive status (e.g. 6-8 weeks) and on current dose for a specified period of time (e.g. 2 – 4 weeks).
Broad Spectrum Agents (i.e., Cognition and symptoms are co-primary indications)

Phase of Illness: Include subjects who have been clinically-stable and in the residual (non-acute) phase of their illness for a specified period of time (e.g. 8 –12 weeks).
Maintained on current antipsychotic and other concomitant psychotropic medications for a specified period of time sufficient to minimize potential complications of assessment of cognitive status (e.g. 6-8 weeks) and on current dose for a specified period of time (e.g. 2 – 4 weeks).

Q3a: What design approaches should be used to isolate change in neurocognitive domains from changes in other symptom domains

Suggested Guidelines:

Adjunctive/Co-Treatment Agents

Hallucinations and Delusions: Include stable subjects, with no more than a “moderate” symptom severity rating (e.g. BPRS Hallucinatory Behavior or Unusual Thought Content item score ≤ 4)
Disorganized Behavior: Include stable subjects, with no more than a “moderate” symptom severity rating (e.g. BPRS Conceptual Disorganization item score ≤ 4)
Negative Symptoms: Include stable subjects, with no more than “moderate” symptom severity (e.g. all SANS global items ≤ 3 or PANSS negative syndrome total score ≤ 15)
Other Symptoms: Include subjects with a minimal level of extrapyramidal symptoms (e.g. SAS total score ≤ 6) and depressive symptoms (e.g. Calgary Depression Scale total score ≤ 10)

Q3b: What design approaches should be used to isolate change in neurocognitive domains from changes in other symptom domains?

Suggested Guidelines:

Broad Spectrum Agents

Hallucinations and Delusions: Include stable subjects, with no more than a “moderate” symptom severity rating (e.g. BPRS Hallucinatory Behavior or Unusual Thought Content item score ≤4)
Disorganized Behavior: Include stable subjects, with no more than a “moderate” symptom severity rating (e.g. BPRS Conceptual Disorganization item score # 4)
Negative Symptoms: Include stable subjects, with no more than “moderate” symptom severity (e.g. all SANS global items ≤3 or PANSS negative syndrome total score ≤15)
Other Symptoms: Include subjects with a minimal level of extrapyramidal symptoms (e.g. SAS total score ≤6) and depressive symptoms (e.g. Calgary Depression Scale total score ≤10)

Q4: Which antipsychotic(s) should be allowed in studies of an adjunctive/co-treatment agent?

Suggested Guidelines:

Stage I: Avoid pharmacodynamic or pharmacokinetic interactions between the experimental agent and the antipsychotic treatment.
Stage II: Evaluate the impact of potential pharmacodynamic or pharmacokinetic interactions with a larger, stratified sample. Ideally, the adjunctive/co-treatment agent should be studied in an “all comers” design, with few if no restrictions on allowed antipsychotics. This approach may require a large sample in Stage II.

Q5: Should antipsychotic polypharmacy be allowed in studies of an adjunctive/co-treatment agent?

Suggested Guidelines:

Exclude subjects who are taking more than one antipsychotic, because antipsychotic combinations are an unnecessary complication in studying an adjunctive/co-treatment agent. The exclusion of subjects who are on multiple antipsychotics will eliminate approximately 20% of patients from studies.

Q6: Should concomitant medications be allowed?

Suggested Guidelines:

Stage I: Avoid pharmacokinetic and pharmacodynamic interactions between the adjunctive/co-treatment agent and any concomitant medications.
Stage II: Potential pharmacokinetic and pharmacodynamic interactions should be examined on an agent specific basis:

SSRIs: metabolic inhibition
Anticholinergics: agents acting at muscarinic acetylcholine receptors
Benzodiazepines and anticonvulsant mood stabilizers: GABAergic and glutamatergic agents

Examination of potential pharmacokinetic and pharmacodynamic interactions may require separate pharmacokinetic interaction studies. Eliminating all concurrent medications excludes approximately 65% of patients.

Q7: How should broad spectrum agents be studied?

Suggested Guidelines:

If broad spectrum agents possess antipsychotic activity, then they should be studied as monotherapy.
Antipsychotic efficacy should be established in trials utilizing standard designs for antipsychotic agents
Cognitive effects should be studied in stabilized subjects randomized to monotherapy with the broad spectrum agent or a cognitively neutral comparator antipsychotic agent.

Q8: Should a maximum level of cognitive impairment be an exclusion criterion?

Suggested Guidelines:

Exclude patients with severe cognitive impairment from the trial only if the validity of the cognitive outcome measure is threatened.
This determination can be made using a combination of clinical information and objective data, such as premorbid IQ scores or premorbid IQ estimates from current reading level.

Q9: Should a minimum level of cognitive impairment be an inclusion criterion?

Suggested Guidelines:

Exclude subjects from a clinical trial only if the level of their cognitive functioning is so high that they perform at ceiling for the cognitive battery and therefore can not demonstrate improvement.
In a properly constructed cognitive test battery, this level of performance is so rare in patients with schizophrenia that actual screening is not necessary. However, any subject who performs at ceiling on the cognitive outcome measure at baseline should be excluded from the trial.

Q10: How should screening assessments be conducted?

Suggested Guidelines:

If at all, then use screening assessments with great caution. A screening battery that is different from the outcome battery is preferred.
Consider the use of reading tests that estimate premorbid IQ to exclude patients whose cognitive abilities are is so impaired that their inclusion threatens test validity.
Exclude patients who perform at ceiling on the cognitive battery at baseline.

Outcome Measures

Q11: Should a co-primary outcome measure be required in addition to cognitive performance?

Suggested Guideline: In addition to change on an approved measure of cognitive performance, the FDA has adopted the position that change on a co-primary measure of functional outcome will also be required for approval of a neurocognitive drug. The co-primary measure should assess an outcome that is clinically meaningful/relevant, but it does not need to be a measure of community functioning, which is so highly dependent on psychosocial services, skills, and social support.

Q12: If a co-primary outcome measure is used, what are its ideal characteristics?

Suggested Guidelines:

A co-primary measure should have the following characteristics:
Good face validity for patient improvement
Expected to change in close temporal proximity to changes on cognitive performance measures
Not heavily dependent on rehabilitation opportunities and level of social support
Practical (from the perspective of the experimenter) and tolerable (from the perspective of the subject)

Q13: What is the best approach to assess the validity of proxy measures of functional outcome and interview-based measures of cognition?

Suggested Guidelines:

• Good test-retest reliability
Demonstrated associations with cognitive performance measures
Demonstrated associations with community functional status

Other Design and Statistical Issues

Q14: What are issues regarding the choice of primary efficacy measure?

Suggested Guideline:

Pre-specify a single reliable and valid primary efficacy measure, either global or specific, based on its psychometric properties and the results of pilot studies

Q15: What are issues regarding the number of testing occasions?

Suggested Guidelines:

Use more rather than fewer testing occasions to mitigate the impact of attrition and to capture change in symptom severity over time.
Use data analytic procedures that incorporate repeated measures of the outcome.

Q16: In light of the expected heterogeneity of severity and response within and across different cognitive domains, what approaches to design and analysis should be used to detect a therapeutic effect?

Suggested Guidelines:

Include subjects only in the residual (non-acute) phase of their illness in order to reduce within group heterogeneity at baseline and to increase the chance of detecting a therapeutic effect.
Use one primary efficacy measure

Q17: What approaches to design and analysis should be used to control for potentially concurrent changes in other symptom domains?

Suggested Guideline:

Statistical approaches cannot be used to rule out pseudospecificity (i.e., an artificially narrow claim of cognitive enhancement that could result from post-baseline confounding, such as reduction in other aspects of the illness, including positive, negative, or depressive symptoms). Pseudospecificity is best dealt with by restricting symptom severity prior to randomization.

Q18: What are implications of the choice of comparison group?

Suggested Guidelines:

RCT must show that cognition changes independent of positive and other symptoms.
Comparator must not impair cognition
To study an adjunctive/co-treatment agent, placebo can be used as the comparator
Choice of comparator for broad spectrum agent poses a challenge, but should be, at worst, cognitively-neutral

Q19: What are issues regarding the duration of a clinical trial of an agent targeting cognition in schizophrenia?

Suggested Guidelines:

Psychometric studies must support repeated administrations of the primary efficacy measure
The trial duration needs to be of significant duration to detect an effect, which will depend, in part, on mechanism of action and dosing properties of the neurocognitive agent
The trial duration needs to be of sufficient duration to show an enduring effect on cognition (e.g. 6 months)
Longer duration studies should use multiple testing occasions, which require the existence of parallel forms of the outcome measure.
Use statistical procedures that incorporate data from multiple assessment times.