Available antipsychotic medications are relatively ineffective for treating the negative symptoms of schizophrenia. Because these symptoms make a substantial contribution to the functional impairments that are common in schizophrenia, they represent an important target for drug development. An earlier National Institute of Mental Health (NIMH) workshop1
focused on some of the important research issues that should be addressed in designing clinical trials of pharmacological and nonpharmacological agents that may improve negative symptoms. Since that report, investigators have gained considerable experience in designing and implementing clinical trials in this area. These experiences convinced members of the International Society for CNS Clinical Trials and Methodology (ISCTM) to revisit a number of these issues with a focus on regulatory issues and instruments for measuring negative symptoms. The decision to revist the prior consensus was based on the following concerns: (1) the prior workshop did not include representatives from industry. It was felt that industry representatives had practical experiences in designing and implementing trials as well as a different perspective on regulatory issues, rating instruments, and design issues; (2) a discussion at a prior ISCTM meeting raised concerns that the Food and Drug Administration (FDA) was reconsidering its decision to not require a functional coprimary instrument in negative symptom trials; (3) the workshop could provide greater detail about critical design issues such as a recommended sample description and trial duration; (4) there has been recent progress on new instruments for measuring negative symptoms; and (5) results and practical experiences from trials carried out since the prior workshop could be considered.
This report provides a summary of ISCTM Workshops on Methodological Issues in Negative Symptom Trials held in September, 2009, in San Diego, California, and October, 2010, in Baltimore, Maryland. Participants included individuals from academia and the pharmacological industry. Robert Levin, MD from the US FDA, participated via teleconferencing in the San Diego meeting and Karl Broich from the European Medicines Agency (EMEA) participated in the Baltimore meeting. At the Baltimore meeting, Jack Blanchard from the NIMH Collaboration to Advance Negative Symptom Assessment in Schizophrenia (CANSAS) presented an update on the development of a new instrument to measure negative symptoms2
(described in this issue). Participants were polled about the issues that they believe should be discussed in the workshops. The meeting organizers (Drs Marder, Daniel, Awad, Alphs, and Keefe) used this input to develop the meeting agendas. Each of the consensus statements is followed by background information supporting the consensus.
1. Will regulatory authorities accept evidence of improvement on a negative symptoms scale as sufficient for drug approval or will improvement on a co-primary measure associated with functioning be required as well?
Because negative symptoms can be reliably measured in clinical settings and the severity of negative symptoms reflects functional impairment, US and European Union (EU) regulators agree that appropriately designed trials using well validated assessments of negative symptoms may lead to a labeled indication of the treatment of negative symptoms without the inclusion of a coprimary measure of functional improvement.
Background: The discussion of regulatory issues for negative symptoms has been influenced by discussions of cognitive impairment. Regulatory authorities in the United States and the EU stated that improvement on a battery of neuropsychological tests would not be sufficient to support approval of a pharmacological agent for improving cognition in schizophrenia. Instead, improvement on a coprimary measure of functioning, functional capacity, or a self-rating of cognition would also be necessary. The explanation for this additional regulatory requirement has been described by FDA representatives at public meetings: First, to the general public, neuropsychological tests may lack face validity. Although performance on these tests has been related to community functioning, it is unclear that improvement on test performance will translate to meaningful improvement in real world activities. Moreover, patients may not be aware of their cognitive impairment and clinicians without specific expertise are unable to assess it in the clinic.
The need for this type of coprimary measure has also been raised in studies of negative symptoms. However, there are important differences in how cognition and negative symptoms are assessed. First, negative symptoms can be evaluated by clinicians, and they can be rated reliably in clinical trials. The severity of symptoms such as restricted affect and apathy is clearly related to functional outcomes. Moreover, as noted in the 2006 consensus statement,1
they have face validity because they constitute a loss of normal function. Improvement in these symptoms would be apparent to clinicians and interested observers, and they would potentially result in a decrease in illness-related disability. This relationship between changes in negative symptoms and functioning has been demonstrated recently.3
The relationship is less clear for improvement on a cognitive test, where it remains questionable whether a small but observable improvement in a score would be clinically meaningful. Finally, the functional relevance of cognitive impairments can be determined by performance-based assessments of functioning with tasks that resemble real world tasks and are affected by cognitive deficits such as impaired memory or attention. It is less clear how apathy, asociality, or restricted affect could be translated into a performance test.
At the workshop, Dr Levin stated that FDA had reconsidered a previous position and at this time would not require a coprimary functional measure for negative symptoms. Dr Broich, repesenting EMEA at the Baltimore meeting, also indicated that a coprimary functional measure would not be required for EU applications.
2. What are the characteristics of subjects who should enter into trials of drugs for negative symptoms? What would be the inclusion and exclusion criteria?
The consensus opinion of the group was that a number of principles should guide the selection criteria: (1) Negative symptoms should be stable and persistent. If negative symptoms fluctuate during a trial, this may increase the proportion of subjects who improve on the control condition. It will increase the variance seen in both groups and, consequently, increase the sample size needed to detect potential differences between treatment arms; (2) Symptoms in other domains, particularly psychotic symptoms, depression, extrapyramidal symptoms, and cognitive impairment, should be stable and not predominant. This will help to assure that change during the course of the trial is not secondary to change in other domains. To help establish that this is the case and to demonstrate the specificity of any changes observed, it is valuable to have measures of psychosis, depression, extrapyramidal symptoms, and cognition in negative symptom trials; and (3) In trials addressing the use of co-medications to treat negative symptoms of schizophrenia, all antipsychotics including the simultaneous use of more than 1 antipsychotic may be allowed except when the antipsychotic has a potential pharmacokinetic or pharmacodynamic interaction with the experimental medication. In such cases, these interactions must be clarified.
3. What would be the optimal duration for a proof-of-concept or a registration trial of an agent for treating negative symptoms?
Many of the symptoms associated with negative symptoms require many months to fully stabilize. Therefore to adequately capture potential changes, the preregistrations trials should be at least 6 months in duration. A briefer duration of treatment is acceptable for proof-of-concept trials.
The time course for improvement in negative symptoms in response to pharmacological interventions continues to be unclear because there are currently no agents with demonstrated effectiveness. Among studies published over the past 10 years, the duration had varied widely from 4 weeks up to 2 years with the majority being over 8 weeks.4,5
Soliciting recent expert opinions, there seems to be an agreement that the duration of pharmacological clinical trials need to be no less than 3 months but optimally 6 month or longer not including a prerandomization phase for the purpose of stabilization.6
The recognized challenge is how to reconcile the need for optimal duration to demonstrate meaningful clinical changes and the practical complexities of long-term trials including subject retention to endpoint and cost.
4. What is the optimal design of a trial of a broad spectrum antipsychotic or that is under evaluation for effectiveness for both psychotic and negative symptoms? What is the optimal design for a trial of a co-medication for negative symptoms that would be added to an antipsychotic?
Two types of trials that demonstrate effective drug treatments for negative symptoms can be conceptualized: (1) trials for a monotherapy indication and (2) trials for the adjunctive treatment of schizophrenia.