Author Archive

Suicidal Thinking and Behavior Assessment Working Group – Comment on FDA Guidance

Tuesday, October 26th, 2010

	November 8, 2010 To: Division of Dockets Management (HFA‐305) Re: Docket # FDA‐2010‐D‐0451 The International Society for CNS Clinical Trials and Methodology (ISCTM) thanks the Food and Drug Administration (FDA), for the opportunity to submit comments on the Guidance for Industry “Suicidality: Prospective Assessment of Occurrence in Clinical Trials.” ISCTM supports the goals if the Draft Guidance to reduce the potential for suicidal behavior, ideation and attempts during drug treatment. We agree that prospective evaluation of suicidal behavior and ideation may add to a more complete assessment of risk to benefit ratio of drugs used in the treatment of psychiatric and onpsychiatric disorders. However, we find the document unclear or incomplete in a number of sections and provide this commentary for your consideration. The ISCTM is a multi‐disciplinary independent organization, devoted to promoting advances that address strategic clinical, regulatory, methodological and policy challenges that arise in the development and use of CNS therapeutic agents. This work is accomplished through partnership with persons in academia, industry, government, policy‐making and the public. Recognizing the importance of this document for our constituency, the ISCTM convened a working group to review and comment on the guidance. Authors (in alphabetical order) Larry Alphs, MD, PhD, Janssen Pharmaceutica, Inc. Phil Chappell, MD, Pfizer, Inc. Douglas Feltner, MD William Lenderking, PhD, United BioSource Corporation Andrew C. Leon, PhD, Weill Cornell Medical College Atul Mahableshwarkar, MD, Takeda Pharmaceutical Company, Ltd Carlotta McKee, ISCTM Jill Rasmussen, MD, psi‐napse Co‐Chairs: Adam Butler, United BioSource Corporation Michelle Stewart, PhD, Pfizer, Inc.
General Comments on the Guidance
	• It would be helpful to begin this document with clearer descriptions of the scope of the guidance that is being provided. Relevant issues of scope are included in the document, but addressing this would be helpful for the reader. In particular is does this guidance only pertain to sponsors who conduct a study under an IND, to non‐IND studies, to academic investigators studying drugs (eg clinicians, NIMH, the VA, etc.), to non‐interventional studies conducted as part of general surveillance of risk/benefit, and/or to post marketing safety surveillance? Reference is made to this guidance serving ‘as a focus for continued discussion among the FDA, pharmaceutical sponsors, the academic community and the public. Does this mean that studies conducted by any of these groups fall under the remit of this guidance? It would be valuable to define “pharmaceutical sponsors” in this context. • The guidance could benefit from a definition of key terms early in the document that are not well defined by the guidance (e.g., suicidal ideation, suicidal behavior, and pharmaceutical sponsors. When key terms are used throughout the document, every effort should be made to use them precisely and consistently throughout the document. • To better frame the intent of the guidance, the document should specifically state at the outset that the goal is to ascertain the risk of suicidal ideation and behavior for those receiving medication relative to comparator and/or placebo. • The C‐SSRS is best viewed as a semi‐istructured questionnaire to elicit the information required to facilitate mapping events to the C‐CASA categories. As such it is more a data collection tool or instrument to arrive at C‐CASA classifications and not a “scale” in the sense that that term is generally used in psychometric literature. For example, there is no evidence that there is a latent construct that underlies the C‐SSRS, that severity is quantified (e.g., as an outcome), or that its items cohere in a meaningful way. Thus we would recommend the term “assessment” be used rather than “scale” throughout the guidance. • The guidance does not address study entry criteria, e.g., recommending thresholds for entering a clinical trial based on suicidal ideation and behavior. Does the FDA have any clarification regarding this issue relative to the guidance? • The guidance should make clearer that the recommendations in the guidance are not intended for trials in which suicidal ideation and/or behavior is the primary or key endpoint. An example would be a trial in which a drug was being studied to show that it decreased suicidal ideation and behaviors. It is not clear that the C‐SSRS would be the assessment of choice in such trials as it has not been developed to track severity or change in suicidal ideation. • The detailed nature of the information that subjects are required to submit for these assessments may be too intrusive and culturally insensitive. This may contribute to attrition of subjects in clinical trials, as well as country/cultural bias in the validity of data generated, thus further complicating the analyses of available data. • Because assessments recommended by the guidance will be used by many people with little understanding of suicide risk, a statement similar to the following should be added to the introductory remarks: “Assessments used to detect and monitor for suicidal ideation and behavior are not adequate to assess an individual’s risk of future self‐harm. The assessment of risk for future self‐harm requires an evaluation by a competent professional.” • The guidance should acknowledge that there are limited published data to support the use of the C‐SSRS for detecting suicidal ideation and behaviors in clinical trials and that additional data on the psychometric properties of the C‐SSRS and similar assessments are needed.
Specific Comments
Line 48 (& 199‐200)	Comment The term “suicidality” is too broad and has been criticized because it bundles ideation and behavior. Early in the document it is recognized that “suicidality is a broad term that includes both ideation and behavior” that may have separate predictive meanings. The use of this term, in the guidance leads to confounding of issues and unclarity. We suggest using the phrase “suicidal ideation and behavior” as being more descriptive and appropriate. There is additional value in discriminating between suicidal ideation and suicidal behaviors for, although they may be related constructs, they are not continuous. In particular, measurement of severity and the ability of suicidal ideation and suicidal behaviors to predict future risk for death may require distinct approaches. Indeed, the nature of and meaning of suicidal ideation may vary over time. For instance, suicidal ideation that is prevalent in young females (teenagers) is much less frequently associated with later risk for death than is that of geriatric males.
49	Should state “…that occur during drug OR PLACEBO treatment.” The guidance should specifically state that the goal is to ascertain the risk of suicidal ideation and behavior for those receiving medication relative to comparator and/or placebo.
51	In the guidance “suicidality” is referred to as an “event.” It is not clear that suicidal ideation always represents a discrete event that can be readily captured.
87‐88	The document indicates that an assessment instrument used to detect suicidal ideation or behavior must map to the C‐CASA categories. However, the document then goes one to indicate that many of the codes of the C‐CASA are not relevant. This statement should be clarifed to indicate that the mapping entails only those relevant categories.
115‐117	Reference is made to the fact that Code 7 has predictive validity. Please provide citation for line 116 regarding the predictive validity of the C‐CASA code 7.
118‐119	Reference is made that codes 5 and 6 are indeterminate and unnecessary for prospectively assessing patients. Based on clinical experience, category 5 can be useful because it is not always possible to clearly ascertain suicidal intent for self‐injurious behavior or whether a fatal event represents a death. We would argue that, if code 7 is valuable for collection, 4 ISCTM Comment: FDA‐2010‐D‐0451 codes 5 and 6 would have similar value. This is particularly true of events that may occur in cultures or subcultures where suicidal thinking or behavior is considered unacceptable. If the FDA is not interested in codes 5, 6, and 9, do data on them need to be collected at all (beyond what would be needed for adverse event reporting if applicable)? Also would alternative instruments be expected to map to these codes or would psychometric validity only have to be identified for Codes 1, 2, 3, 4 and 7?
130	The guidance suggests that the C‐SSRS represents an acceptable instrument for capturing data to be mapped to the C‐CASA. The psychometric data supporting this are not referenced. Such references would be valuable to the reader. Also, since multiple versions of the C‐SSRS exist, it would be valuable for the document to reference the particular versions of the C‐CASA that are supported by this guidance.
140‐142	Other assessment instruments do exist for suicidal ideation and behavior. It would be helpful if the guidance provided a list of other existing instruments beyond the C‐SSRS and provide information on the status of these with the agency (e.g., if they are not fully accepted then this should be noted). The guidance should further provide details on the standard of evidence that would be necessary for use of alternate assessments to be accepted by the FDA as alternatives to the C‐SSRS.
149‐155 (& 233‐ 241)	The guidance requires that instruments ask about various aspects of suicidal ideation (i.e., nonspecific; method but no plan or intent; method and intent but no plan; method, plan and intent) but all of them map to the same C‐CASA code 4. The guidance should clarify that the subcategories mentioned in lines 147‐162 are not a part of the C‐CASA codes. If greater granularity on these subcategories is required by this guidance and needed for additional analyses, it should be recognized that this information cannot be recovered from the C‐CASA categorization data alone. Is this guidance suggesting that additional classification beyond that provided by the C‐CASA is necessary? If so, what is the basis for this requirement? The Suicidality Data Coding Form in Appendix B does not collect this level of information and many sponsors may not routinely database this level of detail which means it would not be available for later analyses without additional effort and specification in the database. Is it the intent of the FDA that such data regarding method, plan and intent be available? Will any additional tools be required to track method, plan and intent, and maintain what appears to be the guidance’s hierarchical classification? Are details about method, plan, and intent important information to gather in an randomized clinical trial? These items would appear to be more appropriate for a tool to assess suicide risk. The guidance appears to be concerned with documenting adverse events related to suicidal ideation and behavior rather than assessing suicide risk per se. It is unclear what the value of some of the detail is to FDA since it will not be summarized in the C‐CASA data from trials.This distinction seems to be only tangentially related to the focus of the guidance, unless an alternative classification system is being proposed. With respect to suicidal ideation, as noted in the guidance, it can be present with varying levels of ideation. Some forms of ideation may not carry as much weight as others and little is known about the predictive validity or other psychometric properties of these specific aspects of ideation (i.e., nonspecific; method but no plant or intent; method and intent but no plan; method, plan and intent). There may be other aspects that are also important to assess that are will not be collected (e.g., controllability, deterrents, etc). Tools could be developed to capture severity or type of suicidal ideation but they will all map to the same C‐CASA category . What is meant by “intent” in this context: Intent to die or intent to carry through with a suicidal plan? It is possible that patients may intend to carry out a plan but have no intent to die (e.g., when motivated by attention‐seeking). The interpretation of “method” seems straightforward, i.e., what the respondent would do or how he/she would kill him/herself. Does “plan” in this context then refer only to time and place? Method would seem to be part of a plan.
156‐161 & (226‐ 231)	The guidance requires that instruments ask about three types of preparatory actions: preparatory acts, interrupted, and aborted, but all 3 map to the same C‐CASA code 3. As with the suicidal ideation domains, the guidance should clarify that these subcategories mentioned in lines 156‐161 (& 226‐231) are not a part of the C‐CASA codes. And as noted for the suicidal ideation levels, if greater granularity on these types is needed for additional analyses, it cannot be recovered from the C‐CASA category data alone. Similarly, the Suicidality Data Coding Form in Appendix B does not collect this level of information and many sponsors may not routinely database this level of detail which means it would not be available for later analyses without a great deal of effort that may entail going back to sites to try and recover the details. Is it the intent of the FDA that such data should be available? Providing detail at this level on rare events such as aborted and interrupted attempts may contribute to noise. The detail that a suicide attempt was interrupted would not be expected to contribute to greater understanding of whether a drug has any impact on suicidal ideation and behavior. Hence collecting such information would impose additional burden without contributing to the primary objective of safety monitoring.
164‐165	Clarity is needed that this should refer only to terms relevant to C‐CASA codes 1‐4 and 7, as they are described in lines 112‐116 of the draft guidance.
177‐179	The sentence about “other instruments” is not clear and it is not obvious what value its inclusion in this guidance provides.
183	We agree that appropriate training is critical to implementation. The guidance could include more clarity on who should deliver the training, and how it should be administered. Our recommendation is that training be done by qualified experts with appropriate experience and training but not necessarily a requirement that it be done by the person who developed the assessment. “Accuracy and consistency” could be clarified or defined in more detail, possibly with examples of how these requirements would be satisfied. Is it necessary to quantify the accuracy and consistency of raters or is it sufficient to show that appropriate training was provided?
186‐187	“Psychometrics” is a broad term. Elaborate more on what psychometric properties should be examined for alternatives. Will inter‐rater reliability suffice? Is there a definition for “well‐established?” Will one study be sufficient to argue an alternative is acceptable? Are there requirements for how this should be documented? The guidance should clarify that it is the psychometric properties that are important for the intended purposes of the instrument (detection and classification) that should be characterized. The authors also note that the C‐SSRS does not have any published psychometric validation data beyond comparisons of interview and IVRS formats (NEED TO ADD CITATION FOR Mundt, Greist, et al.). This information should be referenced in this document.
202‐203	The guidance says that any prospective assessment of suicidality be “designed for the immediate coding…to C‐CASA categories….” What is meant by “immediate” in this context? Should this coding be done at the site before the patient leaves? Many sponsors are collecting data while the patient is at the site then mapping the responses to C‐CASA categories through programming algorithms at a later date, often following database lock when the rest of the study data are analyzed. Sites are instructed to refer patients as needed based on responses to the assessment so there is no delay in seeking follow‐up care if needed; it is just that the mapping to C‐CASA categories may occur at a much later time.
210‐212	The guidance seems to suggest that every instance of suicidal ideation be captured. This is not practicable. Issues of definition, memory, culture and of frequency make it impossible to reliably and meaningfully to capture every suicidal ‘thought.’ Capturing this information would require a careful definition of what constitutes an episode or “event” of suicidal ideation in terms of onset and offset, and in terms of frequency. If a subject has many thoughts every day should each be captured?
253	It is unclear what is meant by concluding that ‘the suicidality question has been resolved until all the data are in hand.’ It is unlikely that suicidality data will ever be ‘all in hand.’ A discussion of risk:benefit of this collection would be valuable. At what point can it be concluded that a drug is associated with an increased risk of suicidal behavior or ideation? Is it determined on the basis of a number of observations? How many? Is it determined on over a period of observation in individuals? If so, what is that period of observation? Should it be relate to the half‐life of the drug? Similarly, at what point is the risk for suicidal ideation or behavior considered so low as to be of no interest?
255‐267	The discussion of “challenging populations” in which it may be acceptable to forego assessment of suicidal ideation and behavior does not provide much detail. The definitions of the populations are vague and there are other populations beyond those listed here where these assessments may be difficult, especially those that are acutely ill. For example, there are numerous issues with acute stroke patients, certain HIV populations, and very young children such as those enrolled in epilepsy treatment trials. There are clinical measures used in the mild‐to‐moderate AD population that rely on assistance from caregivers and it is reasonable to believe that a similar approach to suicidal ideation and behavior would be as reliable as these other measures, so that it may be reasonable for clinical trials in AD to include assessment of suicidal ideation and behavior. Data, of course, are largely lacking for supporting the validity of using any given method for detecting suicidal ideation and behavior in the AD population. If alternative assessments are acceptable, the guidance should provide a list of suitable ones beyond the C‐SSRS and what they would be used for. For example, the Neuropsychiatric Inventory could be used to assess depression/dysphoria in an AD population but would not directly monitor suicidal ideation and behavior. The guidance should provide additional clarity about this issue. The use of the C‐SSRS in children age less than 11 is unlikely to provide valid information. The language used in the C‐SSRS is not appropriate to the language abilities of young children and the ability of very young children to conceptualize of suicide will vary depending on their level of cognitive development. Assessing suicidal ideation and behavior in children, particularly younger children, should be given greater consideration and discussed in greater detail. Studies in critical care settings with drugs that have CNS actions may also not be suitable for collection of suicidal ideation and behavior data, whether due to medical morbidity of patients or the issue of frequency of other assessments. The guidance speaks to populations with cognitive impairment, but not those who are otherwise seriously compromised due to acute illness (e.g., acute stroke patients, myocardial infarction, closed head trauma).
277, 288‐ 289, 332 & 343	The guidance indicates that assessments for suicidal ideation and behavior be done at all planned visits at which other clinical assessments are done. In Phase 1 studies (especially those conducted in‐patient) there are often frequent assessment schedules, including onesthat occur multiple times in one day (e.g. collection of multiple blood samples or in a TQT study continuous monitoring of the EKG). Given this issue, the guidance should provide additional information on the timing for the assessment of suicidal ideation and behavior in trials such as Phase 1 studies where there are frequent scheduled clinical assessments. What recommendations are made for unplanned visits?
328‐332	Clarification is needed regarding which drugs are covered for Division of Neurological Products (DNP). The guidance appears to indicate that all drugs submitted under IND’s to DNP would require suicidal ideation and behavior monitoring. If the thought is any CNS active drug should be monitored, this could mean any drug that crosses the blood brain barrier, e.g., antibiotics.
Appendix B	The coding form provides an idea of what type of data the FDA wants to receive. Is it the intent of the agency that this should be used to develop a CRF that must be used at every visit? Will it be necessary to database individual responses to questions on the assessment tool, e.g., the C‐SSRS? As noted elsewhere in these comments, many sponsors are electing to database responses to assessments such as the C‐SSRS, then use programming algorithms to map the responses to C‐CASA categories at a later date, generally following database lock when the rest of the study data are analyzed.

ISCTM 2009 Autumn Conference – Placebo Response Workshop Summary

Tuesday, October 12th, 2010

Summary of Placebo Response in CNS Clinical Trials Workshop at the ISCTM 2009 Autumn Conference in San Diego

The purpose of the workshop was to gather experts to review the evidence regarding placebo response in psychiatry trials and brainstorm ways to manage this phenomenon and make some recommendations. The workshop was attended by over 75 participants.

Co-Chairs: Amir Kalali and Charles Bowden

Speakers:
Craig Mallinckrodt
Amir Kalali
Charles Bowden
Jelena Kunovac

There were four speakers representing different sectors of professionals involved in clinical trials, but the majority of the time was spent in discussion of the topic.

It was decided to focus on and discuss three main categories of factors impacting placebo response:

•   Study Design
•   Site characteristics
•   Subject characteristics

Study Design

•   Study designs must have “Simplicity to Fit Purpose” e.g appropriate outcome measures and not “overburdening” protocols and subjects. This may also have direct impact on types of patients willing to enter clinical trials
•   Treatment allocation – utilize strategies that randomize more patients to PBO
•   Use of variable PBO lead-in may be helpful
•   Patient rated outcomes may be helpful in non-psychotic disorders reducing recall and rater bias
•   Use of MMRM analysis and subscales have shown better signal detection
•   Adding threshold scores for several key symptoms not easily distorted may help increase signal detection. These can include observed symptoms, as opposed to purely reported symptoms
•   Different strategies for validating baseline severity such as patient ratings, and independent assessment should be explored

Site Characteristics

•   Importance of site culture
•   Principal Investigator involvement
•   Access to appropriate patients
•   Careful selection of appropriate patients
•   Site personnel experience, expertise and conscientiousness
•   Communication to patients and nature of interactions
•   Strive for evidence based site selection by sponsors

Subject Characteristics

•   Subject characteristics shown to impact signal detection
•   True baseline severity/acuity
•   Issues with subjects who have participated in many clinical trials and possible “professional” subjects
•   Subject motivation for participating
•   Subject expectations of improvement
•   Subject understanding of their role as a research participant versus clinical care

Recommendations

•   Study designs must have “Simplicity to Fit Purpose”
•   More intense sponsor engagement with sites
•   Sponsors need to share data with sites with regards to signal detection to facilitate improvement
•   Develop systems of “flagging” inappropriate patients

Prepared by Workshop Co-chairs: Amir Kalali, MD; Charles Bowden, MD

ISCTM 2010 Autumn Conference – Presentation Abstracts

Monday, September 20th, 2010

Session 1: MATRICS Update and Beyond

Introduction
S. Marder

The MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) program was developed by NIMH with the goal of facilitating the development of pharmacological agents for treatment the cognitive impairments in schizophrenia. The developers of the request for proposals – Steve Hyman, Wayne Fenton, and Ellen Stover – were concerned that industry was reluctant to address new treatment targets where there was uncertainty about important issues in drug development including: the best methods for measuring treatment outcome; the optimal design for clinical trials; the most promising molecular targets; and the likelihood that the FDA would be willing to approve a drug for this indication. This brief talk will provide an overview of the products delivered by MATRICS during its 2 years of funding as well as the principles that guided the consensus building processes.

The MATRICS Approach to Measuring Cognition: Foundational Issues and Critical Decisions

M. Green

The NIMH MATRICS Initiative was launched to overcome obstacles to drug development for cognitive impairment in schizophrenia. Major obstacles included the lack of an accepted definition of cognition for schizophrenia and the lack of a consensus assessment battery that could serve as an endpoint for clinical trials. The mandate of the MATRICS Initiative was to create a path for drug approval in this area; hence, the focus was on development of methods for Phase III trials.

For the development of MATRICS Consensus Cognitive Battery (MCCB), the MATRICS Initiative followed a carefully planned method that involved committees and a series of large public meetings. Out of these discussions arose key decisions that influenced the subsequent process and products. These decisions included: 1) A focus on measurement at the level of cognitive domains versus global composite scores; 2) Neutrality on the relative importance of computerization of the battery; 3) Inclusion of the relatively new domain of social cognition in the MCCB; 4) Neutrality on the inclusion of tests from clinical neuropsychology versus experimental cognitive psychology; and 5) Clear emphasis on psychometrics and tolerability/practicality of tests included in the final consensus battery. One additional factor is that there was uncertainty in how to apply the criterion of sensitivity to treatment effects given the lack of a potent drug in this area. This presentation will discuss briefly each of the key decisions and their implications for MATRICS and follow up activities.

Real-world Application of the MATRICS Consensus Cognitive Battery (MCCB) in Multisite Clinical Trials

R. Keefe

Based upon responses from over 90 experts on cognition, clinical trials and schizophrenia, the MATRICS Neurocognition Committee set guidelines for the most important characteristics of a cognitive battery for clinical trials in schizophrenia. These included test-retest reliability, small practice effects, correlations with measures of functional capacity, practicality and tolerability. In initial validation studies completed during the MATRICS contract with NIMH, the MCCB clearly demonstrated these characteristics. It has been an empirical question whether the MCCB would demonstrate these favorable characteristics when administered in the context of the type of large multi-site industry trial for which it was designed. Further, little is known about the size of the placebo effect that can be expected for cognitive enhancement trials in schizophrenia, and whether international versions of the MCCB in non-English languages are able to collect data comparable to the English version used in the United States. Methods: This presentation will discuss five recent unpublished schizophrenia cognition trials that have used the MCCB as a primary outcome measure and followed the MATRICS study design guidelines. The total N from these studies is 1135 subjects with schizophrenia. One trial included 215 stable outpatients from 22 US sites, and the MCCB was assessed at screening, baseline and weeks 4, 8 and 10. A second trial included 323 patients from 29 US sites. This trial used the MCCB to assess cognition at screening, baseline, week 6, month 3 and month 6. Two NIMH TURNS studies have each assessed 60 patients with the MCCB as the primary outcome measure, and a final industry study with MCCB assessments at baseline (N=477), Week 8 (N=452), Week 16 (N=339) and Week 24 (N=367) will be described. Two international trials using non-English versions of the MCCB are underway, and data from these studies will be briefly presented as well. Results: In the 215-patient trial, the composite scores had excellent test-retest reliability (ICC = 0.88) and sensitivity to impairment at screening (T-score = 25.1+/-SD=11.6 for patients compared to 50.0+/-10.0 for controls) and baseline (T=26.7+/-12.1). The Pearson correlation with the UPSA-2 scores was 0.56 (P<.001). In the placebo group, the effect size of the improvement on the MCCB composite score from baseline to week 8, encompassing three assessments, was small (d=0.2). The reliability between assessments in the placebo group was high (all ICC’s >.90). The MCCB had a very low rate of missing data with 99.7% of measures non-missing and none of the 215 patients missing a composite score. The results from the 323-patient trial confirmed these findings, with excellent test-retest reliability of the MCCB composite score (ICC=0.88), low missing data rate (99.8% complete), large correlation with the UPSA-B composite score (r=.61, df=304, P<.001), and a small practice effect (z=0.18). Discussion: The ultimate criterion for the success of a test battery is its repeatable sensitivity to true treatment effects, and no test battery has convincingly demonstrated this criterion. However, the results from five separate trials suggest that the MCCB has proven reliability, practicality, and tolerability for multisite clinical trials, and the practice effect is small, allowing ample room for potential treatment effects.

Assessment of Functional Outcomes

D. Velligan

For a medication to receive an indication for improving cognition in schizophrenia, regulatory agencies require evidence of improvement in both cognition and functional outcome. The Validation of Intermediate Measures (VIM) study was developed to assess the reliability, validity and utility of a number of intermediate measures that have face validity for assessing functional outcome in schizophrenia. Because longer-term functional outcomes such as employment, or changes in marital status are not likely to be improved during the course of a typical clinical trial, the study focused on intermediate measures of functional capacity or everyday functioning that are thought be more amenable to change over this time period. Conclusions of the VIM study indicated that the UCSD Performance-based Assessment (UPSA II), the UPSA Brief and the Brief Version of the Test of Adaptive Behavior in Schizophrenia (TABS) had the best psychometric properties of the scales compared, and were reasonable choices for use as co-primary outcome measures in medication trials examining the efficacy of agents designed to improve cognitive functioning in schizophrenia. However, because a large number of efficacy studies of novel compounds are now conducted as multi-site international trials, the cultural applicability of intermediate measures of functional outcome was examined in a companion study called the Cross-Cultural validation of Intermediate Measures (CIM) Study. In the CIM study, clinical investigators experienced in conducting medication trials in schizophrenia rated each of the subscales of the intermediate measures on the extent to which the subscale would be culturally applicable in their countries, and across genders, income levels, rural versus urban residence, and minority status. Results of the CIM study suggested that with one exception, all subscales of all the intermediate assessments of functional outcome were identified as likely to have problems in their adaptation to non-U.S. cultures. India, China and Mexico presented the greatest challenges in adaptation. A new study is proposed to investigate whether for international trials it may be most appropriate to use customized measures that differ from country to country or to use a new functional battery composed of the subscales rated in the CIM study as likely to be most adaptable across multiple countries and cultural contexts with minimal alteration.

Challenges in Drug Trials for Cognitive Impairment in Schizophrenia

M. Egan

The first wave of drug trials targeting CIAS have concluded and the results are largely negative. Reasons for failure may include issues related to dose, duration of treatment, use of concomitant medication, lack of target engagement, and pursing the wrong target. Several other possibilities are worth considering.

First, design and conduct of the clinical trials could play a role. Current trials are unable to distinguish failed trials (trial insensitive to meaningful change) from negative trials (drug doesn’t work). Demonstration of a practice effect could ameliorate this to some degree. Cognitive remediation (CR) has been suggested but including this substantially increases costs and patient burden Furthermore, CR has not been necessary to demonstrate efficacy in other diseases (e.g. cholinesterase inhibitors in AD and stimulants in ADHD).

Second, the biology of cognition and schizophrenia could require other strategies. Many drug targets may impact only 1-2 specific cognitive domains. If drugs improve, for example, only working memory, the development path would require a specific, related functional measure. This suggests that additional work relating specific domains to function might be needed. A piecemeal approach to cognition may not be ideal but it could be a more plausible alternative from a biological perspective.

Third, given the apparent heterogeneity in schizophrenia, study designs that address this should be considered. Randomized withdrawal, where only clear responders are randomized to active drug vs placebo, may have the potential to preselect a responsive subgroup.

Finally, once proof of concept is achieved, multinational trials would be needed. While much has been done to facilitate this, concerns remain over lack of norms for many languages and uncertainty on the cultural adaptability of functional capacity measures.
Given the many challenges to drug development, continued public/private collaboration may be necessary to demonstrate the viability of clinical trials in CIAS.

Assessing Cognition in Serious Mental Illness: NIMH Perspectives

B. Cuthbert

The purpose of this talk will be to review past and future NIMH perspectives regarding the assessment of cognition in serious mental illness. The MATRICS project is seen as an invaluable first step not only for its substantive role in providing endpoints in clinical trials, but also for its role as a vehicle to address the issues that arise in such an innovative project — such as establishing co-primary measures, forging procedures to deal with language and cultural translation, and integrating various aspects of cognition. The CNTRICS process represents the next generation of assessments, and illustrates the process required to translate basic paradigms in cognitive neuroscience to practical clinical use. For both MATRICS and CNTRICS, a critical need will be demonstrate not only satisfactory psychometric properties, but also sensitivity to the effects of relevant compounds. Over the next several years, NIMH anticipates broadening the scope of these assessments beyond syndromal schizophrenia. As exemplified by the new Research Domain Critieria (RDoC) project and the NIMH Advisory Council Intervention Workgroup Report, NIMH will move toward an emphasis on circuit-based mechanisms that may cut across traditional disorder categories. It is hoped that this approach will foster new treatment development by providing targets with greater validity, and contribute to more effective personalized medicine.

Bridging the Gaps Between Animal Models, Human Neuroscience and Schizophrenia Clinical Trials: Rational Enhancement of Signal Detection

J. Sweeney

Cognitive deficits are a major cause of functional disability in schizophrenia. Developing interventions to reduce these deficits face the well-recognized challenges of a limited knowledge of the neurobiology of schizophrenia and of the neurochemical basis of its associated cognitive impairments. They also face more tractable challenges associated with selecting optimal outcome measures for trials at various stages along the drug discovery/registration pathway. Global cognitive impairment assessed with standardized neuropsychological tests (e.g., MATRICS battery) is linked to functional disability and its assessment is readily implemented across sites for Phase III trials. However, this approach has significant limitations for POC studies: 1) it provides intercorrelated measures of global deficit rather than specific measures of cognitive abilities likely to be influenced by a drug targeting a specific neurochemical mechanism; 2) its measures have proven remarkably resistant to change, not only from acute drug effects but even the presence of acute psychosis; 3) it fails to directly measure drug effect on the target organ – the functional brain systems that support specific aspects of cognition targeted by a drug; and 4) it has only modest linkage to preclinical platforms. These limitations may contribute to the high rate of negative trials across a range of targeted mechanisms.

A new strategy may be needed for POC studies. Rather than use “off-the-shelf” neuropsychological tests alone as outcome measures (be they computerized or otherwise), other types of outcomes should be considered that: 1) have a tight linkage to the neurochemical and functional brain systems specifically targeted by the drug’s mechanism of action, and the specific cognitive operations they subserve (global cognitive improvement is not the place to start); 2) have demonstrated sensitivity to effects of target drug in preclinical models (it is time for translational strategies); 3) have high sensitivity to rapid-onset drug effects (neuropsychological tests may lack sensitivity needed for small sample POC studies); and 4) assess brain as well as cognitive/behavioral outcomes (study the target organ as in other fields of medicine).

To transition to this type of POC strategy, the limited human cognitive neuroscience capabilities in industry typically will require tight industry-academic partnerships. With early involvement in drug discovery, these partnerships can integrate and parallelize preclinical and clinical programs. This strategy can enhance confidence in early go-no go decisions, provide useful ancillary measures for later phase trials, and potentially identify patients most likely to benefit from a study drug. This may require a scaling back of hopes for the quick discovery of a blockbuster drug, but an incremental rational drug discovery process may in the long run provide the greatest hope for developing treatments for the debilitating neurocognitive deficits associated with psychotic disorders.

Cognitive Remediation as a Platform for Clinical Trials: Issues for Trial Design

A. Reichenberg

NEWMEDS – Novel Methods leading to New Medications in Depression and Schizophrenia (http://www.newmeds-europe.com/) initiative is an academic-industry partnership which consists of 19 participating institutions based in nine different EU member states as well as in Iceland, Switzerland and Israel. Nearly all major biopharmaceutical companies including AstraZeneca, Eli Lilly, Janssen Pharmaceutica, Lundbeck A/S, Novartis, Orion, Pfizer, Roche and Servier are participating in the project. Academic institutions involved are: King’s College London, Karolinska Institutet (Stockholm), The University of Cambridge, Central Institute of Mental Health (Mannheim), CSIC (IIBB, Barcelona), the University of Manchester and the Bar Ilan University (Israel). Additionally, two pharmaceutical small and medium-sized enterprises, deCODE (Reykjavik) and Psynova (Cambridge) take part.

This talk will present an overview of NEWMEWDS and its scientific rational. We will discuss how the MATRICS initiative and the MCCB have shaped projects in NEWMEDS, and present work focusing on: (A) the development of cognitive measures ideal for international trials and (B) the design of trials for testing cognitive enhancing drugs in schizophrenia.

Cognitive Assessment for Schizophrenia Clinical Trials in the Post-MATRICS Era

R. Bilder

The MATRICS project achieved its goals of providing consensus about cognitive domains impaired in schizophrenia, and a test battery (MCCB) to measure these. There remain critical challenges and opportunities to develop assessment methods that will ultimately yield improved measurement of relevant functions and inform rational treatment development. It should be recognized that cognitive domains defined by consensus, while offering an important way forward, remain under-specified with respect to: (1) pathophysiological hypothesis about schizophrenia; (2) putative mechanisms of treatments; and (3) specific relations to functional outcomes. Novel strategies for construct definition will be needed that go beyond dimension reduction within the cognitive variable space. On one hand we need to incorporate external biological validation. On the other hand we need to better identify the mediating role of cognitive functions as these impact other instrumental functions and quality of life. Investment in more elaborate Phase II programs is prudent to help surface validity issues that might enhance the odds of success in Phase III. These strategies include instrumenting POC studies to maximize translation of preclinical findings, and deploying “MATRICS-plus” designs in later Phase II to assure domain-specific signal is not missed. The “-plus” measures would ideally demonstrate convergent validity with respect to functional constructs identified as important in the MATRICS process, help refine these constructs psychometrically, and provide additional validation with respect to biological processes affected by schizophrenia or treatment mechanisms putatively underlying cognitive benefits. Instrument development would benefit from open-access content-banks that permit widespread dissemination of tools for basic investigations, and application of methods from modern psychometric theory to advance novel construct definition while maintaining back-compatibility with established measures. Links to real world outcomes can be studied further by leveraging this same infrastructure in broader community networks. Together these strategies can help provide a path for treatment development that puts cognitive assessment in appropriate context considering both brain biology and our shared public health mission.

Building Beyond a Cognitive Battery

S. Koslow

BRAINnet Foundation was established to facilitate the cure of human brain disease. It is a 501(c) 3 US based Tax Exempt research Foundation. The BRAINnet Foundations operating principals are: (1) Free and open electronic sharing of all data; (2) Open research network of collaborating members; (3) Continued expansion of the global database of human brain function in health and disease across the life span with its global membership; (4) Using the same proven standardized protocols and measurements techniques in all studies allowing for data pooling across disorders, sites and studies; (5) Integrates data across the genome, Brainmarkers*, and clinical measures; (6) Open sharing of data without data contribution; (7) Self organizing, cooperative collaboration and openness within the global scientific community to analyze and publish data; (7) Successful competing for grant support with collaborators to carry our large clinical studies of human brain disorders. Currently it has as part of its global consortium of 243 researchers from 13 countries. The database contains clinical, cognitive, brain and gene data acquired on the same subjects with same standardized methods and protocols, with datasets from healthy and multiple clinical brain disorders. Currently 252 peer-reviewed papers reporting on the data have been published. This presentation will provide additional information on the establishment of the Foundation, details of its operation and standardized methods and protocols as well as participation and membership opportunities.

Exemplar Applications and Results From BRAINnet: What Are The Implications for Understanding, Modeling, Diagnosing and Treating Brain Disorders?

S. Silverstein

Following Steve Koslow’s presentation on the development, goals, products and growth of BRAINnet, this talk will review examples of integrative research that has emerged from the initiative. The BRAINnet project has now produced over 250 papers, including studies of healthy people aged 6-100, normal aging, schizophrenia, depression, attention deficit-hyperactivity disorder (ADHD), PTSD, eating disorders, mild cognitive impairment (MCI), and Alzheimer’s Disease. For example, in schizophrenia, relationships between cognition, synchrony, symptoms, grey matter loss, and level of functioning, including in first episode patients, have helped clarify how the illness progresses over time, as well as the links between phenomena at multiple levels of analysis. In depression, data have demonstrated an interaction between BDNF allele type and early life stress that predicts loss of grey matter, psychophysiological reactivity, symptoms, and cognitive deficits. In ADHD, aspects of cognitive and emotion processing deficits have been linked to specific psychophysiological abnormalities. In anorexia nervosa, cognitive and electrophysiological markers have demonstrated differential responsiveness to treatment. Finally, relationships between degree of cognitive decline and specific electrophysiogical indices have differentiated Alzheimer’s disease from MCI and normal aging. These and other data demonstrate the power of an integrative approach grounded in a large and growing database. Specifically, integration of genetic, psychophysiological, cognitive, life history, and personality data can increase our ability to model the etiology and development of psychopathology. Also, the large normative database, and common testing platform for studies of multiple disorders can assist in identifying common vs. unique mechanisms and pathways across disorders. Consistent with the NIMH Research Domain Criteria (RDoC) initiative, this can lead to more effective ways of conceptualizing, classifying, diagnosing, and treating mental illness. Importantly, treatment effects can be examined at multiple levels, in an integrated fashion, with clear reference to age- and gender-matched population norms. Finally, the large (N>8000) and growing database can serve as the basis for a personalized approach to treatment and prognosis.

Session 3: DSM5: Implications for Clincial Trials

Implications of DSM-5 Mood Disorders for Future Treatment Efficacy Trials

J. Fawcett

Jan Fawcett, M.D. is the chair of the Mood Disorders Work Group. He will review key changes in the diagnostic criteria in mood disorders and their rationale. He will address the inclusion of ratings of severity of suicidality and anxiety dimensions across all mood disorders. He will discuss the ways in which these changes might affect inclusion and exclusion criteria for future clinical trials. He will also address how results from current studies may be applied in the DSM-5 context.

Schizophrenia and Other Psychotic Disorders

J. Bustillo

Systematic application of potential validators (eg: neuroimaging, genetics, postmortem) has fallen short of a substantial understanding of the Schizophrenia syndrome as defined by DSM-IV. With the development of DSM-V, there is an opportunity to update or substantially modify the nosology of Schizophrenia and other Psychotic disorders, to better accommodate clinical and research needs. Joining Schizophrenia and Bipolar disorder into a general psychotic syndrome was considered based commonalities in some neuroimaging and genetic findings. Incorporating Schizotypal Personality disorder as part of a Schizophrenia continuum is supported by a larger body of research, but will depend on future determinations regarding the structure of the Personality disorders chapter. The following issues have been identified for possible changes:

1- Eliminate the Schizophrenia subtypes. These are rarely stable in patients, have minimal therapeutic implications and research has not validated them. Symptom dimensions within psychosis (ie: reality distortion, disorganization, negative, mood and cognitive) have been replicated in many datasets. They offer a more structured venue for clinicians to routinely assess important symptoms to target with more specific interventions. The perceived utility and reliability of these dimensions will be examined in the DSM-V field trials.

2- De-emphasize the link between Catatonia and Schizophrenia. Will review the data that supports the creation of a new category for the Catatonic syndrome versus a more conservative approach of adding a qualifier to the main disorders (Schizophrenia, Mood disorder and General Medical Condition).

3- Schizoaffective disorder. There is a clinical need to accurately capture the prominent mood symptoms that occur in schizophrenia for optimal therapeutics. Also, the proper delineation of the border between mood and psychotic disorders may accelerate the discovery of biomarkers. The DSM-IV Schizoaffective category is unreliable but widely used in clinical settings and researchers are generally averse to study it. The DSM-V field trials will examine the reliability of: a) further operationalizing Criterion C from “…mood episodes are present for a substantial portion of the total duration of the active and residual periods of the illness”, to “…for a majority of the total duration…”; and b) the elimination of Criterion B, which requires a temporal dissociation between the presence of mood and psychotic symptoms (this Criterion is a source of discrepancy with ICD-10).

4- Psychosis Risk Syndrome. The functional outcome in Schizophrenia remains poor even in compliant, non-substance abusing patients, so the need for very early identification and treatment is great. Several diagnostic schemes for defining mostly adolescents with emergent, mild to moderate delusions, hallucinations and/or disorganized speech have been tested in the last decade. The DSM-V field trial will examine the reliability of a set of criteria based on the NAPLS study, to differentiate such health seeking adolescents from those with schizophrenia, bipolar and depressive disorders. Reliable definition of this syndrome may facilitate the development of fundamentally new therapeutic strategies with the hope of altering the course early in the illness.

Regulatory Perspectives from FDA and EMEA

M. Mathis

Mitchell Mathis, M.D. is the Deputy Director of the Division of Psychiatry Products in the FDA. He will comment on the relationship of current and future diagnostic categories on both overall drug development programs and labeling. Karl Broich, M.D. Deputy Head of Federal Institute for Drugs and Medical Devices will provide perspectives from the European EMEA vantage point.

General Discussion

R. Hirschfeld

Robert Hirschfeld, M.D., co-chair of the session has extensive research experience in depression research and in the relationship of diagnostic criteria to clinical assessment and treatment. He will initiate the discussion with his perspective on implication for clinical trials and treatment and facilitate comments from the audience

Conflict of Interest Policy

Thursday, July 29th, 2010

Article I Purpose

The purpose of the present conflict of interest policy is to protect the integrity and reputation of the International Society for CNS Clinical Trials and Methodology, Inc. (hereafter “the Organization”) and prevent the occurrence of any action taken which may result in or create the appearance of:

Giving preferential treatment to a person or an organization (including by over-representation from a single company on appointed committees).
Using an office in the ISCTM for personal gain.
Acting with less than complete impartiality or independence.
Adversely affecting the confidence of the membership, regulatory agencies, patients, patient advocacy organizations, or the general public in the Organization.

When the Organization is contemplating entering a transaction, an arrangement, a presentation, or a poster presentation that might benefit the private interest of an officer or committee member of the Organization, there is potential for conflict of interest. Conflict of interest might also result from a transaction expected to produce a possible excess benefit to an individual or their affiliated organization.

This policy is intended to supplement but not replace any applicable law or regulation governing conflict of interests relevant to nonprofit and charitable organizations.

Article II Definitions

Interested Person: Any director, principal officer, committee member, or working group chair with governing board delegated powers, who has a direct or indirect financial interest, as defined below, is an interested person. Any member at large of the Organization or a non-member expert when engaged in ISCTM-specific events, projects, or programs is an interested person.
Financial Interest: A person has a financial interest if the person has directly or indirectly, through business, investment, or family:
1. An ownership or investment interest in any entity with which the Organization has a transaction or arrangement,
2. A compensation arrangement with the Organization or with any entity or individual with which the Organization has a transaction or arrangement, or
3. A potential ownership or investment interest in, or compensation arrangement with, any entity or individual with which the Organization is negotiating a transaction or agreement
4. Is an employee of a sustaining corporate member company
5. A potential ownership or investment interest in, or compensation arrangement with, any entity or individual with which the Organization has scientific interactions where the individual with the claim is in a position to have potential influence on the exchange in a capacity in which they act on behalf of the Society (examples of the potential impact on interactions include review/approval of scientific content for an ISCTM function, determination of participants in a scientific process, and decisions by a Society committee or working group, etc.)

Compensation includes direct and indirect remuneration and gifts or favors that have a value exceeding the threshold defined as “substantial value” by the PhRMA Code (or relevant comparable Association National Code as most applicable). Compensation may be monetary or non-monetary.

A financial interest is not necessarily a conflict of interest. Under Article III, Section 2. a person who has a financial interest may have a conflict of interest only if the appropriate governing board or committee decides that a conflict of interest exists.

Article III Procedures

When a concern about possible conflicts of interest is referred to the executive committee, the executive committee shall determine if there is reasonable cause to believe there has been a serious violation of the conflict of interest. In such cases, the executive committee or a committee appointed by the executive committee will act as the governing board charged with reviewing the alleged conflict of interest.
Duty to Disclose: In connection with any actual or possible conflict of interest, an interested person must disclose the existence of the financial interest and be allowed to disclose all material facts to the directors and members of committees with governing board delegated powers considering the proposed transaction or arrangement. Disclosure statements for members of the Executive, Scientific, Finance, and Poster Committees and Working Group Chairs shall be provided by the Secretariat to the appropriate committee chair.
Determining Whether a Conflict of Interest Exists: After disclosing the financial interest and all material facts, and after any discussion with the interested person, they shall leave the governing board meeting when the determination of a conflict of interest is being discussed and voted upon. The remaining governing board members shall decide if a conflict of interest exists.
Procedures for Addressing the Conflict of Interest:
1. An interested person may present the perceived conflict at the governing board meeting. After the presentation, they shall leave the meeting during the discussion of, and the vote on, the transaction or arrangement involving the possible conflict of interest.
2. The chairperson of the governing board shall, if appropriate, appoint a disinterested person or committee to investigate alternatives to the proposed transaction or arrangement.
3. After exercising due diligence, the governing board or committee shall determine whether the Organization can obtain with reasonable efforts a more advantageous transaction or arrangement from a person or entity that would not give rise to a conflict of interest.
4. If a more advantageous transaction or arrangement is not reasonably possible under the circumstances not producing a conflict of interest, the governing board or committee shall determine by a majority vote of the non-conflicted directors whether the transaction or arrangement is in the Organization’s best interest, for its benefit, and whether it is fair and reasonable. In conformity with the above determination, it shall decide whether to enter into the transaction or arrangement.
5. Conflict of interest or potential conflict of interest may, following disclosure, also be addressed by recusal from a potentially conflicted process or decision.
6. If the governing board has reasonable cause to believe a member has failed to disclose actual or possible conflicts of interest: In that case, it shall inform the member of the basis for such belief and allow the member to explain the alleged failure to disclose.
7. When the governing board has reasonable cause to believe there has been a violation of the conflict of interest: In that case, it shall inform the member of the basis for such belief and allow the member to explain the alleged infringement. Violations may include any action which might result in or create the appearance of:
  1. giving preferential treatment to any organization or person
  2. using one’s office or position for personal gain
  3. adversely affecting the confidence of the Organization’s membership, regulatory agencies, patients, patient advocacy organizations, or the public in the Organization
8. If, after hearing the member’s response and after making further investigation as warranted by the circumstances, the governing board determines the member has failed to disclose a material actual or possible conflict of interest or has violated the conflict of interest policy, it shall take appropriate disciplinary and corrective action, up to or including termination of membership and notification of other concerned parties. Termination of membership will exclude membership for a period not less than 2 years.

Article IV Records of Proceedings

The minutes of the governing board meeting and meetings of all committees with board delegated powers shall contain:

The names of the persons who disclosed or otherwise were found to have a financial interest in connection with any actual or possible conflict of interest, the nature of the financial interest, any action taken to determine whether a conflict of interest was present, and the governing board’s decision as to whether a conflict of interest existed.
The names of the persons present for discussions and votes relating to the transaction or arrangement, the content of the meeting, including any alternatives to the proposed transaction or arrangement, and a record of any votes taken in connection with the proceedings.

Article V Compensation

A voting member of any committee who receives compensation, directly or indirectly, from the Organization for services is precluded from voting on matters related to that member’s compensation.
A voting member of any committee whose jurisdiction includes compensation matters and who receives compensation, directly or indirectly, from the Organization for services is precluded from voting on issues about that member’s compensation.

Article VI Annual Statements

Each director, principal officer, and member of a committee with governing board delegated powers shall annually sign a statement that affirms such person:

Has received a copy of the conflicts of interest policy,
Has read and understands the policy,
Has agreed to comply with the policy, and
Understands the Organization is charitable. To maintain its U.S. federal tax exemption, it must engage primarily in activities that accomplish one or more of its tax-exempt purposes.

Article VII Periodic Reviews

To ensure the Organization operates consistently with charitable purposes and does not engage in activities that could jeopardize its tax-exempt status, periodic reviews shall be conducted. The systematic reviews shall, at a minimum, include the following subjects:

Whether ISCTM’s compensation arrangements and benefits are reasonable, based on competent survey information, and the result of arm’s length bargaining.
Whether partnerships, joint ventures, and arrangements with management organizations conform to ISCTM’s written policies, are properly recorded, reflect reasonable investment or payments for goods and services, further charitable purposes, and do not result in inurement, impermissible private benefit, or an excess benefit transaction.

Article VIII Use of Outside Experts

When conducting the periodic reviews as provided for in Article Vll, the Organization may, but need not, use outside advisors. If outside experts are used, their use shall not relieve the governing board of its responsibility for ensuring periodic reviews are conducted.

Acceptance and Disclosure Form (to be completed by Executive, Scientific, Finance and Poster Committee members and Working Group Chairs)

Revisions Approved 17 January 2023

Whistleblower Policy

Monday, July 26th, 2010

This Whistleblower Policy of the International Society for CNS Clinical Trials and Methodology, Inc. (“ISCTM”): (1) encourages staff and volunteers to come forward with credible information on illegal practices or serious violations of adopted policies of ISCTM; (2) specifies that ISCTM will protect the person from retaliation; and (3) identifies where such information can be reported.

1. Encouragement of Reporting. ISCTM encourages complaints, reports or inquiries about illegal practices or serious violations of ISCTM’s policies, including illegal or improper conduct by ISCTM itself, by its leadership, or by others on its behalf. Appropriate subjects to raise under this policy would include ethical violations, financial improprieties, accounting or audit matters, or other similar illegal or improper practices or policies. Matters concerning alleged discrimination or harassment should be raised via ISCTM’s human resources channels or existing procedures for administering complaints, unless those channels are themselves implicated in the wrongdoing. This policy is not intended to provide a means of appeal from outcomes in those other mechanisms.

2. Protection from retaliation. ISCTM prohibits retaliation by or on behalf of ISCTM against staff or volunteers for making good faith complaints, reports or inquiries under this policy or for participating in a review or investigation under this policy. This protection extends to those whose allegations are made in good faith but prove to be mistaken. ISCTM reserves the right to discipline persons who make bad faith, knowingly false, or vexatious complaints, reports or inquiries or who otherwise abuse this policy.

3. Where to report. Complaints, reports or inquiries may be made under this policy on a confidential or anonymous basis. They should describe in detail the specific facts demonstrating the bases for the complaints, reports or inquiries. They should be directed to the Executive Director or the President. If both of these persons are implicated in the complaint, report or inquiry, it should be directed to ISCTM’s General Counsel. ISCTM will conduct a prompt, discreet, and objective review or investigation consistent with existing procedures for administering complaints as applicable. Staff or volunteers must recognize that ISCTM may be unable to fully evaluate a vague or anonymous general complaint, report or inquiry.

4. General Counsel:
Elliott Adler
eadler@ebalaw.com
(240) 497-1400
7316 Wisconsin Avenue Suite 420
Bethesda, MD 20814

2010 6th Annual Scientific Meeting – Translational and Cultural Adaptation of Key Outcome Measures in International CNS Trials – Session Summary

Friday, May 28th, 2010

International Society for CNS Clinical Trials and Methodology Annual Meeting
Washington, DC
22-24 February 2010

Chairs: Amir Kalali, MD; Richard Keefe, PhD
Speakers: Amir Kalali, MD; David Daniel, MD; Richard Keefe, PhD; Paul Harvey, PhD; Karl Broich, MD; Ravi Anand, MD

The Current Reality of Outcome Measures in International Clinical Trials: Should We Be Doing Things Differently?

Amir Kalali

Dr. Kalali framed the questions to be addressed by the session. What is our practice now in the use of outcome measures in international trials and what should we be doing? Dr. Kalali noted that there is variability in the quality and a heterogeneity in the focus of symptom outcome measures used in clinical trials. Some scales, such as the HAM-D, were not originally designed to assess outpatients in clinical trials and contain items that are not very sensitive to change. Patient-reported outcome measures (PROs) are a different kind of measure than clinician-rated scales, and may require different approaches to translation and adaptation. There are guidelines for translation and validation of PROs available (the ISPOR Principles of Good Practice) but there are no equivalent guidelines for clinician-rated scales.

Dr. Kalali defined some commonly used terms surrounding the adaptation of scales for international use. If translation is thought of as conceptually accurate conversion from one language to another, linguistic validation is the validation of that conceptual accuracy by a pilot study. Cultural adaptation adds to linguistic validation item customization and analysis of the psychometric properties in the new culture. Standardization is accomplished when there is complete psychometric validation and establishment of standard scores in the new language and culture. Translation is often the only step taken as there are practical issues of budgetary and time constraints. At present there is a lack of consensus on when translation is necessary variability among sponsors in their approaches. It would be useful if 1) the field developed consensus on these issues for clinician-reported outcome measures, 2) there could be official translated versions available to all, and 3) more methodological research were conducted addressing these issues.

Challenges and Best Practices in Training and Monitoring Measurement of Psychopathology in Linguistically and Culturally Diverse Settings

David G. Daniel

Dr. Daniel gave an example of the challenges associated with the use of psychiatric rating scales by presenting data showing the different patterns of YMRS ratings among US, European, and Indian raters. The key question he posed was: What are the most appropriate endpoints for training, certification, and measures of inter-rater reliability? This question is comprised of several other questions. Should rater training be unified across all cultures in a study or should it emphasize “synchronization” within a cultural region? Should an effort be made to synchronize each individual item on rating scale or to focus on the total score? Should efforts be focused on standardizing cross-sectional measurement or on standardizing assessment of change? Should the emphasis be on agreement with a “gold standard,” whether centrally or regionally determined, or on concordance among raters, whether global or regional?

While these questions do not easily lend themselves to comprehensive answers, Dr. Daniels made some observations that could guide planning of cross-cultural rater training and measurement. The measurements that may be the most difficult to standardize involve sexuality, aggression, and attitudes toward authority. Items based solely on interviewer observations are especially hard to standardize. Forced shifts from entrenched cultural practices tend to regress back to habitual practices over time. The manner in which feedback is given, in particular whether it leads to loss of face, affects its acceptability. Native language experts synchronized to global practices may be the best approach to giving feedback to raters. Cultural neutral measures of concordance, such as agreement with the mode, may be useful in international trials. Total scores may be more relevant and less sensitive to cultural influences than individual items.

Translating and Implementing Measures of Neurocognition in Eastern Europe and Asia

Richard S. E. Keefe

Dr. Keefe began by reviewing the components of the MATRICS battery and of the BACS and BAC-A batteries. The guidelines for adapting psychological tests for different languages and cultures have been established and refined for several decades. The guidelines delineate four aspects of test equivalence: construct equivalence, functional equivalence, translational equivalence, and metric equivalence. Back translation alone is not enough to establish translational equivalence since it may not account for meaning in the new culture. The question “where does a bird with webbed feet usually live?” provides an example. In Swedish “webbed” is translated as “swimming,” making the question easier to answer. To the extent that a test is not culturally sensitive or linguistically equivalent, cognitive outcome measures will increasingly depend upon features that are unrelated to the construct intended, and thus will be increasingly less likely to be sensitive to real treatment change. Furthermore, in the US population is used to testing, and in American culture speed is valued. In other cultures there is more of an emphasis on being correct. Speed may not be valued and may even be considered rude. If a test is dependent on understanding English or American culture, a drug relying on that test as an outcome measure will not demonstrate an effect. Dr. Keefe used the example of MATRICS testing in Singapore, where the t-scores vary wildly across different ethnic groups.

Social cognition and emotional recognition tests are particularly sensitive to cultural changes. Cultural issues with other key tests include problems of translation for verbal memory tests; issues with letter-number sequencing in Mandarin, for example, which does not sequentially order letters; different emotional valences associated with the same word in different cultures; and differences in the level of comfort with computers.

There are good reasons to collect community normative data for translated versions of cognitive batteries. Differences in the difficulty level between English and translated tests and cultural variations in the meaning of terms will be detected and adjusted for. Scores are put on a common metric across languages, based on the mean and standard deviation of stratified community samples. This enables comparison across samples using different languages.

Detailed attention to the issues surrounding the development and implementation of culturally valid neurocognitive tests is likely to enhance any real signal in a clinical trial with cognitive endpoints.

Cultural Considerations of Functional Outcomes in Chinese and Other Cultures

Philip D. Harvey

For years behaviorally oriented therapists have appreciated the “competence-performance distinction,” that is, the distinction between the “can I do it?” and “do I do it?” This is a critical decision for attempting to enhance outcomes by targeting disability directly rather than targeting its determinants. For practical reasons, real-world outcomes, such as marriage, employment, and residential status, are unrealistic targets for treatment studies. Thus measures of competence may be most the important outcome measures. Whether competence can be measured in a valid way and whether it can be measured across cultures are open questions.

Dr. Harvey presented data that showed that no correlation between cognitive ability and work or marital status. A large-scale study in patients with schizophrenia found that it was possible to predict residential status with good sensitivity and specificity with the UPSA. The evidence from several studies is that cognitive and functional capacity are closely correlated and that the UPSA correlates well with cognitive ability.

There have been two studies to date measuring performance-based disability across cultures. The first measured cognition and disability across cultures, in rural Sweden and the Bronx. Patients in Sweden and more likely to be financially independent and living independently, but this seemed to be due to the greater government involvement in caring for these patients. The second was a study in China using the UPSA-B and comparing healthy subjects to patients with unipolar depression, bipolar disorder, and schizophrenia. At the lowest level of education there was not a significant difference among the groups. However when subjects with less than 6 years of education were excluded, the performance of the healthy subjects was clearly better than that of the patients.

Cultural Aspects of Outcome Measures – European and US Regulatory Viewpoints

Tom Laughren

Dr. Laughren began by noting that this whole area has not received a lot of attention from the Division, especially questions surrounding instruments that measure function. Lorie Burke and the SEALD (Study Endpoints & Label Development) group at the FDA have recommended to the Division that for multinational trials FDA ask for information on item validity and probably on language subsets. Dr. Laughren said that a guidance on these issues will be coming. A lot of work already has been done, such as the ISPOR standards and work by the International Society on Quality of Life and the International Test Commission. The FDA’s guidance on patient-reported outcomes begins to address these issues as well and many of the same basic principles apply. Translation and cultural adaptation issues will be discussed at end-of-phase two meetings and pre-NDA meetings. Two domains in particular, sexual function and suicidality, stand out as challenges for assessment across cultures. Dr. Laughren noted in conclusion that the integrity and validity of multinational clinical trials depends on the validity of the measures.

Karl Broich

Dr. Broich said that Dr. Laughren had nicely summarized the regulatory perspective and that European regulators had similar views. (see video) There is an EMA document on clinical data collected from outside the EU, but it is written more for use by EMA assessors. EMA have seen differences in outcome in different countries and regions. One schizophrenia study found significant differences for the drug over placebo in Russia but not in the EU or US. Three drugs are approved for fibromyalgia in the US but not in the EU because large effects were observed in the US population but not in the EU population.

Discussion

Ravi Anand

Dr. Anand began by noting that the use of diagnostic psychiatric, cognitive, or functional ability instruments outside the settings they were developed for is fraught with significant issues. Abnormal scores may be attributed to pathology rather than to factors such as educational level, literacy, and cultural differences in cognitive and perceptual information processing, possibly leading to errors of overdiagnosis, or, for similar reasons, to underdiagnosis. The issue is complicated by different cognitive and perceptual development in populations with different cultural and physical environments. Members of different cultures are exposed to different perceptual and cognitive problems in daily life. Thus test materials not validated for a cultural group carry different psychometric properties and normative cut-offs than for the original group.

The ‘gold standard’ solution is conceptualize, develop, test, and validate instruments in the actual population to be studied. The ‘silver standard’ would be to translate with cultural adaptation, perform reconciliation testing checking for linguistic distortion, and perform a validation study to support the results. The ‘iron standard’ is to translate, back translate, and reconcile. Diagnostic instruments require far greater standardization than outcome instruments. Diagnosis should not be made with translated instruments.

Summary: ISCTM 2010 National Mental Health Research-to-Policy Forum: Industry/Academic Relationships: Continuing Collaboration in an Era of Evolving Standards

Wednesday, May 12th, 2010

Principled Research in the Face of Conflicts of Interest

Chairmen: R Keefe, Duke University Medical Center; N Schooler, State University of New York

Speaker: R. McKinney, MD, Duke University

Summary

Main themes that were emphasized during Dr. McKinney’s presentation included the following:

• Conflicts of interest (COIs) are ubiquitous – e.g. car mechanics, dentists, neurosurgeons.
• Because of this, we have a natural sense of COIs which can be used to assess the appropriateness of COIs in academic/industry settings.
• Questions to ask ourselves include: Do they impact primary professional obligations?
• It is easiest to measure financial COIs, and we tend to focus on those.
• We can recognize COIs, but can’t know how much it affects behavior. Research shows that even small gifts may have effects.

Q&A included the following:

1. What about conflict for the institution as well as the investigator? “Institutional COI” – Duke has a committee to review. Reference was made to the Nancy Oliveri case at the University of Toronto. She received a Hematological drug and experienced side effects, spoke up about it, but UT (who was being paid by manufacturer) did not support her.
2. Have you asked lay public; done market research? For example, lay public sees cutoffs of $10k/25k as substantial amounts. Yes; community said $25k is “too much”
3. Lower/minimal limits make functioning impossible. Can we answer questions from a pharmaceutical employee at a poster session? Grassley has suggested zero.
4. How much COI should you have? Ex: FDA advisory committee – there may be little knowledge among members with no COI. Preference is to minimize COI, esp. when there are dichotomous decisions (e.g., approve a drug or not, as with FDA advisory committees).
5. How do we manage the perception of COI, and have a positive impact? Stress the importance/value of interaction between academia and industry – start with the assumption that there is value. Advocate for more academic/industry interaction, but well-policed.
6. ISCTM receives a substantial proportion of its funding from industry sources. Do you have any advice for us on how to manage that perception in the current environment? 1) transparency – we believe in it, this is the mission. 2) advocate for patients first.
7. Academia/Industry dichotomy may be false. COIs exist for both. “if you don’t have conflict, there shouldn’t be any interest”

Session Summary: ISCTM 2010 National Mental Health Research-to-Policy Forum: Comparative Effectiveness Trials in CNS Disorders: Rationale, Elements and Challenges

Wednesday, May 12th, 2010

Chairs: Nina Schooler, Ph.D., State University of New York; Charles Bowden, M.D., University of Texas Health Science Center at San Antonio

Speakers: T Ten Have PhD, MPH, University of Pennsylvania SOM; B Heinssen PhD, National Institute of Mental Health; N Schooler PhD, State University of New York; L Dixon MD, MPH, University of Maryland School of Medicine

Discussants: D Meltzer MD, PhD, University of Chicago; M Rawlins MD, National Institute for Health and Clinical Excellence (NICE)

Summary

Comparative effectiveness studies generally try to answer the question “How do different treatments compare as utilized in clinical practice?” They use a variety of strategies to compare alternative interventions for a diverse group of stakeholders. Speakers in the session will define the settings and key methodological elements for comparative effectiveness research. The example of large-scale comparative effectiveness trials now being planned, the NIMH RAISE initiative, will be discussed. The session will include consideration of analytical methodologies which may be particularly useful in synthesizing and conveying results from such studies in ways that yield more effective new treatments and adequately manage multidimensional outcome variables.

Key Issues in CER of Design and Analysis

T. Ten Have, PhD, MPH

Goals and Strategies of the NIMH Recovery After an Initial Schizophrenia Episode (RAISE) Initiative

B. Heinssen, PhD

RAISE will test whether early, aggressive and pre-emptive intervention can slow or halt clinical and functional deterioration in schizophrenia. This has substantial potential cost savings for society (2002 cost of schizophrenia in US: $62B).

The NIMH RAISE Initiative. Two Parallel Approaches to a CER Question: Case Study I

N. Schooler, PhD

Key concepts: 1) study populations will be chosen to be representative of clinical practice, 2) interventions will focus on the individual rather than the average patient, 3) we will compare two or more interventions directly. N=400, 2 years of treatment, site-level randomization to either community care or multi-dimentional psychopharmacologic and psychosocial treatment intervention.

The NIMH RAISE Initiative. Two Parallel Approaches to a CER Question: Case Study II

H. Goldman

One key difference between Case Studies I & II is that case II will be run in NY & MD states, to provide public funding for treatments. N=370, 2 years of treatment. Individual-level randomization will be to a “Connection Team” (recovery, skills training, and employment/education specialists, as well as psychopharmacologist) or “Connection Partnership” (recovery-oriented care coordinator). Assessments occur every 3 months.

Academic Discussant

D. Meltzer, MD, PhD

1. Emphasis on Prevention is important

Session Summary: ISCTM 2010 National Mental Health Research-to-Policy Forum: The Role of Comparative Effectiveness Research in Future Mental Health Policy Decision Making

Wednesday, May 12th, 2010

Chairmen: Reuven Ferziger MD, J&J North American Pharmaceuticals; Ronald Manderscheid PhD, SRA International; D Steinwachs PhD, Johns Hopkins University; Benjamin Druss MD, MPH, Emory University

Speakers: Bryan Luce PhD, MBA, United Biosource Corporation; Michael Rawlins MD, National Institute for Health and Clinical Excellence (NICE); Richard Frank MD, Harvard Medical School

Discussants: Jean Slutsky PA, MSPH, Agency for Health Care Research and Quality; M Schoenbaum PhD, National Institute of Mental Health; David Shern PhD, Mental Health America; M Rawlins MD, National Institute for Health and Clinical Excellence (NICE); K Broich MD, Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte); Joseph Parks MD, Missouri Department of Mental Health; D Jarvis CPA, MCPP Healthcare Consulting, Inc.; S Leff PhD, University of Pennsylvania

Summary

This program gathered experts in CNS trial methodology and policy-makers from the US and Europe to focus on policy implications of Comparative Effectiveness Research (CER) for the treatment of psychiatric diseases, and development of scientific methodologies needed to conduct and utilize CER studies of psychiatric treatments for diseases such as schizophrenia, bipolar disorder, autism and depression, which are among the most costly problems in health care.

CER 2010: Overview and Critical Review of the Current Science and Politics of Comparative Effectiveness
B Luce, PhD, MBA
This comprised a general overview, including definitions of CER, and an historical overview.
Federal efforts failed; private sector efforts, and ExUS efforts, have been more successful (e.g. NICE, the National Institute for Health and Clinical Excellence).

Since 1990, deepening US commitment has taken several forms: the Agency for healthcare quality & research; Medicare evidence development & coverage advisory committee; CER stimulus funds; the health reform legislation includes CER institute & Medicare commission.

The political lesson seems to be: develop evidence at arm’s length from policy; exclude cost-related analyses; sell Medicare’s conditional coverage policy as a positive way to cover new technology; capitalize on the perceived success of NIH comparative trials, and the increased concern about the cost of health care.

Keynote Address: The Role of CER in Future Mental Health Policy Decision Making
Michael Rawlins, MD
Comparative Effectiveness Research is becoming an emphasis of legislation and future policies to establish the value of different therapies, services and systems approaches to care. In this session, leaders in mental health and leaders in the development of CER will address questions like: What are the urgent mental health questions that would be addressed by CER for mental health? How should these questions be prioritized? What are the present capabilities and unmet needs for CER studies in mental health? What research disciplines need to be engaged and how should they collaborate? How can mental health stakeholders and policy makers insure that particular CER approaches to mental illness are methodologically sound? That they account for the diversity of people with mental illness and the range of settings of mental health care? Should CER be used to inform only quality of care or also cost effectiveness? What can we learn from the experience of NICE in the UK? How do leaders in US healthcare policy view the potential of CER to improve care for people with mental illnesses?

2010 6th Annual Scientific Meeting – New Approaches to Assessing the Safety of Marketed Drugs – FDA, Industry, and Academia Perspective – Session Summary

Friday, April 16th, 2010

International Society for CNS Clinical Trials and Methodology Annual Meeting
Washington, DC
22-24 February 2010

New Approaches to Assessing the Safety of Marketed Drugs – FDA, Industry, and Academia Perspective

Chairs: Stephen Marder, MD; Mauricio Tohen, MD
Speakers: Philip Wang MD, DrPH; Bennett Levitan MD, PhD; Judith Racoosin, MD, MPH

Approaches to Safety Assessment: A Pharmacoepidemiological Perspective

Philip Wang MD, DrPH

The first presentation was by Philip Wang who reviewed recent developments in the availability of datasources and methods enabling pharmacoepidemiologists to play an expanded role in post marketing surveilance of medicines. Examples of studies were presented to illustrate how pharmacoepidemiology can help ensure that the use of psychotropic medications is safe, effective, and cost-beneficial.

Psychopharmacoepidemiology arose (as did pharmacoepidemiology) largely following the thalidomide experience and the subsequent changes at the FDA (Kefauver-Harris Act). Pharmacoepidemiological tools include general population surveys, use of data from practice-based networks, government administrative data, and health plan data. New study designs include effectiveness trials and simulations. The scope of pharmacoepidemiology is expanding to include descriptive work, in order to provide a more real-world perspective, as well as analytic approaches to evaluate modifiable determinants of use/outcomes and interventions. An example (Wang, J Clin Psychopharm 2005) was shown in the area of depression treatment, illustrating suboptimal antidepressant use trends not changing over time. An additional example was a review of conventional antipsychotic use in the elderly (Wang NEJM 2005) which identified a risk of short-term mortality that appeared greater than that observed with atypicals. Wang also referred to an evaluation of the impact of co-pay introduction in British Columbia from 2002 to 2003 on elderly antidepressant use, showing a decline in new starts of antidepressants. An additional evaluation assessed a change allowing the first-line use of clozapine and found declines in mortality suggested to be due to a reduction in suicide. Wang also referred to an evaluation of the cost-effectiveness of the use of a genomic responsiveness test for clozapine at an incremental cost of $950 resulting in a QALY value 0.02, incremental C/E ratio $48K/QALY (favorable convention less than $50K/QALY) (Perlis J Clin Psychopharm 2005). In contrast, the use of an SSRI genomic responsiveness test at $500 translated into an incremental QALY of 0.0054, and unfavorable $94K/QALY (Perlis Neuropsychopharm 2009).

Approaches to Safety Assessment: An Industry Perspective

Bennett Levitan, MD, PhD

Pharmaceutical companies are increasingly pressed to demonstrate not simply efficacy and safety of their products, but a superior benefit-risk profile compared to alternative treatments. The increased pressure for these benefit-risk assessments is made all the more difficult by the lack of any standardized or approved approach to performing them. The variety of safety endpoints, with varying timescales and degree of impact on patients, makes quantitative approaches difficult. As a result, efficacy and safety results from clinical studies are often reported separately, and benefit-risk is often only characterized qualitatively. This presentation focused on approaches to prepare for, characterize and communicate benefit-risk assessments quantitatively. Topics included considerations for endpoint definition, number needed to treat/harm, net clinical benefit, maximum acceptable risk and the use of patient preference approaches to weighting the different health states patients may experience in a clinical trial.

Levitan highlighted an increasing pressure on sponsors to demonstrate a favorable benefit-risk for new treatments relative to existing treatments, but noted a tendency to delay benefit-risk assessment until late in development. Selected unweighted methods include Number Needed to Treat/Harm (# patients treated to provide 1 additional favorable or adverse event) – benefit-risk as ratio between NNT and NNH. Introducing confidence intervals complicates understanding and brings out limitations – example provided where safety outcome is not statistically significant (CI overlap with 0). Benefits of NNT/NNH is that it is relatively easy to calculate and interpret, but overstates small risk differences and does not lend itself easily to comparing more than 2 endpoints. Excess Number of Events provides the additional number of patients with an event between treatments – doesn’t have problem of ratio with 0 as with NNT/NNH. Value of visualization of excess events by category but problem is bundling diverse events that may not be equally important. Weighting strategies include Utility Weighting, Preference Weighting, Multicriteria Decision Analysis (MCDA), and Quality-Adjusted Life Years (QALYs). Favors Preference Weighting, which are determined by asking subjects (~n=200) to choose between treatments in a web-based survey and building model with preferences converted to weights that reflect relative importance. Example provided of choosing HRT with steeper slopes on satisfaction score from none to severe quantifies impact. MI risk relative to benefit with HRT demonstrated that good and best benefit are favorable relative to risk. Second example in AD demonstrates delay in progression highly valued relative to risk. Approach can inform regulatory interactions. Display of risks with weighting may help to manage diverse adverse event reports (including events that may be difficult to separate from disease process). Idea suggested to include a box similar to food labeling with NNT/NNH or Excess Number of Events. Calculation of Net Clinical Benefit integrates benefit and risk as difference in excess number of events in one treatment versus a second. Issue of weighting ethics was discussed by Margaret Somerville.

Approaches to Marketed Medical Product Safety Assessment: An FDA Perspective

Judith Racoosin, MD, MPH

The last several years have witnessed a remarkable growth in interest in medical product safety, and especially in post-approval medical product safety. At the US Food and Drug Administration (FDA), many new initiatives have developed in the Center for Drug Evaluation and Research. In addition to evaluating spontaneous adverse event reports and examining specific drug/adverse event association in large, population-based databases, FDA is also interested in using external databases to identify drug safety signals earlier than current methods do. The New Molecular Entity (NME) Pilot Project was completed in March, 2008, and ongoing implementation has begun; it involves a systematic, collaborative, and comprehensive review of available safety data. The FDA Amendments Act of 2007 includes several initiatives aimed at increasing transparency of the FDA in the area of post-marketing safety. All these initiatives were discussed in some detail.

FDA receives reports through “passive” Adverse Event Reporting System (AERS) with in excess of 4 million reports. Sources include patients, healthcare professionals (and sponsors – not on slide). Helpful to have challenge/dechallenge/rechallenge data and co morbidities impact interpretation. Good reports characterized as having event description, details of all treatments, patient details (including medical condition, co-morbidities, family history, other risk factors), diagnostic documentation, and information on dechallenge/rechallenge. Recognizes external events can complicate reporting by inflating perception of effect. Cases often confounded by other possible etiologies than treatment and complete diagnostic information is frequently lacking. AERS limitations include duplicate reporting, “extensive” underreporting, variable report quality, reporting biases, and core problem around uncertainty of actual numerator for events in population versus actual denominator of number exposed (and matching them accurately). AERS strengths include inclusion of all US products, simple reporting system, ability to detect events not seen in clinical trials, good for events with rare background rates (e.g., agran), and case series evaluation for identification of trends, drug indication, population, and other safety concerns. Also can look at large subpopulations (e.g., elderly), use in indications beyond what is labeled, chronic use, and medically complicated patients. ASTOR project is a new FDA initiative on AE reporting.

SENTINEL approach may provide a more “active” system with access to large safety databases. This may permit real-time surveillance, improved access to subpopulations of interest, and better monitoring of common adverse events (that may not be suspected to be related to a treatment). Sentinel initiative was launched in May 2008 with on-going effort to define the “how and what”.

There has been a public-private partnership between FNIH, FDA, and PhRMA called OMOP (Observational Medical Outcomes Partnership) to evaluate value, feasibility, and utility of observational data to evaluate risk/benefit. Select events known to be of concern (e.g., aplastic anemia, acute liver injury, MI, renal failure) with a defined list of commonly prescribed drug classes (ACEi, antidepressants) will be investigated. Also, a “Mini Sentinel” contract has been awareded to Harvard Pilgrim Healthcare to develop a coordinating center for a distributed system.

New Molecular Entity Postmarketing Safety Evaluation Pilot Program is a collaboration between Office of Surveillance and Epidemiology and Office of Drug Evaluation I. It utilizes SAE reports, periodic safety reports, medical literature, data from clinical trials, and data on related compounds (in same pharmacologic class).

The Title IX of 2007 FDA Amendments Act covers enhanced authorities regarding postmarketing safety of drugs. It includes provisions on enforcement, postmarketing studies, benefit-risk assessment, DTC advertising, assurance of pharmaceutical safety, database for authorized generic drugs, and adverse drug reaction reports and postmarket safety.

McMahon provided the following websites as reference:

1.http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/default.htm
2.http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm185252.htm
3.http://www.fda.gov/Safety/FDAsSentinelInitiative/default.htm