Author Archive
Friday, May 25th, 2012
Co-chairs: Stephen Potkin, MD; Henry Riordan, PhD
This session of the Biomarkers Working Group (BWG) will expand upon the 9th Annual Scientific Meeting which summarized the activities of the BWG regarding the qualitative and quantitative evidence for the grading of imaging biomarkers in schizophrenia with a focus on structural MRI. The upcoming session will investigate the linkage between these imaging biomarkers and genetics. Genes and psychiatric disorders such as schizophrenia are clearly related to brain development and function. Brain imaging as a biomarker provides quantitative measurement of brain structure, function and receptor occupancy. Genetic and brain imaging studies in isolation have had limited explanatory power of the causes of schizophrenia and in understanding the response to pharmacological treatment. However, simultaneously considering both brain imaging and genetic factors may yield clear advantages in the quest for useful quantitative biomarkers in clinical trial settings. These quantitative biomarkers may actually be nearer to the underlying genetic etiological influences than clinical diagnostic categories and have the benefits of less heterogeneity and variability than clinical symptoms. Integrated biomarkers such as these can be used in clinical drug development to improve our understanding of the pathophysiology of schizophrenia, to provide new targets for drug development, enrich study populations for Proof of Mechanism or Target Engagement studies, and to develop predictors of clinical response and the development of side-effects. Tools currently exist to accomplish many of these goals but there are also many barriers that need to be overcome. A portion of this session will be dedicated to the practical application of various analytic tools that are designed not only to overcome many of these issues but to help establish the evidence base for these biomarkers and provide essential data needed for biomarker confirmation and validation as well.
Thursday, May 24th, 2012
Congratulations to Larry Alphs, MD, PhD, recent recipient of the 2011 Johnson and Johnson Volunteer of the Year Award for his volunteerism on behalf of the ISCTM. All who have worked with Larry over the seven and a half years of the Society’s existence realize that this award is well deserved. Larry has contributed countless hours to building the Society, first as a Founder, then Scientific Chair, President-elect, President and now as Past President. His integrity, work ethic, and insight into the challenges facing the field of CNS drug development have been fundamental in moving ISCTM from vision to reality.
Thank you, Larry, from all your colleagues at the ISCTM!
Saturday, May 5th, 2012
Chair: Ginger Haynes, PhD
The adaptive design workshop will present a case study illustrating how statisticians and clinicians collectively prepared an argument for using adaptive design in Phase IIB rather than a traditional design. This argument was to be made to senior management who may be very skeptical to accepting or implementing new strategies. Evidence provided in the case will include relevant upfront costs, overall duration of the trial, sample size differences, overall cost, and as well as potential challenges from regulatory agencies. This case study is designed to demonstrate the practical value of adaptive design to a non-statistical audience and generate group discussion about additional evidence that would be convincing in a business environment.
Tuesday, May 1st, 2012
ISCTM 8th Annual Meeting, Washington, DC
Tuesday, 21 February 2012
National Mental Health Research to Policy Forum
“Are Clinical Trials of New Treatments for Chronic CNS Diseases Early Enough and Long Enough?”
Co-Chairs: Reuven Ferziger, MD; Larry Ereshefsky, PharmD; Ron Manderscheid, PhD
Dr. Ereshefsky opened the session, stating that the goal was to review strategies for improving the design and conduct of long-term clinical trials in CNS diseases. The focus of the session was on Alzheimer’s disease (AD), which was considered to be very timely in light of the recent challenge from President Obama to have effective treatments by 2025, and schizophrenia, a chronic disease with a long-term course and high healthcare costs. Dr. Manderscheid noted that it was hoped that the ideas presented at this session could form the basis for policy paper with recommendations for changing the approach to research in schizophrenia and AD.
Part 1: Framing the Issues
Dr. Goldman discussed the needs that policy makers have for data from long-term studies in CNS diseases such as AD and schizophrenia evaluating different treatment interventions. The Mental Health Treatment Study (Social Security Administration), evaluating the effects of better access to treatment and employment services in patients with schizophrenia or affective disorders, and the Recovery After an Initial Schizophrenia Episode study (RAISE; NIMH), evaluating the effect of early intervention in schizophrenia were cited as examples of government sponsored long-term studies. Issues associated with early treatment and long-term follow-up can impact the following policy areas: disability (when to re-evaluate), vocational (ability to return to work), labor, educational (ability to return to school), healthcare finance (cost/benefit), and housing.
Dr. Manderscheid discussed the epidemiology and policy goals in the treatment of AD and schizophrenia. Long-term follow-up is needed on patients who are released from psychiatric hospitals to collect information on treatment and outcomes. Ideally this should be for 30-50 years; however, this is generally not feasible. Unfortunately, case registries used for tracking these patients have been largely abandoned due to lack of funding.
Dr. Heinssen gave the perspective on schizophrenia and emphasized the need to identify new targets in treating schizophrenia and the importance of early intervention. In the U.S., initiation of treatment in schizophrenia is often delayed 1-3 years after the first episode, despite evidence that delaying treatment leads to a worse long-term outcome. The current model for managing chronic schizophrenia is inefficient, resulting in high rates of unemployment among patients with schizophrenia and annual economic costs in excess of $60 billion. Long-term studies evaluating outcomes in patients who receive early intervention need to be conducted. Initiatives from the NIMH to evaluate early intervention strategies include the North American Prodrome Longitudinal Study (NAPLS), looking at the prodromal state and factors that influence conversion to psychosis, and the RAISE study. To date, very few prevention trials in prodromal schizophrenia have been performed, with only a half dozen randomized, controlled trials (RCTs) being conducted to evaluate medications, along with cognitive behavioral therapy, in reducing the transition to psychosis over a 12 month period.
Dr. Anand provided the perspective on the need for earlier intervention and long-term trials in AD. Currently available treatments for AD are approved for use during the mild to severe stages of the disease; however, behavioral symptoms can be identified 2-3 years before the diagnosis is made, and pathological changes in the brain may occur up to 10 years prior. The worldwide prevalence of dementia is currently 25 million and is expected to reach 80 million by 2040 if no treatment is available to halt or delay the progression of the disease. Current costs of AD in the US alone are $148 billion annually. Despite this high cost and a steadily increasing mortality rate for AD, funding for AD research has significantly lagged that of other major diseases, such as HIV, cancer and heart disease. The patients included in clinical trials of approved drugs for AD are thought to be too severely ill to gain much benefit from a disease modifying agent. Unfortunately, trials done with approved AD medications in patients with Mild Cognitive Impairment (MCI), considered pre-AD, also failed to show an effect on disease progression, possibly because an intervention in these patients was already too late. Going forward, strategies to identify at-risk patients even earlier in the pre-dementia phase are needed, as are novel therapeutic agents that will arrest or significantly delay the pathological process. A delay of even one year in the onset of AD could result in substantial cost savings of approximately $1 trillion in the US alone. Long-term therapeutic trials of 5-10 years’ duration, with treatment initiated very early in the disease process, are needed.
Dr. Kraemer discussed the alignment of policy goals with research capabilities, and emphasized the need to do a better job of investigating the treatments that we have to ensure that effective treatments are not discarded and that a lot of money is not wasted on ineffective treatments. Although long-term trials are needed, they are fraught with problems, including high cost, sporadic funding, high dropout rates, lack of compliance, and influence of other factors, such as concomitant treatments, on the outcome. In addition, priorities change over time and new questions may develop that ongoing studies are not designed to address. Also, in disease prevention studies, risk factors change as patients age. Often, answers gained in research studies are not relevant to the questions that policy makers need addressed. Going forward, the following changes in the way long-term studies are conducted should be considered: articulate specific research questions; focus on meaningful effect sizes, rather than p values; explore for moderators of treatment response, e.g. using sequential RCTs or looking at different outcomes in different stages of the trial; perform “accelerated lifetime studies” using overlapping cohorts of patients at different stages of the disease rather than following all patients for 5-10 years. These strategies should mitigate the issues with long-term trials, such as high dropout rates, and should decrease sample sizes, increase effect sizes, and allow results to be available sooner.
Part 2: Policy Shareholders Perspectives
Dr. Breier presented the industry perspective, and noted that CNS diseases are a very high risk area, with only 10% of promising drug candidates ever getting launched. Disease modifying agents for schizophrenia or AD would certainly be of interest, but long development times (>8 years) are an impediment. A clear regulatory path to registration is needed, including definition of the very mild/pre-symptomatic population to be included, and the requirements for a “disease prevention” or “delayed time to onset” claim. An initiative similar to MATRICS for cognitive impairment associated with schizophrenia would be a good model for academic/NIH/FDA/industry collaboration on defining the design, primary outcome measure(s), selection criteria, etc. for these studies. Unique challenges related to these trials would be the need for biomarkers to identify subjects, determining sample size (i.e. estimating conversion rates), trial duration and retention of subjects. Smaller proof-of-concept trials may not be feasible with disease prevention as the target, unless a surrogate marker is identified. Although earlier treatment would be profitable, treating young patients in the schizophrenia prodrome raises ethical issues. Development of new and novel treatments would be favored over expanded use of existing drugs. A one-year, double-blind RCT comparing olanzapine and placebo in patients diagnosed with prodromal symptoms of psychosis was presented as an example of the challenges in doing these trials. In this study, recruitment and retention of patients was very difficult, significant side effects were noted, and the trial was stopped early.
Dr. Laughren gave the FDA perspective on long-term schizophrenia trials. The challenges in performing trials in schizophrenia include the fact that it is a lifelong disease, with severe functional impairment, morbidity and mortality, and currently we have a very limited understanding of the disease. There are many stakeholders involved, including patients and their families, advocacy groups, government and private healthcare providers, researchers, Pharma and FDA. If treatments are to be evaluated in prodromal schizophrenia, it needs to be better defined. Treatment goals could include delaying the onset of the first episode, rather than disease prevention. Use of non-drug therapies, in addition to drugs, need to be considered. As with all drugs, for a disease modifying agent to be approved, “substantial evidence of efficacy from well controlled trials”, must be provided. Standard designs for acute schizophrenia trials would most likely not work for trials assessing delay in disease onset. Regarding long-term treatment trials in schizophrenia, maintenance studies are currently not required for approval of an antipsychotic drug. Long-term, randomized-withdrawal trials have been performed for most drugs, and generally come out positive, but don’t really assess effects of the drug in the long-term course of the disease. Suggestions have been made for improving registration trials, including doing more efficient, sequential, short-term trials; however, this model would lead to longer development time, which does not fit the business model. Regulatory acceptance of observational trials has also been suggested, but these would never be accepted to support efficacy. FDA efforts to improve conduct of schizophrenia trials include exploratory analyses of summary data and patient level data, and establishment of data standards for trials. The NEWMEDS consortium, which is an international collaboration of academia and industry, is also working on this.
Dr. Katz provided the FDA opinion on long-term trials in AD, focusing on trials of disease modifying agents. Trials of amyloid modifying agents are ongoing; however, there are a number of problems that still need to be addressed, including identifying appropriate patients for inclusion, use of appropriate measures to assess drug effects, and determining adequate duration for these studies. Patients diagnosed with AD may already be too late in the disease process to benefit, but currently, for sporadic AD, there is no way to accurately identify with high precision which asymptomatic patients will progress to dementia. MCI may also be too late, as these patients already have substantial amyloid burden. From a regulatory perspective, a drug that could significantly delay or prevent dementia would certainly be approvable. However, to provide evidence of efficacy, you would need to demonstrate an effect on a surrogate marker that predicts clinical benefit, as well as show an effect on at least one clinical outcome, e.g. time to diagnosis of AD, cognitive measure, or global outcome. The duration of these trials should be as short as possible to demonstrate a clinically meaningful drug effect, but most likely would need to be several years in duration.
In the ensuing discussion, Dan Begel (Psychiatrist) suggested that there is disconnect between what is evaluated by the clinician in the field vs. clinical trials, and that better measures need to be developed to truly assess what the patient is thinking and feeling. Dr. Kraemer suggested using several measures and developing a composite outcome that would give a better overall picture. In response to a question by Nina Schooler, an example of overlapping sequential cohorts was provided by Dr. Manderscheid, in which cohorts of patients with overlapping age ranges, e.g. 40-45, 45-50, 50-55, etc., would be run separately but simultaneously, and the data would be pieced together to create a long-term follow-up study. Judy Kando noted that accelerated development using large, long-term trials has been done routinely in other areas, such as oncology and cardiology. Dr. Kraemer commented that these trials have problems similar to those in CNS diseases. Dr. Laughren acknowledged that cardiovascular diseases are better understood, making long-term prevention trials easier to conduct. Dr. Anand added that attrition is also less of a problem in these areas than in CNS, where we often see a 30% dropout rate in a 6-week study; this may be related to the fact that patients with cardiovascular diseases may have no noticeable symptoms when treated with placebo.
Dr. Ereshefsky suggested that a national screening effort, as was done for AIDS, should be considered for AD; however, since there are no available treatments to prevent/delay the disease onset, it was questioned whether this would be of value and whether or not patients would want to know. Dr. Anand added that screening at this point would be impractical because of the lack of adequate biomarkers and the need to screen patients as early as 50 years of age, to capture the early stage of the disease. Up to 100 subjects may need to be screened to find one confirmed pre-AD patient.
Part 3: Research Stakeholder Perspectives
Dr. Breier described the current status of early intervention trials in schizophrenia. These studies require an enriched sample, and there is a need for better diagnostic markers to identify patients in the prodromal phase. An ADNI-like initiative was suggested to identify surrogate endpoints. To aid in recruitment of subjects and standardization of procedures, a clinical trial network was proposed with each site using similar protocols for neuroimaging, e.g. measuring cortical gray matter changes. Progressive brain changes have been noted in untreated first episode schizophrenic patients. Other biological measures could include N-acetyl cysteine. A 12-month study in which serial MRI/MRS is performed was proposed.
Dr. Anand presented that status of long-term trials in AD. Ongoing treatment trials in both prodromal and mild/moderate AD are being conducted using amyloid-modifying agents, including secretase inhibitors and anti-Aβ antibodies, which it is hoped will arrest or slow the progression of the disease. In addition, several large, multi-center, long-term, collaborative trials are ongoing or planned, including ADNI, AIBL, DIAN, A4 and ICTUS, which are designed to better understand the progression of AD, and include neuroimaging and assessment of biomarkers, in addition to cognitive testing, and in some studies, the evaluation of drug therapy (to be provided by Pharma). Unfortunately, to date most amyloid-modifying therapies have failed to demonstrate a therapeutic effect or have been associated with significant toxicity. One possible reason for the lack of effect may be that the patients included in these studies have been too far along in the disease process to benefit. Also, amyloid-modifying agents impact only one facet of AD pathology, and do not affect other processes such as changes in tau. A proposal was made that patients included in prodromal AD trials should have the following characteristics: memory complaints (subject or informant); presence of amyloid on PET; and lack of clinical symptoms, significant structural changes in the brain or high CSF tau. These studies would require a large sample size (>300/group) and need to be conducted for up to 10 years. To reduce attrition, no restrictions should be made on use of concomitant medications, and patients with concomitant illnesses should be allowed to continue. The proposed primary efficacy endpoint would be a 30% decrease in the rate of cognitive decline on a composite measure at 3 years. Other measures should include behavior, functioning, neuroimaging and genetic/bio-markers. For regulatory purposes, the company would break the blind internally at the 3-year time point and submit these data for approval. Patients would continue on blinded treatment during long-term follow-up, with an option to switch patients to the active treatment, if proven effective. The long-term treatment phase of the study would require alternative funding, perhaps through a government/industry partnership.
In the panel discussion, Dr. Kraemer noted that AD and schizophrenia are most likely not due to a defect in a single gene; therefore, a combination of genetic markers along with biomarkers will be needed to identify patients at risk. Substantial data on patient characteristics could be obtained from large RCTs and risk studies that have already been conducted. In addition, lessons learned from long-term risk studies in other areas, e.g. cardiology, may be helpful. Dr. Marder noted that in schizophrenia we can’t predict the outcome after the initial episode; therefore, we can only treat the symptoms as they occur. Currently, we do not have the ability to change the trajectory of the illness. Dr. Ereshefsky raised the possibility that a surrogate illness approach might be useful, e.g. Down’s syndrome for AD, since similar amyloid pathology is observed. This would be difficult in schizophrenia, although targeting gray matter changes (up to 4% decrease/year), rather than prodromal symptoms might be one approach.
In the subsequent discussion, Janet Williams suggested that unblinded data from all clinical trials, including failed studies, should be made available for analysis. It was noted that the Coalition Against Major Diseases, an academic/regulatory/industry collaboration, has more than 6000 AD patients in its database, including data from biomarkers and ADNI. Adapting standards for data collection in clinical trials going forward would make it easier for pooling data in these types of large databases. Dr. Kraemer cautioned that, when pooling data from large multi-center trials there is large variability among sites, and pooling of sites leads to regression to the mean; instead, each site should be looked at separately for effect size.
Monday, April 30th, 2012
Co-Chairs: Stephen Marder MD; David Daniel MD
This workshop on clinical trials methodology for studies targeting negative symptoms is a continuation of a process for re-evaluating recommendations based on emerging data. This group will review new data from a number of sources including recently reported trials; studies evaluating the properties of newer instruments for measuring negative symptoms; and recent analyses from the European Union NEWMEDS data base. The group will also review the recommendations from the NEWMEDS negative symptom meeting from April, 2012.
Friday, April 27th, 2012
Co-chairs: Nina R Schooler, PhD; Dawn Velligan PhD
This workshop will examine possible models and examples of psychosocial treatment platforms for RCTS. It will consider the advantages and disadvantages of specifying a uniform psychosocial platform in multi-center psychopharmacology clinical trials. Advantages include minimizing error variance due to differences among sites in the kid of support provided and therefore reducing error. Possible disadvantages include increased cost and the possibility that the platform will benefit a placebo treatment differentially.
Wednesday, April 18th, 2012
Biomarkers Working Group Dinner
22 Feb 2012
Chair: H Riordan
The dinner session presented a good opportunity for Henry Riordan and Nathen Chen to update the ICTM membership regarding the mission and activities of the BWG by. Dr. Riordan began the session with an overview of the origins of the BWG as well as a review of the BWG mission statement and deliverables. Dr. Chen then provided updates on the qualitative grading data presented at the fall session in addition to the major findings in his poster. Dr. Riordan followed by reviewing the quantitative data and analyses conducted to date and introduced the ISCTM membership to the services offered by Dr. Evidence who have been invited to next ISCTM meeting.
By way of background Dr. Riordan noted that as CNS drug development advances toward an increasingly personalized approach to treatment, the role of various biomarkers has become ever more important for informing clinicians about the relative safety, tolerability and efficacy of a range of CNS drugs and products. In addition, biomarkers can aid in the development of novel therapeutic agents, identify susceptible populations, provide endpoints for clinical trials and even serve as predictor variables. The growing interest in biomarkers raises many challenges for diverse stakeholders regarding both the structure and elements of clinical trials that are needed to establish valid scientific data in support of these biomarkers. Unfortunately, CNS drug developers currently lack sufficient data and many of the tools necessary to successfully implement the use of biomarkers in the drug development process. Given this, and the burden of development and qualification of biomarkers in terms of both time and cost, the formation of collaborative international groups to undertake these biomarker related challenges is essential. These challenges also provide a unique opportunity for meaningful industry-academia-government collaboration; and the BWG was formed to help meet these challenges while ensuring that the interests and expertise of the International Society for CNS Clinical Trials and Methodology are both thoughtfully considered and communicated to the Society’s members.
Dr. Chen then summarized the qualitative evaluation of the utility of imaging biomarkers in schizophrenia as a measure of treatment response. Schizophrenia treatment studies that included the structural or functional imaging modalities, including vMRI, fMRI, FDG-PET, receptor occupancy PET & SPECT, and DTI were identified, categorized, and evaluated. The following table summarizes his report on the results of this qualitative grading of evidence evaluation for these putative imaging biomarkers.
| |
Paper Identified |
Abstract Reviewed |
Articles on Target |
Key Findings |
Evidence Level |
|
sMRI
|
265
|
100
|
35
|
– Volume loss of frontal grey matter in schizophrenia at various stage
– Loss of both grey and while matter vs treatment by typical antipsychotics
– Loss of grey matter but increase of while matter vs treatment by atypical antipsychotics
|
A–
|
|
fMRI
|
1881 |
15+ |
15 |
– Evidence for psychopharmacological effects on cerebral physiology (e.g., percent signal change in frontal lobe regions).
– Evidence for psychopharmacological effects on functional connectivity
|
B
|
|
DTI
|
250 |
16 |
10 |
– No prospective study prospectively examined between group treatment effects
– Anisotrophy in pts generally lower than healthy controls; lower still in pts with “poor outcomes
– Anisotrophy reductions in pts take place earlier in the course of illness, closer to the time of first psychotic episode and stabilize in its chronic phase, but inconsistent findings and confounded by age and illness duration.
|
D
|
|
FDG-PET
|
7 |
7 |
7 |
– Resting rCBF was significantly lower in schizophrenia compared to normal controls
– Schizophrenics has significantly higher right and left contrast enhancement compared to normal controls
– Antipsychotics was associated with greater change toward normal values & away from the values found in the unmedicated comparison group for dorsolateral prefrontal cortex gray matter and white matter underlying medial prefrontal and cingulate cortex.
|
C+ – B–
|
|
PET
|
184 |
40 |
22 |
– Model to characterized dose –occupancy relationship
– Striatal D2/D3 occupancy predicted both improvement of positive symptoms and occurrence of EPS
|
B+ – A–
|
|
SPET
|
50 |
25+ |
25 |
– See PET
– Limited 5HT2A blockade in antipsychotic action
– Confirm neurotransmitter dysfunction of D2, 5-HT2A, NMDA, GABA, muscarinic receptors
– Regional Cerebral Blood Flow (rCBF) analysis suggested hypofrontality
– Evidence of differential rCBF related to antipsychotic efficacy and cognitive improvements
|
B+ – A–
|
By way of follow up and in order to determine the quality of evidence to support the application of imaging biomarkers in clinical trials of schizophrenia Dr. Riordan reviewed the relevant sMRI literature – the area that had the highest overall qualitative rating. Brain regions examined included whole brain, lobar volumes, basal ganglia and ventricular volumes, as well as grey and white matter. Analysis of intervention effects on brain volume (across different types medication) revealed a moderate but non-significant overall effect size (g=0.452, 95% CI= -0.56, 0.17)). An analysis of homogeneity including all studies revealed no significant variance among effect sizes that would support examining the effects of moderator variables (QB[133]=133.299 12, p<0.45). Significant decreases associated with treatment were noted for a total white matter volume that was seen early in treatment and grew in response to study duration. Interestingly some evidence was also noted for an increase in grey matter for two atypical antipsychotics. While these initial results did not fully support the qualitative evidence grading they did suggest that it is possible to more confidently select specific brain regions that are more likely to be sensitive to antipsychotic medication effects. Further work is needed relating these ESs to changes in schizophrenia symptoms and outcomes.
Key Outcomes of the BWG Dinner Session:
•Provided a summary of the qualitative grading data for imaging biomarkers (sMRI, fMRI, DTI, FDG/receptor PET & SPECT) suggesting highest rating for sMRI.
•Reviewed the quantitative data and meta analytic procedures for sMRI changes in various ROIs associated with treatment effects with largest ES for white matter decreases over time.
•Introduced the process and services offered by Dr. Evidence that could potentially be utilized by the BWG in future activities. A formal presentation by Dr. Evidence on replication of meta analyses at the Fall 2012 meeting is anticipated.
•Explored the possibility of registering schizophrenia imaging biomarkers meta analysis on Cochrane Collaboration as well as approach to publication supporting the utility of key biomarkers (cognition, ERP, imaging etc.) in a proof of concept setting.
Wednesday, April 18th, 2012
ISCTM Negative Symptoms Working Group Dinner
21 February 2012
Chairs: S Marder, D Daniel
J. Rabinowitz updated the group on NEWMEDS, an initiative in which pharmaceutical companies are sharing some of their data on negative symptoms in schizophrenia. The database now holds from 5 companies including 23,000 patients with schizophrenia, generally from studies in acute schizophrenia. Estimates of the percentage of patients with schizophrenia with prominent negative symptoms vary widely depending on which of the various definitions in the literature is employed. A discussion ensued on whether one can even talk about some patients having predominantly negative symptoms without making positive and negative ‘competing’ domains .
Dr. Marder also informed the group about an international meeting on negative symptoms methods that will be held in Florence on April 19, 2012. Interested members may contact him for additional information.
S. Marder provided an update on the development of the CAINS scale, a new negative symptoms scale being developed by a working group that grew out of the NIMH-MATRICS Consensus Development Conference on Negative Symptoms. The CAINS had 24 items in beta testing but is now down to 16 items in 2 subscales: the experience subscale and the expression-related subscale. These 2 subscales are intended to be scored separately and not to yield a total score.
The CAINShas been studied in 160 patients at 4sites for test-retest reliability for and convergent and divergent validity and has been found to have good reliability, especially for the experience subscale, and good convergent validity with other negative symptoms scales and with the UPSA and some cognitive measures. The final version of the CAINS will be posted sometime in the early spring.
D. Daniel discussed the BNSS, the Brief Negative Symptom Scale, a 13 item scale that also grew out of the NIMH-MATRICS Consensus Development Conference on Negative Symptoms. It is in development and has shown good reliability and concurrent and discriminant validity. A paper on the psychometric properties of the scale was published in 2011 by Kirkpatrick et al in the Schizophrenia Bulletin.
The group discussed the question of how and when informants should be used in rating negative symptoms. Caregivers have valuable information about patients’ symptoms but they have they own agendas and varying levels of contact with patients possibly leading to increased variability in the results.
Two issues proposed for future discussions were:
1) Does it make sense to exclude patients with depressive symptoms when studying negative symptoms ?
2) Are there any physiologic measures that could be used in studying negative symptoms?
Thursday, April 12th, 2012
The session was held on February 21, 2012. Presenters included Co-chairs Mark A. Ammann, Pharm D, Michael Klein Phd, Heddie Martynowitz, MS and Marta Sokolowska, PhD.
Heddie Martynowicz opened the session summarizing what will be discussed, and briefly addressed clinical and regulatory aspects of abuse liability potential assessment. She emphasized the importance to understand FDA guidance issued in 2010, which represents the most comprehensive guidance in the world at this point of time,
Mark A Amman informed the audience about the background of FDA Draft Guidance. In June of 2006, Cross Company Abuse Liability Consortium (CCALC) was founded. CCALC is a “Grass roots” Industry organization, consisted of approximately 80 people representing over 25 pharmaceutical companies. Different work-groups were formed, including regulatory, preclinical, clinical and risk management work-groups. The Objectives of CCALC are to collaborate to educate one another and to outreach for open scientific exchange with key stakeholders. Dr Amman outlined the key activities to date, which led
to Draft Guidance on Assessment of Abuse Potential of Drugs in January 2010 and presentation to the FDA in November 2011, where FDA provided a Draft Decision Tree for Assessment of Abuse Potential. Challenges in assessment of abuse liability were discussed among all relevant stakeholders.
The objective was to develop a preclinical and clinical methodology that was reliable, has clearly interpretable results and is predictive. Based on preclinical and clinical methodology, we should be able to determine whether there is a risk of abuse ands additionally qualify and quantify the risk. The overview of Draft Guideline was Issued January 2010.
Dr Michael Klein discussed FDA Guidance and Decision Tree on Assessing Abuse Potential of New Drugs. Abuse potential is a safety-related issue that must be addressed during NDA review. All safety assessments provide important information for the drug label , patient and public. The definitions of Abuse Potential and Abuse Liability were introduced, as well as requirements for Abuse Potential Assessment. Applicable Federal Laws were outlined.
Details of FDA published draft Guidance on Assessment of Abuse Potential of New Drugs were presented. The guidance addresses many questions, some of them being : 1. When to assess the abuse potential of a drug in relation to a drug development time frame? 2. Pre-IND Testing – what abuse potential data is needed at this stage? FDA is hoping that Draft Guidance will help companies manage the risk. It was suggested that by the end of Phase 2 may be the right time to do abuse potential. FDA also recommends that studies are to be repeated once therapeutic dose has been determined (Phase 3). FDA also accepts as valid Abuse Potential studies that use as negative control placebo as we do not know a lot about abuse potential of drugs already approved by FDA. Interesting comment was made by Dr Marta Sokolowska, who reviewed several case studies. While discussing the Abuse Potential Study conducted to assess abuse potential of Cymbalta. Dr Sokolowska noted that abuse potential of Cymbalta was compared to desipramine and methylphenidate. While scientific community was impressed by the study, FDA believed only needed is to compared Abuse potential of Cymbalta to Placebo.
Draft Decision Tree for the Assessment of Abuse Potential was presented by the FDA in November 2011 at a joint meeting by FDA, NIDA/NIH and the College on Problems of Drug Dependence. The authors are Katherine Binson PhD and Stephan Sun, MD-CSS. The objective of the Draft Decision Tree is to improve regulatory efficiency, consistency and transparency, align with real world development and allow for active dialog with feedback from stakeholders. The Draft Decision Tree aligns to Phases of drug development, from non-clinical studies to the NDA review. As drug development progresses, scientific questions related to abuse potential are answered through the outcomes of each study.
Use of the Decision Tree will allow a Sponsor to identify abuse potential early in the development process and manage the risk of the drug development. FDA welcomes feedback, based on real-life examples from pharmaceutical development.
Wednesday, February 29th, 2012
ANDREW C. LEON
LEON ANDREW C. LEON, 60, a professor and leading biostatistician in psychiatry at Weill Medical College of Cornell University, died suddenly Feb. 18 at his home in the Poconos. His work heavily influenced the finding and acceptability of new drugs and treatments for mental illness. Dr. Leon was highly sought after internationally for his expertise in testing and evaluating methods of treatment. Born in Cleveland, he grew up in Shaker Heights, earned a BGS at Ohio University, Master’s degrees at Florida A&M and Columbia Universities, and a PhD in Statistics at the City University of New York. He was a lifelong Cleveland Indians fan, dedicated runner and swimmer, environmentalist, and jazz fan. He was universally liked for his kindness, sincere interest in others, and devotion to family and friends. He is survived by his wife Yuki Okuma; daughter Angelica; two brothers, Hap and Peter; sister, Sally; and nephew Milan Aviles. A private memorial service for family and friends will take place on Saturday, March 3 in Stroudsburg PA. The family suggests that contributions in Andy’s name be made to Doctors Without Borders.
Published in The Plain Dealer on February 26, 2012
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