Author Archive

WS6: Adaptive Design in CNS Trials

Monday, June 6th, 2011

Chairs: Vladimir Dragalin, PhD; Jose Pinheiro, PhD; Virginia Haynes, PhD

Potential benefits of adaptive designs in CNS trials, specific challenges and solutions for their implementation, and comparisons to conventional trial designs will be discussed and illustrated. The importance of using simulations in planning adaptive clinical trials will be emphasized and demonstrated.

WS2:Evaluating Biomarkers for Schizophrenia: Issues in Identification, Categorization and Evaluation

Monday, June 6th, 2011

Chairs: N Chen, S DeSanti

WS3: Assessing Assessment Methodologies: Weighing Choices Based on Indications, Study Design and Needs

Monday, June 6th, 2011

Chairs: M Davidson, M Detke

ISCTM 7th Annual Scientific Meeting – Session 1 Amyloid Hypothesis – Summary

Friday, May 20th, 2011

Background

Unfortunately, to date the numerous amyloid-targeting drugs and vaccines developed to treat symptoms or modify the course of Alzheimer’s disease (AD) based on the amyloid cascade hypothesis have largely failed, causing some researchers to question the validity of the approach, as well as the clinical trials methodologies employed. This notion was recently reviewed in a session entitled “Do Clinical Results to Date Suggest That Drug Development Based on the Amyloid Hypothesis of Alzhiemer’s Disease is Dead” at the 7th Annual Scientific Meeting of the International Society of CNS Clinical Trials and Methodology (ISCTM) in Washington DC.

Summary

The session was led by industry veterans, academicians and regulatory experts.  Data for various amyloid drugs was reviewed and it was generally suggested that, despite the fact that most amyloid-targeting drugs/vaccines mechanistically were able to impact their intended targets in the predicted manner, these treatments have largely been clinically ineffective or in some cases even deleterious due to a variety of methodological and design flaws including under-powering, poorly chosen outcome measures, and short time frames.  However, one of the most salient factors contributing to these failed trials concerns subject inclusion criteria, as it was determined that that these amyloid-based interventions may have been administered much too late in the course of AD illness.  Moreover, the various mechanisms of actions of drugs targeting amyloid, suggest that the stage of the illness needs to be better matched to the pharmacological intervention. There was a general sentiment expressed that several good drugs may have been simply applied at the wrong stage of illness.  Therefore, investigating amyloid agents in patients who are in the prodromal (pre-clinical) or even “pre-prodomal” phases of illness would be more advantageous when assessing efficacy.  Although it was even suggested that the mere appearance of a measurable biomarker implied that it might be too late to significantly impact disease state, the consensus opinion supported the argument that having qualified biomarkers in the arsenal of CNS drug development tools is very useful.  In summary, it was concluded that despite decades of research in pre-clinical models, few strategies are adequately validated or predictive to effectively guide drug development.  This has been borne out by the negative results of the clinical trials completed to date.  Going forward, it was recommended that an earlier stage of the disease should be targeted and a combination of biomarkers and clinical measures should be used in clinical trials of disease-modifying treatments. 

Introduction: Ravi Anand, MD and Larry Ereshefsky, PharmD

Dr. Anand reviewed the development of the amyloid hypothesis of AD, from the original neuropathological findings of plaques and tangles made by Alois Alzheimer through the discovery that amyloid plaques correlated with the degree of dementia and contained amyloid beta peptide (Aβ).  The identification of the Amyloid Precursor Protein (APP) gene and the discovery that patients with early onset AD had genetic mutations leading to amyloid deposition formed the basis for the hypothesis that accumulated Aβ leads to a cascade of events resulting in neuronal death.  Based on this hypothesis, numerous therapies were developed targeting Aβ formation, clearance and toxicity, including β- and γ-secretase inhibitors, α-secretase enhancers, vaccines to enhance clearance of Aβ, and agents to inhibit Aβ aggregation. To date, none of these agents has shown significant improvement in cognitive function in AD patients, and some have been associated with significant worsening or toxicity.  Therefore, it is possible that Aβ metabolism is the wrong target.  Shortcomings of the amyloid hypothesis of AD include the fact that neurotoxicity of Aβ has not been demonstrated, and the amyloid load does not seem to correlate with the onset of dementia or cognitive deficits.  Although the altered metabolism of amyloid in AD is supported by a large body of evidence, there is no evidence that reversal of this process will lead to therapeutic benefit in AD patients.

Dr. Ereshefsky noted that secretase inhibitors (gamma and BACE1) appear to be engaging the presumed target for clinical effect since dose-related reductions in CSF Aβ40/42 and increases in soluble APP have been observed.  Similarly, vaccines targeting Aβ have resulted in increases in amyloid clearance, yet in all cases to date, clinical benefit is marginal.  For γ-secretase inhibitors, too much inhibition appears to be detrimental, with side effects demonstrating a lack of selectivity consistent with significant NOTCH engagement. Unfortunately, semagacestat demonstrated statistically significant worsening in cognition at the highest dose used in clinical trials in Alzheimer’s patients.  .Possible explanations for the disappointing results may be that the drugs were given at the wrong stage of illness (too late), that tau-opathies might be a more relevant disease target, and/or the measures used to assess efficacy, e.g., ADAS-Cog and the ADCS-ADL are susceptible to culture, language, educational, and socioeconomic bias.  Currently, global trials in ‘pre-mild’ Alzheimer’s Dementia are being initiated; however, reliable severity typing in International trials might also lead to confounding effects, thereby reducing the clinical trial’s signal detection sensitivity.

Frank LaFerla, PhD

Dr. LaFerla discussed the pre-clinical models used for AD and their appropriateness for predicting the success of Aβ-modifying therapies.  Agents that are currently being tested in AD patients worked in pre-clinical models; however, clinical trials of amyloid modifying agents to date have been uniformly disappointing, possibly due to the following: AD does not have a uniform path in all patients, co-morbidities must be taken into account, and treatment may be ineffective once Aβ and tau pathology has set in, with treatments being unable to reverse decades of pathological changes.  Also, animal models in mice may not adequately represent pre-AD, i.e., they do not mimic the neuronal loss and tau pathology seen in humans.  A triple transgenic mouse model, which includes the human APP gene and shows age-dependent build-up of plaques and tangles, along with significant cognitive impairment, was discussed.  Passive immunization to remove Aβ in this model did not improve cognition if there was no effect on tau.  Numerous negative studies (i.e. no effect on pathology or cognition) in mouse models with various therapies have been conducted but have not been published. 

A new approach to treating AD pathology using neural stem cells (NSCs) was discussed.  The advantages of using NSCs include 1) no ethical issues, 2) NSCs are transplanted into neural tissue, and 3) NSCs can differentiate into neurons, oligodendrocytes or astrocytes.  NSCs injected into the hippocampus of AD transgenic mice improved memory without affecting Aβ or tau pathology.  Most cells migrate to the dentate gyrus and become glial cells, not neurons.  

Improvement appears to be due to increased synaptogenesis via a neurotrophic mechanism, i.e., increased expression of BDNF.  However, many unresolved issues need to be addressed before using NSC transplants in humans with AD.  

Suggestions for the future included the need for developing better animal models of AD that mimic sporadic disease, not just the genetic disease, as well as the heterogeneity of AD seen in humans.  Mouse models that develop tau pathology and neuronal damage are needed.  In clinical trials, treatment should be initiated sooner to improve the response, and targets other than Aβ should be considered. 

Holly Soares, PhD

Dr. Soares presented a summary of findings from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) focusing on progress in biomarker research, especially as they apply to disease progression.  Biomarker-based clinical trials that reliably predict those patients more likely to progress to Alzheimer’s disease will help researchers identify the best study participants, better characterize disease progression, and reduce the number of subjects needed to detect efficacy signals.  From the myriad biomarkers utilized across the ADNI programs it was reported that, although some biomarkers such as beta amyloid, tau and PIB are prone to large variation, non-normal distributions, and have generally been associated with only modest longitudinal changes, other biomarkers such as FDG PET, have shown greater sensitivity to changes over time.  For example, it was suggested that prodromal patients with greater deficits in glucose metabolism are more likely to progress to AD.  Additionally, two cognitive markers reflecting delayed procedural memory and lateral temporal cortical thickness may also help predict rate of decline in AD.  This rate of decline (slope) of AD is influenced by age, baseline levels of cognition, apolipoprotein E (ApoE) status and various other biomarkers. This slope is variable and trials that have durations of 18 months or less may need to select patients who are rapid decliners.  In addition to ADNI, the Coalition Against Major Diseases has developed a new shared and standardized database.  This database containing information from approximately 4,000 Alzheimer’s subjects has also provided important information regarding the natural history of disease progression by looking at the placebo arms from eleven industry-sponsored clinical trials.

Lon Schneider, MD

Dr. Schneider presented an overview of recent clinical trials in AD and discussed ways to move forward.  Despite more than 20 years of clinical research on AD treatments, only cholinesterase inhibitors and memantine have been approved.  Promising therapies, based on animal models, have not translated into clinical benefit in humans.  Numerous treatments with varying mechanisms of action have failed in Phases 2 or 3 of development, including those targeting amyloid.  Failures may be related to a number of issues, including the fact that the cause of AD is not known, there are no validated drug targets, and the outcome measures we are using, e.g. ADAS-Cog, may not be appropriate.  Trials are getting longer (18 months is standard for amyloid-modifying therapies) and are dependent on the placebo group worsening, which is problematic as the placebo response for the ADAS-Cog varies greatly among studies, individual patients and the stage of the disease. 

An overview of anti-Aβ therapies in development, including Aβ immunotherapy (antibodies, immunoglobulins, vaccines), γ-secretase inhibitors and modulators, BACE inhibitors and fibrilogenesis inhibitors was provided.  Results of Phase 2 studies for amyloid-modifying agents, including an Aβ antibody immunotherapy (Bapineuzumab), a γ-secretase modulator (Tarenflurbil), a γ-secretase inhibitor (BMS 708163) and a drug that inhibits Aβ oligomer formation (Scyllo-inositol) were discussed.  In each case, decisions were made to proceed to Phase 3 studies, despite limited evidence of efficacy (cognitive benefits) and/or significant safety issues noted at higher doses in the Phase 2 studies.  In general, the results from Phase 2 studies have not been predictive of the outcomes in Phase 3 trials.

It was recommended that in moving forward, we need to better understand the disease process and the pharmacology of the drugs being tested, and need to design better trials using multivariate outcomes that are more appropriate.  The causes of variability also need to me minimized.  “Prevention trials” in AD must be initiated earlier, before Aβ and tau pathology is evident, as this may be too late.

David Henley, MD

Dr. Henley, presented the background information and the results from failed Phase 3 trials of a γ‑secretase inhibitor (Semagacestat) conducted by Eli Lilly and Company.  By inhibiting γ‑secretase, semagacestat was expected to decrease levels of Aβ in the brain, and the formation of amyloid plaques.  In Phase I studies, semagacestat lowered levels of Aβ1-40 in plasma of healthy volunteers and AD patients, and dose-dependently decreased the CSF Aβ synthetic rate.  Despite this biomarker evidence of effects on the target enzyme, two large Phase 3 trials in mild to moderate AD patients were stopped following an interim analysis which showed that patients on semagacestat had significantly greater worsening on clinical measures of cognition and activities of daily living.  In addition, the drug was associated with an increased risk of skin cancer, possibly related to its interaction with the Notch receptor.  Other drugs targeting amyloid that had robust Phase 2 biomarker data, e.g. bapineuzumab, flurbiprofen and tramiprosate, have also failed to show clinical benefit. 

Possible reasons for the failure of γ‑secretase inhibitors may relate to the fact that there are six different types of γ‑secretase, and over 50 different substrates for the enzyme have been identified; therefore, it is not know which of these targets are being affected.  Amended protocols are ongoing in patients who stopped the medication to determine if cognitive worsening is reversible and to continue collecting biomarker data.

George Grossberg, MD

Dr. Grossberg discussed proposals for designing the next generation of disease-modifying trials in AD.  Some of the weaknesses in the current approaches include defining the target population, e.g. prodromal AD (pre-Clinical) vs. MCI vs. mild AD, lack of agreement on diagnostic criteria, need for better assessment of other risk factors and co-morbidities, e.g. vascular pathology, and need for use of biomarkers for inclusion.  In particular, with regard to amyloid-modifying therapies, the optimal time in the disease process and where in the amyloid cascade to intervene is not known.  In addition, it is not known if the formation of amyloid plaques and neurofibrillary tangles are related and whether they are the cause of AD or a reactive process.  A revised amyloid cascade hypothesis incorporating the effects of aging and other risk factors needs to be developed.

An important question is whether treatments targeting removal of Aβ from the brain in AD patients are viable.  There is evidence that Aβ may have neuroprotective effects and that removal of Aβ may result in oxidative stress.  Earlier intervention may have greater benefit, as mitochondrial injury related to Aβ has been observed prior to plaque formation.  Other proposed alternative approaches include inhibition of Gamma-Secretase Activating Protein (GSAP), enhancing brain metabolic activity, blocking Amyloid Beta-Derived Diffusible Ligand (ADDL), which affects synaptic signaling, and anti-amyloid “combination therapy”, e.g. combining a BACE inhibitor with a γ‑secretase inhibitor and using lower doses of each.  Possible approaches targeting tau pathology include reducing hyperphosphorylation of tau (kinase inhibitors), reducing tau aggregation, promoting clearance of hyperphosphorylated tau, and promoting microtubule stabilization.

Prevention strategies for AD are the ultimate goal; however, at a recent NIH State-of-the-Science Conference on Preventing AD and Cognitive Decline, the consensus was that there is currently no evidence to support use of any pharmaceutical agents or dietary supplements in the prevention of AD.  Going forward, primary prevention trials for disease-modifying agents must identify the population of very early AD patients to target, possibly using biomarkers to identify” at risk” individuals before clinical symptoms are present.  Diagnostic criteria, validated surrogate biomarkers for following disease progression, and sensitive outcome measures will need to be defined for these studies.  The use of enriched patient populations and stratification of subjects based on biomarkers should be considered to enhance signal detection and help identify responders.

Russell Katz. MD and Karl Broich, MD

Russell Katz and Karl Broich from the FDA and EMA regulatory agencies, respectively, summarized the circumstances under which a biomarker or unvalidated surrogate measure could be adopted as a primary efficacy variable.  These represented personal views and not those from their respective agencies.  A “surrogate marker” can be defined as “…a laboratory measurement or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and is expected to predict the effect of the therapy”.  The FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit, or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity.  It was acknowledged that there is no accepted definition or clear threshold of evidence supporting the term “reasonably likely” which is subjective and open to interpretation.

Surrogates are sought after as they should ideally permit a significant decrease in both the duration and size of studies, shortening the development timelines and saving money, and accelerating approval.  However, surrogate markers remain not yet sufficiently understood and there are none validated for use as a sole primary measure of effectiveness in definitive trials of CNS investigational drugs.  Surrogates are particularly useful when the clinical benefit of the drug is likely to be well in the future and when there are no other therapies; they may not be as useful when clinical effects are easily measured in a reasonable time frame and therefore, surrogates are often proposed as the most realistic way to support a claim for disease progression in AD,an ambitious goal for any CNS drug development company.

It was implied that the disappointing AD trial results to date with amyloid-modifying therapies have failed to support the utility of amyloid-targeted surrogates in AD trials.  In the absence of compelling information, an ideal but as yet undefined indication for testing an amyloid based unvalidated surrogate would be in the setting of very early stage of AD.  In this case subjects would be included in trials even though they are essentially asymptomatic, but may be at high risk for AD at a later time based on some combination of risk factors including but not limited to family history, ApoE genotype status, medical history, etc.  In this trial setting the assessment of traditional AD outcome measures such as the ADAS-Cog or CGIC/CIBIC would be irrelevant.  Instead, a correlation between the effects on a surrogate marker and an appropriate clinical outcome (such as cognition either as a single scale or domain) could be considered for a disease modification claim in AD in which a slowing of progression is seen.  Prevention trials were viewed as too cumbersome and almost unattainable.  It was also suggested that a defined change in a biomarker and cognition (even with no global measure provided) may be adequate for approval, pending an advisory meeting to support the validation of the biomarker.

European regulators also identified the need for a link or plausible correlation between a biomarker (such as a PET ligand that labels beta amyloid plaque in the brain or MRI of the medial temporal lobe) and a desired clinical outcome.  To facilitate this, a two-step approach was outlined, which shows a delay of progression based on signs and symptoms initially, followed later by a correlation with biomarker data to support a disease modification claim in AD.  Because a “disease modifying” effect cannot be established conclusively based on clinical outcome data alone, such a clinical effect must be accompanied by strong supportive evidence from a biomarker program.  As this is difficult to achieve without an adequately qualified and validated biomarker, a two-step approach may be more suitable. If in the first step, delay in the natural course of progression of the disease based on clinical signs and symptoms of the dementing condition can be established, this may be acceptable for a limited claim, e.g. delay of disability. If these results are supported by a convincing package of biological and/or neuroimaging data, e.g. showing delay in the progression of brain atrophy, a full claim for disease modification could be considered. (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003562.pdf).

ISCTM 7th Annual Scientific Meeting – Mitochondrial Systems Working Group Dinner – Summary

Monday, March 21st, 2011

Mitochondrial Systems
Working Group Dinner
21 Feb 2011
Chair: C Bowden

Several recently published examples of mitochondrial dysfunction in brain, particularly in diminished oxidative metabolism to supply energy to brain neurons,  were provided by ISCTM members involved in this work group.  In the aggregate, the data support the hypothesis that mitochondrial dysfunction can be causal of primary observable disease, rather than fundamentally consequent to other primary disease processes.  For example, children of diabetics displayed significant reductions in size of mitochondria compared to controls, raising the possibility that insulin resistance could serve as one biomarker of mitochondrial dysfunction.  Similarly, a microarray study of cortical tissue in Alzheimer Disease, in press in Molecular Psychiatry, co –authored by Terry Goldberg, implicates genes operational in mitochondria,

Disturbances in systems biology and evidence of genetic disturbances are likely to be causally contributory to a variety of severe, chronic psychiatric and neurological disorders, classical mitochondrial disorders, and, possibly, milder forms of cognitive impairment.  Consequently, directing new drug developments toward mitochondrial systems, as well as the upstream inputs that either facilitate mitochondrial resilience or adversely impact mitochondrial functions is a promising strategy .  Two relevant examples are BDNF and Bcl-2.  Valproate and other histone deacetylase inhibitors (HDAC) increase BDNF, and consequently promote survival of dopaminergic neurons.  Bcl-2 is protective against many adverse endogenous and exogenous insults (stroke, elevated glutamate, ß amyloid, methamphetamine.  Lithium, via GSK-3 inhbition, protects Bcl-2 against degradation from such insults.
 
Workgroup participants agree that a straightforward review of mitochondrial function, emphasizing those aspects directly relevant to CNS function, could serve to inform a wide range of scientists working in related clinical and basic areas of CNS diseases.  We see several aspects of mitochondrial systems that are amenable to potential drug development and other non-drug interventions.
Relatedly, several features of mitochondrial function, possibly interlinked with genomic data, appear suitable for treatment as biomarkers both for diagnosis and treatment selection.
 
ISCTM members desiring to join this workgroup, or who have relevant information for our collating efforts are encouraged to contact Dr. Bowden.

ISCTM 7th Annual Scientific Meeting – Negative Symptoms Working Group Dinner – Summary

Monday, March 21st, 2011

Negative Symptoms
Working Group Dinner
21 Feb 2011
Chairs: S Marder, D Daniel

1.  To establish persistent and predominant negative symptoms a  4-6 week prospective lead-in is recommended, along with a retrospective look back period. The latter is difficult to document in a multicenter industry sponsored clinical trial setting.

2.   Requiring a minimum level of negative symptoms for inclusion could invite baseline inflation by investigators , but is necessary to establish an inclusion criteria of persistent predominant negative symptoms.

3.  To establish a minimum inclusion score of negative symptoms for entry a CGI-negative symptoms score of moderate or greater and/ or an average score of moderate or greater on the PANSS negative factor would be acceptable. .   

4.  The group did not establish a consensus on whether a maximum limit of positive symptoms should be an inclusion criteria for negative symptom trials.   The group agreed that requiring “predominant” negative symptoms may be too limiting.  “Prominent” may be better.  A CGI-positive symptom score of mild or less and/or  a PANSS positive subscale average score of mild or less were mentioned as measures that could be useful in this regards.  Specific positive symptom item scores could also be utilized.

5.  Baseline inflation by investigators may be addressed by : 1) using a different scale for inclusion criteria vs. primary outcome; 2) variable length placebo lead- in prior to randomization; 3) surveillance of ratings and regular feedback to raters;  (4) use of remote raters who won’t be biased toward inclusion

6.  What is the threshold for “clinically meaningful” change? For registration trials a global measure should be combined with an effect size of at least .5 on either the PANSS Marder factor, NSA-16 or SANS.  Among global measures a CGI keyed to negative symptoms is among the acceptable global measures for this purpose.   This combination would also be useful in proof of concept studies, although more flexibility is usually appropriate in a proof of concept study..

7.  A relatively homogenous patient sample is acceptable in proof of concept studies. In contrast,in registration studies a less homogenous  sample that is more likely to generalize is more appropriate.

8.  In selecting a measure of functional improvement in negative symptom studies it is important to avoid a functional scale that reproduces or largely overlaps with the negative symptom scale. The QLS strongly correlates with negative symptom scales but is measuring largely the same thing. The SFS is also redundant to negative symptom scales. The SOFAS and PSP are functional scales that are relatively less redundant to negative symptom scales.  

9.  The CAINS and BNSS are the products of separate but overlapping work groups that grew out of  the  NIMH-MATRICS Consensus Development Conference on Negative Symptoms. They incorporate all 5 currently recognized domains of negative symptoms. They include both anticipatory and consummatory anhedonia, and separate behavior and internal experience. They are designed to primarily rely on information obtained by interview of the patient.  The BNSS is shorter and is available currently for clinical trial use, probably most appropriately as an exploratory variable.  It has been used in relatively few subjects, thus far. The CAINS has been tested in more patients but is undergoing continued revision and field testing and currently has limited availability for clinical trials.     

10.  Data presented by Roche indicates that negative symptoms are a major contributor to psychopathology in about 55% of patients seen in their long-term trials.

11.  Important characteristics of an instrument for measuring negative symptoms include:  valid across countries and cultures;  sensitive to change; simple and short.

ISCTM 7th Annual Scientific Meeting – Suicidal Thinking and Behavior Assessment Working Group Dinner – Summary

Thursday, March 17th, 2011

Suicidal Thinking and Behavior Assessment
Working Group Dinner
21 Feb 2011
Chairs: A Butler, M Stewart

Clinical Trials for Alcohol Dependence: The Alcohol Clinical Trials Initiative (ACTIVE) and Beyond

Wednesday, March 2nd, 2011

Chairs: Nina R. Schooler, PhD; Raymond F. Anton, Jr. MD
 
Speakers include:
 Raymond F. Anton, Jr. MD, Medical University of South Carolina
 Karl Broich, MD, BfArM
 Raye Litten, PhD, National Institute on Alcohol Abuse and Alcoholism
 Roger Meyer, MD, Best Practice Project Management, Inc.
 Joe Palumbo, MD, Johnson & Johnson Pharmaceuticals
 Celia Winchell, MD, US Federal Drug Administration
LINK TOProgram Agenda

ABSTRACT: The American College of Neuropsychopharmacology (ACNP) ACTIVE initiative is in remarkable harmony with the goals of ISCTM. A consortium was developed that included academia and representatives from the FDA, NIAAA, and the pharmaceutical industry to work together to identify and clarify clinical trials methodology to evaluate medications to treat alcohol dependence. 

ACTIVE has been addressing a number of questions that are critical for studies of medications to treat alcohol dependence. These include the drinking outcomes that are meaningful and acceptable to all parties, including practitioners, the definition of a “treatment responder,” how to handle missing data in clinical trials, the role of patient self-reported outcomes, and the need for biological markers of drinking and treatment response. Of particular importance, the group has adopted a data-driven approach to many of these questions and shared data from development programs that have been made available to ACTIVE for analysis such as:  Questions regarding optimal trial length and definition of a primary outcome measure?; What is the optimal outcome measure for such trials and would acceptance of a new measure lead to greater activity in the area.

The goals of the session are:
1.    To inform ISCTM about the work of the ACTIVE consortium
2.    To advance understanding of epidemiology of alcohol dependence
      and clinical trial outcome measures
3.    To develop strategies for incorporating the alcohol
       clinical trial investigators in ISCTM activities
4.    To understand the reasons for limited industry
       activity in alcohol dependence

Beyond Insomnia – Issues in Non-restorative Sleep

Wednesday, March 2nd, 2011

Chairs:  Tom Macek, PharmD, PhD; Tom Roth, PhD

Speakers Include:
 Karl Broich, MD, BfArM
 Russel Katz, MD, US Federal Drug Administration
 Robert Morlock, PhD, YourCareChoice, LLC
 Verne Pitman, PharmD, Pfizer, Inc.
 Tom Roth, PhD, Henry Ford Hospital
LINK TO Program Agenda

ABSTRACT: Non restorative sleep is an impairment in sleep quality and is characterized by a subjective feeling of being unrefreshed upon awakening and may occur in some individuals who experience normal length of sleep time, time to sleep initiation, night-time arousals and other sleep parameters that are not abnormal. This session will provide an overview of the differential diagnosis, phenomenology, epidemiology, and characteristics of non-restorative sleep in the general population.  In addition, the session will explore whether objective electrophysiological markers exist to characterize non-restorative sleep, the association with other chronic diseases, and also subpopulations of patients with NRS.

Meta Analysis: Methods and Applications to Policy

Wednesday, March 2nd, 2011

Chairs:  Andrew C. Leon, PhD,  Virginia Haynes, PhD

Speakers Include:
Michael Borenstein, PhD, Biostat, Inc.
John Davis, MD, University of Illinois
Joel Greenhouse, PhD, Carnegie Mellon University
Virginia Haynes, PhD, Eli Lilly and Company
Andrew C. Leon, PhD, Weill Cornell Medical College
Rhonda Robinson-Beale, MD, United Behavioral Health
John Seaman, PhD, Baylor University
LINK TOProgram Agenda

ABSTRACT: Meta-analysis is a broad term used in clinical research to describe pooled analyses as well as merging information from multiple clinical trials. This session will provide an overview of the frequentist and Bayesian approaches to meta-analysis as well as the roles and limitations of meta-analysis. Extensions and alternatives to meta-analysis will be presented using CNS examples. Implications and importance of meta-analysis for policy-makers will be discussed.