2012 Autumn Conference – Concurrent Workshop Sessions
WS1: Adaptive Design Workshop
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.
WS2: Integrated Imaging and Genetic Biomarkers in Schizophrenia Workshop
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.
WS3: Options and Methods to Improve Cognitive Assessment in Clinical Trials of AD and Its Precursors
Co-chairs: Holly Posner, MD; Phil Harvey, PhD
Objectives: Understand the challenges in assessment of cognitive enhancement studies in AD and its precursors. Critically evaluate whether sophisticated statistical techniques are adequate to overcome psychometric challenges in existing instruments. Propose alternatives in the event that it appears as if current data sets cannot be salvaged. Evaluate new approaches to assessing outcome using new performance-based strategies.
Background: The Alzheimer’s Disease Assessment Scale (ADAS-cog) is a composite of several neuropsychological tests and is the de facto cognitive outcome standard in AD trials. This scale was rationally derived on the basis of knowledge and measurement techniques that are now close to 30 years old and many of the items lack sensitivity to a broad range of impairments in the AD spectrum. Thus, the instrument typically generates data that is insensitive to impairment in milder cases and hence is handicapped in its ability to detect changes.
Multiple pharmaceutical companies have re-analyzed ADAS-cog and other AD/ MCI/ Prodromal AD endpoints in an effort to improve the sensitivity of the outcome measure to detect improvement from a pharmaceutical or biologic intervention. Some companies have used purely statistical methods and others have also used psychometric analysis, like IRT. Most have also attempted to combine multiple outcomes measures, such as MMSE, CDR, and other scales along with ADAS-Cog data. A sampling of these efforts will be presented.
There is an understandable sense of urgency regarding solutions to the low sensitivity issue and an understandable reluctance to wait for alternative instrumentation to be developed. Since very large and expensive drug development decisions can rest on the quality of outcomes assessments, key stakeholders require a thorough understanding of whether statistical techniques can overcome the intrinsic limitations of existing assessment methods. At the same time, if statistics cannot resurrect data collected with older methods, then new strategies must be developed or alternative regulatory approaches will be needed. Critical evaluation of the competing strategies of “charge forward now” vs. “develop something that works” is required. Further there are recent developments in co-primary assessments in other conditions, such as schizophrenia, that have been applied with considerable success in mildly impaired cases.
Potential deliverable: we plan on producing a white paper, starting out by laying out the issues:
· Questionable sensitivity
· Possible inadequate coverage
· Urgent need to assess less impaired patients
· The tension of the need to run trials vs. the need to have an outcome measure that works.
This would include a review of the publicly available information on salvaging ADAS-cog data with statistics. It would also outline previous efforts at consensus-based outcomes development, including evaluation of the time-line for this. Finally, the white paper could comment on the regulatory perspective and whether some thinking, like we have seen in schizophrenia, on performance based measures of everyday functioning could be a substitute for current cognitive measures supplemented by clinical judgments and informant reports.
WS4: Medication Development for Stimulant Dependence Workshop
Co-Chairs: Thomas Kosten, MD; Joseph Palumbo, MD
Stimulant dependence (cocaine and methamphetamine) has no FDA approved pharmacotherapy, in spite of development of these medications for over 25 years. The behavioral pharmacology of this disorder provides excellent animal models, but potential medications evolved from these models have been clinically disappointing, as reviewed by Dr. Koob. Many of these medications have been taken into human laboratory studies to evaluate potential medical toxicity from interactions with abused stimulants and to assess surrogate measures such as craving, euphoria, adverse subjective effects, and behavioral responses, as reviewed by Dr. Newton. These behavioral responses include selecting money or other reinforcers rather than the stimulant while under the influence of potential treatment agents. Several agents have show good safety and potential efficicay including disulfiram, bupropion, modafinil, and a cocaine vaccine. Outpatient clinical trials have confirmed some of these medications as effective in phase 2 single site and multisite randomized, placebo controlled trials, but none has progressed to a phase 3 NDA study, as reviewed by Dr. Kosten. Pharmacogenetics involving the adrenergic and dopaminergic systems is showing some promise for increasing the efficacy of these medications by selecting appropriate candidates for optimal efficacy. The lack of industry support for moving on to NDA studies involves many factors including an unclear FDA pathway to approval without clearly defined outcome guidelines. The planned workshop and ongoing study group will work with NIDA and the FDA to define such guidelines for NDA approval studies in order to facilitate industry participation. Dr. Palumbo will review these opportunities for industry collaborations with academia and NIH and FDA in getting approved medications for stimulant addictions.
WS5: Negative Symptoms Workshop
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.
WS6: Precision Medicine in CNS Clinical Trials Workshop
Co-Chairs: Douglas E. Feltner, MD; Aidan Power, MD
Precision medicines target treatment to a diseased population using a specifc genetic or biologic marker that can be assessed with a diagnostic test. Precision medicine (also known as personalized or stratified medicine) has become a standard approach to the development of new anti-cancer therapeutics. The adoption of precision medicine approaches in neuroscience therapeutics has lagged that of oncology and other therapy areas.
In response to the increasing number of precision medicines being developed, regulatory agencies have recently drafted several guidances related to the qualification and use of biomarkers in clinical trials. These include the recent FDA guidance on drug development tools, ICH guidance on the format of genomic biomarker qualification submissions, FDA standards for clinical trial imaging endpoints, FDA guidance on clinical pharmacogenomics, and FDA guidance on in vitro companion diagnostic devices.
This workshop will seek to identify the opportunities and barriers for developing precision medicines in neuroscience indications. Alzheimer’s disease, schizophrenia, and major depressive disorder will be used as examples to highlight the issues. Both scientific and practical opportunities and challenges will be addressed, including state of the science, sponsor organizational challenges/opportunities, regulatory interactions, and payor and implementation opportunities/challenges. A second goal of this workshop will be to identify those individuals interested in advancing precision medicines for neuroscience indications and assessing whether a precision medicine workgroup should be formed to develop precision medicine expertise and knowledge within ISCTM, and to advance the goal of developing methods for the evaluation of precision medicines in neuroscience clinical trials.
WS7: Psycho-Social Treatment Platforms in Psychopharmacology Workshop
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.
WS8: Approaches to Improve Signal Detection in Studies Comparing Drug and Placebo Workshop
Chair: Amir Kalali, MD
Previous work by participants in this workshop has identified four areas of focus: Fit for purpose design, sponsor engagement, data sharing, and patient selection. This session will focus on developing strategies to address these issues as well as continue development of manuscript.
