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Session Summary: 2010 6th Annual Scientific Meeting – Clinical Trials in the Prodromal Phase of Alzheimer’s Disease – Methodological Challenges and Clinical Outcomes
Monday, March 29th, 2010This session was chaired by George Garibaldi from F. Hoffmann LaRoche and Michael Davidson from the Department of Psychiatry, Sheba Medical Center, Israel.
The focus of this session was to characterize both the validity and utility of clinical trials designed to assess treatments for prodromal Alzheimer’s disease (AD). It is widely held that early intervention in neurodegenerative diseases prior to the emergence of overt clinical symptoms is desirable and should result in a greater impact on disease progression. However, assessing the therapeutic index in a prodromal phase of these diseases is often beset by a number of methodological challenges. One set of difficulties rests in sensitively and specifically identifying subjects at risk for these conditions in order for clinical study evaluation. Also, because these neurodegenerative diseases are often slow to progress to their ultimate outcome, biomarkers must be identified that predict long term results. Using AD as a model, this session focused on providing recent approaches to identifying prodromal AD patients and the use of biomarkers to track those changes in a clinical trial setting. Clinical, industry and regulatory input was provided regarding tactical and procedural issues regarding the implementation of these approaches in future clinical trials.
Michael Davidson, MD adeptly set the stage for the discussion by describing the challenges faced when identifying and providing prodromal disease treatments. Dr. Davidson began by gave several examples of both short and long interval prodromes in CNS that preceded the onset of syndromic events by days, weeks, months or even years as a means to defining the salient features of a prodrome. Whether the most important feature is the time lag between the prodrome and event it heralds; the inevitably of the event; the sensitivity/specificity of the prodrome; the symptomatic resemblance to the full blown illness; or the pathophsyiological relationship (causal path between the prodrome and the disease) appears to be vary widely according to the definition being applied. Dr. Davison went on to define the utility of non-surrogate and surrogate biomarkers in prevention citing well established examples from cardiovascular medicine as well as their use and misuse. Distinguishing AD prodrome from biomarkers is equally subjective. Interestingly, inferences made about prodromes can be made from interpreting the failure of observation trial in prospective settings. Noting that almost every disease is gradual what is really desired is to find a particular population that can benefit from intervention and any arguments on semantic may be irrelevant.
The keynote address was delivered by John C. Morris, MD who provided an overview of the AD prodrome and implications for patient selection and study design. Dr, Morris posited that prodromal AD typically is distinguished from DAT by a “failure to meet the threshold for dementia”, implying a dichotomous condition of “no dementia” vs. “dementia”. However, AD is marked by continuous neuronal deterioration and applying a threshold to determine clinical status is therefore arbitrary, ambiguous, and variably applied. As dementia requires functional impairment caused by cognitive loss (assessed by intra-individual decline, using one’s previously attained level of function as the control) this impairment” depends upon adequacy of information and the clinician’s “threshold”. However, impairment in MCI/CIND is typically determined by inter-individual comparison of cognitive test performance (often for episodic memory) rather than a decline from previously attained levels leading to both false positive and negative inclusion of patients. The focus on memory performance ignores early manifestations of AD as it has been shown that initial change is in visuospatial abilities (speeded performance) may predate memory difficulties in some persons. Further, etiology is not fully considered as MCI/CIND encompasses non-AD dementias, reversible causes of cognitive impairment, and even some low-performing normal individuals. Normative control groups may contain some patients with preclinical AD and relative performance of prodromal samples is misleading stemming from cutoff levels that are too lenient. Thus, the inclusion of people in the preclinical stage of AD in supposedly “normal” samples overestimates the decline in cognitive ability that is attributed solely to age. Dr. Morris also noted that preclinical AD is characterized by cognitive decline marked by inflection points two to three years prior to diagnosis and this sharp decline is often in included in normative data.
Dr. Morris suggested that in an effort to reduce this heterogeneity informant-based clinical assessments are needed to capture intraindividual decline resulting in functional impairment. Additionally, using a cognitive cut off to define “impairment” and also incorporate biomarkers to establish likelihood that AD is causative (such as that by Dubois) can also be helpful. Numerous examples of biomarkers in cognitively normal people were provided and in general conclusions from this data suggested that: cerebral Aβ42 deposition is the pathobiological phenotype of APOE4 and increases as a function of age in preclinical AD; Aβ42 changes characterize preclinical AD; while tau abnormalities occur later to mark symptomatic stages; A reduction of CSF Aβ42, and increased CSF tau identify very early symptomatic AD, in some instances prior to sufficient fibrillar Aβ for PIB detection; and nonfibrillar cerebral Aβ deposits (diffuse SPs) and preclinical AD are not benign and both CSF and amyloid imaging Aβ markers in normal elders predict symptomatic AD.
Dr. Morris supported the inclusion of such biomarkers in trials to both support accuracy of AD diagnosis, to enrich the sample, and to confirm the presence of the therapeutic target. Obviously, using biomarkers as surrogates world require validation. However, trials using agents that alter CSF production /clearance may benefit from their use nonetheless. Finally, Dr. Morris proposed a paradigm shift in which AD researchers would move from notions of cure to prevention. In this manner the detection of cognitively normal individuals with preclinical AD would be paramount and intervention to prevent neurodegeneration and symptomatic AD would be the goal. In this shift, biomarkers such as CSF levels of Aβ42 and tau as well as amyloid imaging and are essential to detect preclinical AD (as once dementia occurs Aβ may no longer be the primary driver) .
Following the keynote address Harry Haroutunian, MD offered clues to identifying the prodrome for AD by presenting clinical correlations with various postmortem findings with a strong focus on the effects of age. Dr. Haroutunian emphasized the notion that although researchers have long recognized that age is the most important risk factor for developing AD, we have typically thought about age uniformly, viewed it as a confounding factor in analysis and have only recently begun to conduct systematic evaluations using specific older age cohorts. This is very important as data suggests that the 85+ population is the fastest growing segment of our society and that dementia in the oldest old (>85 or >95) is a stronger predictor of morality than cardiovascular disease or cancer. Further data suggesting the association between age and neuritic plaques and neurofibrillary tangles and their role in cognition was presented by Dr. Haroutunian. In an attempt to determine transcriptional vulnerability Dr. Haroutunian conducted an assessment of RNA expression using Gene-Chips in patients stratified by dementia severity groups and concluded that amount of abnormal RNA expression varied in different brain regions. When evaluating the gene expression profile across fifteen different brain ranges in the young old versus the old-old Dr. Haroutunian reported that only 30% of the abnormally expressed genes are common to both groups suggesting a unique biological basis for dementia for each cohort. This effect was not accounted for by cognitive reserve as defined by educational level. Thus, phenotype appears to matter significantly to the neurobiology of the disease and therefore to therapeutic response. Medical illness, such as obesity, diabetes and hypertension and their treatment are just a few of the phenotypic variables that appear to be affected by age. For example these factors appear to shift from a traditional risk to more protective factors from mid life to late life and those older patients with these risk factors actually have less cerebral pathology (plaques and tangles) than their younger cohorts. In summary, Dr. Haroutunian noted that both age and phenotype are crucial to dementia neurobiology and potentially in therapeutic outcome.
Rachel Schindler, MD presented a summary of the recent developments in biomarkers and how these have changed clinical trials design. Dr. Schindler reviewed the well established challenges to typical to AD clinical trials such as including relatively large numbers of requisite patients, duration, progressive samples, and subjective assessments. The utility of various biomarkers was discussed in a comprehensive review including cutoffs for Aβ42 (at 190 pg/ml) and p-Tau in order to maximize clinical trial screening and enrichment of potential subjects. The utility of combing biomarkers to differentiate AD form FTD, CJD and to predict MCI conversion to AD was also reviewed. Volumetric MRI as a biomarker was also examined in terms of disease state with regional changes appearing to have the best utility in early progression while whole brain changes are somewhat better for progression after the onset to AD, suggesting that volumetric imaging is one of the best biomarker for disease progression. Similarly, hypometabolism in the posterior cingulate cortex was identified as the earliest and most sensitive functional marker for predicting conversion form MCI to AD. Dr. Schindler posited that there is a correlation between cerebral structural/functional imaging and biochemical makers with the degree of cognitive impairment and that many of these changes occur well before the diagnosis of dementia. Therefore, the use of biomarkers aids the conduct of trials in early AD when many therapeutic agents may have their greatest effect. The use of biomarkers in such trials could potentially reduce the sample size needed through identification of subjects, reduce trial duration, demonstrate a mechanism of action, monitor the effect of the intervention and possibly serve as the primary outcome measure in addition to or in place of cognitive and functional measures.
In a continuation of this theme Mark Cantillon, MD presented data specifically on neuroimaging as a biomarker for prodromal treatment providing evidence for both its utility as well as limitations. Dr. Cantillon posited that the five best biomarkers in AD research included both markers of neurodegeneration (CSF tau, FDG-PET and structural MRI), as well as markers of brain abeta deposition (CSF Aβ42 , and PET Aβ imaging). Dr. Cantillon presented evidence on various biomarker performance in the context of clinical trials assessing precision for detecting change, the clinical relevance of findings, and the possible impact on trial design concluding that structural MRI was the best potential candidate for trials of prodromal AD. In the assessment of clinical relevance Dr. Cantillon proposed examining baseline makers’ ability to predict change in cognition and examining how changes in biomarker relate to changes in cognition. Baseline biomarkers may also help to predict conversion form MCI to AD. However, Dr. Cantillon cautioned that multivariate models of time to conversion generally do not provide evidence for biomarker significance when clinical variables are included in the model. When clinical variables are omitted from such models the p values for biomarkers are significant. For example, using FDG PET average metabolic levels on specific regions of interest can be helpful but FDG-PET has shown the greatest utility when examining average metabolic level across all regions of interest. Dr. Cantillon presented evidence for surrogate markers that can potentially replace or be used as secondary endpoints in trials with the most promising markers having relatively better precision than standard performance measures. Although the correlation with cognitive change is moderate at best and there is not enough data to capture treatment effects or to convince health care authorities at this time real value remains when using these biomarkers even when not as surrogate markers. For example, these biomarkers have shown the greatest utility in clinical trials when used for entry criteria to confirm diagnosis, as stratification tools and as covariates with brain atrophy being the most promising.
The final session was conducted by Ravi Anand, MD who provided an industry perspective on clinical trials in prodromal AD reviewing several past trials. Dr. Anand began by presenting various definitions of MCI and prodromal AD emphasizing the pivotal role of a deficit in recall that does not correct itself with cueing. This general definition was used across multiple past industry trials of MCI and may be a key to future definitions of prodromal AD. Dr. Anand acknowledged that the clinical construct of MCI in past trial was not very useful and suggested that the failure of past industry trials was not a function of the rate of conversion (estimated to be anywhere between 5 and 15% depending upon the trial) but more a matter of inappropriate treatment for the symptomatology, an inappropriate set of outcome measures and the enrollment of inappropriate patients who had disease severity that was not virtually unchangeable at the point of intervention. The fact that approximately half of the sample of one such trial meet autopsy criteria and 70% had hippocampal atrophy suggests that the patients had much greater disease severity than originally thought. Other evidence from the PAQUID trial suggested that deficits in the Isaacs Set test, a measure of semantic memory and fluency, were evident more than a decade before the earliest signs of AD while deficits in visual memory and MMSE were not seen until alter. Thus, it may be more useful to think of prodromal AD as the transition between healthy aging and MCI with performance deficits being in a single cognitive domain. It is possible that the only way to reliable elicit such cognitive deficits may be under challenge condition such as high stress. Supporting this diagnosis would be a lack of, rather than a demand for, functional and behavioral deficits as well as biomarkers that would be used mainly to exclude patients (only minimal MRI atrophy would be permitted). Many of these notions were generally supported by panel members who stressed the need for repeated assessments beginning relatively early in a model that relies on within subject ratings to increase sensitivity. It was recommended that slope analyses be used to detect the earliest point of deflection in prodromal AD. Panel and audience members also suggested several technologies to aid serial cognitive assessments and suggested that brain health could be viewed in the same way the blood pressure with every potential patients knowing and tracking their biomarker numbers. Given the changing population trends and accompanying financial burdens, the panel supported the notion of focusing on treatments that would delay the onset of AD even for 1, 3 or 5 years. Similarities between statins and AD biomarkers were noted and there was much discussion concerning the heterogeneity of populations as well as the generalizability of biomarkers from those patients who have familial AD to those who have sporadic AD. Finally, much like cardiovascular health the panel opined that it is likely that some type of treatment “cocktail” will most likely provide the greatest benefit to patients. The panel also agreed that more research would be needed in the identification of research methodologies appropriate for treatment trials at this earlier point of intervention.
Clinical Trials in the Prodromal Phase of Alzheimer’s Disease – Methodological Challenges and Clinical Outcomes Are Addressed at ISCTM Annual Meeting
Monday, March 8th, 2010A half-day session, characterizing the validity and utility of clinical trials designed to assess treatments for prodromal Alzheimer’s Disease (AD), chaired by Michael Davidson, MD, Professor and Chairman of the Department of Psychiatry at Tel Aviv University and George Garibaldi, M.D., Clinical Development, Roche Pharmaceuticals was held on February 24,2010, at the 6th Annual Meeting of the International Society for CNS Clinical Trials and Methodology (ISCTM) in Washington, DC.
A half-day session, characterizing the validity and utility of clinical trials designed to assess treatments for prodromal Alzheimer’s Disease (AD), chaired by Michael Davidson, MD, Professor and Chairman of the Department of Psychiatry at Tel Aviv University and George Garibaldi, M.D., Clinical Development, Roche Pharmaceuticals was held on February 24,2010, at the 6th Annual Meeting of the International Society for CNS Clinical Trials and Methodology (ISCTM) in Washington, DC.
A half-day session, characterizing the validity and utility of clinical trials designed to assess treatments for prodromal Alzheimer’s Disease (AD), chaired by Michael Davidson, MD, Professor and Chairman of the Department of Psychiatry at Tel Aviv University and George Garibaldi, M.D., Clinical Development, Roche Pharmaceuticals was held on February 24,2010, at the 6th Annual Meeting of the International Society for CNS Clinical Trials and Methodology (ISCTM) in Washington, DC.
A half-day session, characterizing the validity and utility of clinical trials designed to assess treatments for prodromal Alzheimer’s Disease (AD), chaired by Michael Davidson, MD, Professor and Chairman of the Department of Psychiatry at Tel Aviv University and George Garibaldi, M.D., Clinical Development, Roche Pharmaceuticals was held on February 24,2010, at the 6th Annual Meeting of the International Society for CNS Clinical Trials and Methodology (ISCTM) in Washington, DC.
A half-day session, characterizing the validity and utility of clinical trials designed to assess treatments for prodromal Alzheimer’s Disease (AD), chaired by Michael Davidson, MD, Professor and Chairman of the Department of Psychiatry at Tel Aviv University and George Garibaldi, M.D., Clinical Development, Roche Pharmaceuticals was held on February 24,2010, at the 6th Annual Meeting of the International Society for CNS Clinical Trials and Methodology (ISCTM) in Washington, DC.
Recent advances into AD pathology and accompanying biomarker technology have suggested that early intervention in neurodegenerative diseases prior to the emergence of overt clinical symptoms is advantageous and should result in a greater impact on disease progression. However, assessing the therapeutic index of a prodromal phase of disease is often beset by a number of methodological challenges which were expertly addressed by an expert panel of clinical, industry and regulatory scientists who provided tactical and procedural advice regarding the implementation of these approaches in future clinical trials of prodromal AD.
This session reviewed the many challenges faced when identifying, testing and providing prodromal disease treatments in terms of the sensitivity/specificity of the prodrome; the causal path between the prodrome and the disease, and the use and misuse of biomarkers. Dr. John Morris, MD, Distinguished Professor of Neurology at Washington University in St. Louis provided an overview of the AD prodrome with implications for patient selection and study design. Dr. Morris stated that “prodromal AD typically is distinguished by a failure to meet threshold for dementia, implying a dichotomous condition of no dementia or dementia. However, AD is marked by continuous neuronal deterioration and applying a threshold to determine clinical status is therefore arbitrary and ambiguous. Current definitions of preclinical AD are typically determined by inter-individual comparisons of cognitive test performance (often episodic memory) rather than a decline from previously attained levels leading to both false positive and negative inclusion of patients”. Dr. Morris promoted the inclusion of biomarkers in trials in order to help support accuracy of diagnosis, to enrich the sample, and to confirm the presence of the therapeutic target.
Dr. Marc Cantillon of Merck Research Laboratories confirmed that biomarkers have shown the greatest utility in clinical trials comes when they “are used for entry criteria to confirm diagnosis, as stratification tools, and as covariates; with the five top biomarkers including both markers of neurodegeneration such as CSF tau, FDG-PET and structural MRI, as well as markers of brain abeta deposition such as CSF Aβ42, and PET Aβ imaging, with brain atrophy being the most promising to date for trial application”.
Industry veteran Dr. Ravi Anand concluded the session by reviewing past trials in Mild Cognitive Impairment (MCI) citing their common failure “not from a low rate of conversion to AD but more a matter of inappropriate treatment for the symptomatology, an inappropriate set of outcome measures and the enrollment of inappropriate patients who had disease severity that was virtually unchangeable at the point of intervention”. Dr. Anand opined that “it may be more useful to think of prodromal AD as the transition between healthy aging and MCI with performance deficits being in a single cognitive domain. Supporting this diagnosis would be a lack of functional and behavioral deficits, as well as biomarkers that would be used mainly to exclude patients”. These notions were supported by panel members including Dr. Michael Davidson who agreed “that the clinical construct of MCI as we know it is probably obsolete and if we are to help future patients a new model is needed – one that relies on within subject measures that are sensitive at the earliest point of deflection in prodromal AD. Given the changing population trends and accompanying financial burdens the benefits of delaying the onset of AD for even for a year or two would be of tremendous value”. Presentations and video of the session are currently being posted for viewing by ISCTM Members, accessible through the ISCTM Library.
The ISCTM (www.isctm.org) was founded in 2004 to gather representatives from academic and clinical specialties, the pharmaceutical industry, and regulatory bodies to exchange ideas about important clinical and public-health challenges, to examine the development of novel treatments for major psychiatric and neuropsychiatric disorders, and to support advances in methods of evaluating such treatments that are scientifically sound, ethical, and feasible. To achieve this mission, ISCTM conducts two scientific meetings per year. The Autumn Scientific meeting will be held October 13-14, 2010 at the Hyatt Regency – Inner Harbor, Baltimore, MD. View Preliminary Agenda (Submitted by H. Riordan)
NIMH, Policy Makers and CNS Research Leaders Speak on the Bridge from Mental Health Research to Policy
Sunday, March 7th, 2010WASHINGTON–(BUSINESS WIRE)–The International Society for CNS Clinical Trials and Methodology (ISCTM) gathered in Washington, D.C. last week to discuss some of the most important issues facing neurology and psychiatry today. As part of the 7th Annual Meeting, during the Research-to-Policy Forum, government and industry researchers debated the impact of national health reform on mental health care. “Understanding the viewpoints of a diverse group of stakeholders is critical for developing a more rational approach to determining how (and how much) the private and public sectors should invest in clinical research,” according to Dr. Ramy Mahmoud, Chief Operating Officer at OptiNose. (Full Release)
Clinical Trials in Prodromal Alzheimer’s Disease: An Industry Perspective
Tuesday, February 2nd, 2010Ravi Anand, M.D., Richard D. Hartman, PhD, Munaf Ali, PhD.
Currently available treatments for patients with Alzheimer’s disease (AD) have not provided substantial and/or long-lasting improvements in cognition, behavior or activities of daily living (ADL). Based on the small magnitude of the benefits accompanying these treatments in patients with established AD, their effect on important outcomes such as quality of life, increased productivity, ability to function independently, time to hospitalization, is of limited clinical, societal, or economic benefit. Experts have estimated that their impact on Quality Adjusted Life Years (QALY) is low, and consequently they are not considered cost-effective.
Many factors may explain the lack of availability of highly effective treatments for patients with AD. These include the limited ability of the five marketed drugs to produce improvement in patients with AD. It is also possible that the stage of the disease in which these agents were tested is too severe to allow for more than palliative, short-lasting, clinically significant benefits. Mild to moderate/severe AD, for which these drugs are approved, represents a stage where there is significant atrophy in various parts of the brain, extensive neuro-degeneration and synaptic loss, highly significant reduction in neurotransmitters, and a loss of high level cognitive skills and at least instrumental activities of daily living. Currently, ongoing studies with immune modulating agents such as monoclonal antibodies, whether directed against beta amyloid (Aβ), or tau protein, or inhibitors of various secretases involved in amyloid processing, all target patients with established AD that have the same brain deterioration as noted above, and are unlikely to produce substantial long-lasting benefits.
Studies in patients with Mild Cognitive Impairment (MCI) with some of these agents have also been unsuccessful in demonstrating treatment benefits. Data from autopsy studies in patients who died during the stage of MCI have indicated that a majority of these patients met pathognomonic criteria for AD, thus demonstrating that patients with MCI are at least at the stage of mild AD, although their clinical signs and symptoms are relatively mild. Based on the long duration and progressive nature of the pathological processes underlying AD, it seems logical to assume that, if treatments are to provide benefits to patients that allow them to maintain their ability to function independently, enjoy a high quality of life, and show significant increases in QALY, cost-effectiveness, and societal benefits, treatment should be started at a stage of AD, which is very early with regard to neuro-degeneration, cognitive/behavioral dysfunction, and preservation of ADLs. This stage, rather than MCI, should be considered as “Prodromal” AD.
There are many challenges in designing clinical trials to test new therapies in patients with “Prodromal” AD, including achievement of a consensus on diagnostic criteria for “Prodromal” AD, development of sensitive and specific diagnostic tools, identification of potential targets for therapeutic intervention, development of new drugs that can delay and/or modify the disease process, and determination of appropriate outcome measures and trial designs to assess the effects of drug therapies on the symptoms and signs of “Prodromal” AD.
The first major hurdle in developing therapies for “Prodromal” AD is obtaining agreement among academia, industry and regulatory agencies on the definition of the syndrome and its existence as a distinct diagnostic entity. Patients with true “Prodromal” AD represent a subset of the population of patients diagnosed with MCI, and are characterized by greater than expected deficits in cognitive function, based on age and education level, that do not interfere with functional abilities. “Prodromal” AD is difficult to diagnose and may precede the development of AD by as much as 10 years. Therefore, diagnostic criteria must be very specific, and the accurate diagnosis of “Prodromal” AD will require a specialized battery of neuropsychological tests(verbal fluency, Free and Cued Selective Reminding Test, free recall, etc. ), as well the use of neuroimaging, such as structural and functional MRI (e.g. hippocampal/ medial temporal lobe atrophy) and PET (e.g. FDG-PET, or PIB uptake) and/or other biomarkers (e.g. CSF levels of Aβ1-42 , or total tau/ Aβ1-42 ratio; neural thread protein; AD7C-NTP in CSF and urine) to ensure that patients have the disease, as well as to distinguish it from other types of MCI. Advances in genomics and new proteome-based plasma biomarkers, together with recognition of risk factors for developing AD, such as age, ApoE ε4 genotype, and PS1/2 mutations, may allow for identification of patients with incipient stages of the disease, as well as individuals at high risk for AD.
Based on the above, the following criteria are proposed for identifying “Prodromal” AD:
· Patient and/or caregiver reported deficit in cognition
· Deficit on a cognitive measure (compared to normal, based on age and education) limited to one cognitive domain
· No functional impairment, based on detailed examination
· No manifest behavioral symptoms
· MRI evidence excludes more than minimal atrophy
· Changes in CSF markers (Aβ1-42, tau/ Aβ1-42 ratio not consistent with AD).
Another key issue in designing drug trials to evaluate treatments for prodromal AD is the choice of outcome measures. The changes in cognitive function over time in these patients may be subtle, thus requiring very sophisticated and sensitive measures in order to have adequate power to distinguish differences between drug-treatment and placebo. As cognition appears to be a valid, sensitive and predictive marker of progression, change in a cognitive measure over time, rather than a paradigm such as ‘time to conversion’ to AD (which has proven to be unreliable and insensitive to change in MCI trials) should be considered as the primary efficacy measure. It is unlikely that benefits in global evaluation, behavior, and ADLs can be shown in these patients, as prodromal AD patients will not experience deficits in these parameters at this stage. Evaluation of specific biomarkers in conjunction with cognitive testing would most likely be required to assess changes over time.
A 2007 survey of the prevalence of AD in the US estimated that there were more than 5 million AD patients; this is likely to increase to7.7 million by 2030 and ~16 million by 2050. The annual cost of AD, including both direct and indirect costs, is likely to be more than $148 billion/year. The impact of effective treatments against AD will be greater in the 4th and 5th decade of life than at age 90. It is estimated that a treatment for prodromal disease that can delay the onset of AD by even 1 year will mean a gain in QALY of 0.52, and reduce the incidence of AD by 210,000 cases per year and annual costs by $19 billion. Assuming 454,000 new cases of AD will be diagnosed in 2010 and 959,000 in 2050, the cost savings, assuming $150,000 per QALY, will be $1.03 trillion. These estimates are based purely on measuring benefits of a delay in onset of disease, and not on altering disease progression. These expected cost savings should stimulate research by academia, government and industry into developing treatments and targeting patients before AD becomes established.
The Current Reality of Outcome Measures in International Clinical Trials: Should We Be Doing Things Differently?
Tuesday, January 19th, 2010This talk will review current practices in implementing outcome measures in international clinical trials, with regards to translation and cultural adaptation. Questions addressed will include: Are the current practices adequate? Do we have data to inform us? Would enhanced methodologies be useful?
(AKalali)
Challenges and Best Practices in Training and Monitoring Measurement of Psychopathology in Linguistically and Culturally Diverse Settings
Tuesday, January 19th, 2010Training data from international clinical trials will be reported with respect to diversity in rater credentials, experience and interview skills. Training data demonstrating cultural diversity in perception of affective, psychotic and negative symptoms will be presented.
Current practices with respect to cultural adaptation, validation and translation of scales and in training, certification and monitoring of their use by raters will be presented and critiqued with respect to validity, reliability and practicality.
(DDaniel)
2009 5th Annual Scientific Meeting – Methodological Issues in Traumatic Brain Injury – Session Summary
Thursday, December 10th, 2009A Plenary Symposium of the International Society for CNS Drug Trials Methodology (ISCTM),
Arlington, VA, 3 March 2009
Chairmen: Tom Macek, PharmD, PhD, Takeda Global Research and Development, Deerfield IL and Alan Faden, MD, Georgetown University Medical Center, Washington, D.C.
Speakers:
Mark Lovell, PhD, University of Pittsburgh Medical Center, Pittsburgh, PA,
Col. Michael S. Jaffee, MD, and Karen Schwab, PhD, Defense and Veterans Brain Injury Center, Washington, D.C.,
Douglas Smith, MD, University of Pennsylvania, Philadelphia, PA,
M. Ross Bullock, MD, PhD, University of Miami, Miami, FL.
Summary
Although mild traumatic brain injury (mTBI) or “concussion” affects over 1 million victims each year in the United States (reference), it is not generally recognized as a major health issue. However, this ‘mild’ form of injury induces persisting neurocognitive and psychiatric dysfunction in many of these patients, exacting an enormous emotional and financial toll on society. The symptoms of post-concussive injury, as measured by the Post-concussion Symptom Scale, include emotional, sleep, somatic, and cognitive disturbances (Pardini, Lovell et al 2004).
Thus far, pharmacological treatments for mTBI are elusive, as well as mechanistic or interventional studies for exploring the pathophysiological consequences that translate from animal to human or human to animal. In understanding mTBI as a distinct consequence of injury, it must also be recognized that there exists tremendous range of symptomatology and situations within the mTBI patient population that contribute to the disparity of these outcomes. Moreover, systematic methods of the study of mTBI may be confounded by additional factors, which, as in the example of military populations, have life-threatening consequences for not only the patient, but also those conducting such investigation. These methodological issues may contribute to the limited therapeutic treatments for this trauma, as well as limited pharmacological or interventional treatments to improve outcome.
On March 5, 2009, a joint meeting was held between the American Society of Experimental NeuroTherapeutics (ASENT) and the International Society of CNS Clinical Trials Methodology to review and discuss the etiological and methodological issues facing this patient population. Both organizations are committed to the advancement and development of improved therapies for CNS disorders, as well as the methodological challenges in the development of these improved therapies. Experts in the nosology, clinical research, and translational medicine were gathered in Arlington, VA for these purposes and identify and discuss areas in which such advances may be made. This session was chaired by Alan Faden, MD (Georgetown University) and Tom Macek, PharmD, PhD (Takeda Global Research and Development). Speakers included Mark Lovell, PhD (University of Pittsburgh Medical Center), Col. Michael S. Jaffee, MD, and Karen Schwab, PhD (Defense and Veterans Brain Injury Center), Douglas Smith, MD (University of Pennsylvania), and M. Ross Bullock, MD, PhD, University of Miami, Miami, FL.
mTBI – A diversity of patient populations
While some similarity of the clinical course of patients suffering from mTBI may be common to patients with mTBI, the diversity of injurious situations that lead to the clinical course of mTBI is highly heterogeneous. The consequence of this diversity is that a universal, systematic approach to the study of mTBI is not currently feasible. Within both civilian and military populations, there are commonalities as well as divergences in clinical course, the situations leading to injury and a multitude of other confounding variables that contribute to the difficulty in studying this heterogeneous population.
In the realm of athletics and sport, mTBI is a common occurrence, particularly in children. In his talk, entitled “mTBI in the Civilian Population: New Frontiers in Diagnosis and Treatment”, Dr. Lovell described the pervasiveness of mTBI in the civilian population. To this, it is estimated that approximately 1 million children per year, in the US, have mTBI, accounting for approximately 10% of all pediatric evaluations. The CDC estimates that 1.6-3.8 million sports-related mTBIs annually.
Sports-related injuries offer a unique opportunity to study the effects of mTBI, in that, there is a unique opportunity to conduct baseline and post-injury assessments, in an at-risk population, as well as the longitudinal course of recovery.
Within athletes, poorer outcome is associated with repetitive injury, younger age, and also female gender. In sports played by both sexes, it was noted that the rate of mTBI is higher in females, than in males and that high school athletes have prolonged time to recovery when compared to college or professional athletes.
Because athletes may face pressure to return to competition prematurely, methods for evaluation of severity of injury and recovery are necessary to objectively assess readiness for athletes to compete.
Like athletes, members of the military also face situations or scenarios that lead to high prevalence of mTBI. Col. Michael Jaffee, MD, presented “Characterization and Study of Acute Military Mild Traumatic Brain Injury in the War-Zone”. The ongoing conflicts in which the United States military is engaged – Operation Iraqi Freedom and Operation Enduring Freedom – have unfortunately shed light on the high prevalence in combat troops. Studies in which troops returning from Iraq or Afghanistan were screened for mTBI, approximately 15- 23% of returning soldiers and 18.5% of veterans at VA medical centers screened positive for mTBI (refs). Ironically, due to improvements in body armor and combat lifesaving techniques, the incidence of mTBI may be relatively higher than in previous conflicts.
Understandably, the theater of battle does not lend itself well to the clinical study of this population, as troops face potential lethal consequences during enemy engagement. Not only the emergent consequences of injury, but the long-term risks of unresolved mTBI in military theater – slower reaction time, decreased concentration, and slowed thinking – may have residual consequences if the soldier is not fully recovered.
To this, the Military Acute Concussion Evaluation (MACE) has been developed for the screening of mTBI as soon as possible after injurious events such as blast, fall, vehicle crash, or impact. The components of the MACE include description of injury, the Standardized Assessment of Concussion (SAC), and brief neurologic and cognitive evaluations.
While tools and instruments have been developed for the acute assessment of mTBI, the methodological challenges to the clinical study are unique. During combat, the mission supersedes all other activities. The injury may occur great distances from study sites. Also, as with athletes, there may be pressures to participate or a general unwillingness to seek treatment. In addition, due to the nature of their activities, the combat soldier is drastically unique from the general population. These men and women may face constant sleep deprivation, hyper-arousal, psychiatric or other physical comorbidities that make direct comparisons to a “control” population virtually impossible.
Like the acute study of mTBI in combat troops, the longitudinal study of mTBI in combat troops is equally challenging. In her talk entitled “Studies of Chronic Problems after Mild TBI in Military Populations: Challenges in the Characterization of Chronic Problems and Design of Treatment Trials”, these methodological challenges were described by Karen Schwabb, PhD.
Returning combat troops may have undetected or misdiagnosed mTBI. The identification and diagnosis of injury in is paramount to adequate treatment and recovery from injury. In one study, 51% of 47 patients seen in a British trauma center with a TBI did not have a diagnosis of TBI recorded (ref). To address the difficulty in identifying mTBI, a post-deployment screening instrument which assesses injury and consequences of injury, which may be suggestive of mTBI. A number of personality, psychiatric, and psychosocial consequences of mTBI contribute to the difficult transition from military theater to recovery.
As most mTBI improve with time, there is very little class I evidence to support different treatment methods or modalities in the returning military population. Therefore, well-controlled, randomized, clinical trials are desperately needed to address these issues.
Clinical trials in this population face the added challenges of perceptions that they are resource intensive, the lengthiness of well-designed studies, challenges in IRB approval in multi-center studies, issues in blinding, as well as financial incentive for sponsors of pharmacotherapy trials in which the perception that such pharmaceutical studies are, in effect, futile. Add to this the more-traditional issues with recruitment, randomization, and the added complexities of multiple deployments, comorbidities and concomitant pharmacotherapy and the complexity becomes even greater. It is, however, in the name of military readiness that such trials are conducted to more effectively treat these patients.
Lost in translation – Human to animal and animal to human
A number of animal models exist to explore potential therapies for the treatment of mTBI. In nonclinical studies, numerous agents with diverse pharmacological properties have been described which predicted potential therapeutic benefit. Unfortunately, in clinical studies of these agents, none have demonstrated the promise in phase 3 trials which observed in either early clinical trials (phase 2) or in nonclinical studies. To this point, many of the models utilized in nonclinical studies may be somewhat too precise to be utilized for accurate prediction of potential therapeutic benefit in a tremendously heterogeneous and variable patient population.
Douglas Smith, MD, described in his talk “mild TBI: Animal to human translation” newer techniques to help explore and understand the pathology associated with mTBI. Dr. Smith described the hypothesis that mTBI may be most accurately described as Diffuse Axonal Injury (DAI), the most important and most common underlying pathology of mTBI. In addition, DAI is difficult to detect and difficult to model. To address the difficulty in modeling mTBI, a porcine gyrenecephalic model of head rotational acceleration has been developed. Unlike other animal models of mTBI, this model results in diffuse axonal injury observed in parallel studies in humans post-injury by diffusion tensor imaging (DTI) fiber tractography (ref). Histopathological changes in pig post-injury confirm regional edema or hemorrhage and surrogate protein markers of brain pathology were identified after mTBI in the serum of both patients and swine. In addition, an in vitro model of axonal stretch injury of cultured neurons is used to explore the biochemical changes associated with insult. Post-injury, these cultured neurons display many of the properties associated with DAI – delayed elasticity, interruption of protein transport, and swelling of axons. At the core of the pathological insult following injury is an acute disruption of sodium channel function. A consequence of injury is damage to the inactivation gate of sodium channels, leading to an acute increase in intracellular sodium. The electrochemical imbalance caused by this increase in sodium and reversal of the sodium-calcium exchanger and activation of voltage-sensitive calcium channels and an increase in calcium influx. The increased intracellular calcium activates proteases such as calpain which target the inactivation gate of the sodium channel. In addition, an acute increase in sodium channel expression is noted post-injury, which may be a compensatory mechanism to restore normal sodium channel function. Models such as these employed by Dr. Smith add to the understanding of the underlying pathological changes post-mTBI and may add greater predictability of potential human therapies utilized in clinical trials.
It is this failure of the translation from animal to human studies that has plagued this area of research, as no treatment has been approved for mTBI. There are, however, a number of examples of clinical studies that have been conducted in TBI or related disorders (eg, stroke), but a multitude of failures – particularly in phase 3 – have been reported in recent years after very promising nonclinical and early clinical results.
M. Ross Bullock, MD, PhD, addressed this difficulty in his talk entitled “How do we optimize neurotrauma trial design: where do we go from here?”. In it, Dr. Bullock described the large number of clinical studies that have been conducted in mTBI and in related disorders such as stroke. Despite promising early results and large investments by both pharmaceutical companies and governmental organizations, the results in late-stage clinical trials have been disappointing. In stroke research, the high degree of failures has resulted in a collaborative effort between industry and academia (Stroke and Industry-Academia Roundtable or STAIR) to specifically identify methodological approaches to improving potential outcomes or optimization of study design to improve chances of success (ref). The outcome of STAIR has been a call for the utilization of sensitive and less variable outcome measures, the development of new methods of analysis of study data, and improvements in homogeneity through the use of novel study designs and more focused patient populations.
In the realm of mTBI, application of staged, strategic clinical development for novel therapies is imperative for improving success. That is, in the development of compounds for treatment of mTBI, it is imperative that the pharmacokinetic parameters of the compound are well characterized and adequately penetrate to CSF to ensure effective delivery to the target organ (brain). In addition, mechanistic studies to better understand the mechanism of action and incorporation of biomarkers into clinical trials are essential to fully elucidate the potential effectiveness of experimental therapies or for effective, strategic decision-making.
Clinical development programs have also suffered from the common pressures to quickly move from phase 2 to phase 3, without fully understanding phase 2 results. In addition, due to the modest nature of magnitude of improvement in TBI and mTBI trials, Dr. Bullock contended that many of these studies may have been adequately powered to detect the true difference between treatments. The need for larger sample sizes (~3000) should be considered to detect these small differences. And, comparable to other CNS disease areas, there are needs to also improve the quality of data reported in clinical trials and there may be a limited number of “quality” research centers to conduct these complicated assessments and evaluations. Lastly, Dr. Bullock called for greater public/private collaborative efforts to expand our understanding of mTBI.
Discussion and Take-home Messages
” mTBI comprises a great unmet medical need in the general population, particularly in specific at-risk groups (such as athletes and military)
” The consequences of mTBI are potentially significant, causing disruptions in a number of emotional, sleep, somatic, and cognitive disturbances
” Difficulties in developing new therapies for treatment of mTBI are confounded by the lack of predictability of animal to human outcomes in this heterogeneous population
” Instruments and measures of greater sensitivity are needed to improve signal detection in clinical trials; novel study designs and alternative methodological approaches should be utilized to improve signal detection
” As with stroke and the STAIR initiative, the collective understanding of mTBI and potential therapies would greatly benefit from a formal partnering between governmental, academic, and pharmaceutical institutions
Translational and Cultural Adaptation of Key Outcome Measures in International CNS Trials
Wednesday, November 11th, 2009Co-chairs: Richard Keefe, PhD; Amir Kalali, MD
The increase in the number of CNS trials outside of North America and Western Europe has required the use of a variety of key outcome measures outside of the cultures in which they were developed. Since culture is a major determinant of the manner in which psychopathology is experienced, reported, and assessed, regional and country-specific patterns of measuring psychopathology are potential confounds in interpretation of clinical trials data. The literature is sparse regarding best practices for validating clinician-rated, patient-reported, and performance-based outcomes in international settings. This session will address the processes for validating and standardizing administration procedures for key CNS outcome measures such as patient-reported outcomes, psychiatric rating scales, cognitive measures and functional outcomes.
Clinical and Regulatory Challenges of Applying Personalized Medicine to Clinical Trials for CNS Diseases Are Addressed at ISCTM Meeting
Wednesday, November 11th, 2009October 16, 2009 09:47 AM Central Time
SAN DIEGO–(BUSINESS WIRE)–A half-day session, on the application of the principals of personalized medicine to the development of improved treatments for central nervous system disorders, chaired by Larry Alphs, MD, PhD, Medical Affairs Johnson and Johnson and George Garibaldi, M.D., Clinical Development, Roche Pharmaceuticals was held on 6 October 2009, at the Autumn Meeting of the International Society for CNS Clinical Trials and Methodology (ISCTM) in San Diego, CA.
Recent advances in medicine, like the sequencing of the human genome, have yielded exciting new tools that promise to help physicians tailor treatments to individuals and their diseases. Dr. Alphs stated, “Personalized medicine represents the future of medicine around the world. This approach has revolutionary implications for industry sponsors of trials, the regulatory approval system and clinical practice.” At this session clinicians, statisticians and leaders from the pharmaceutical industry discussed the formidable challenges that must be overcome to realize the full potential of personalized medicine. This session reviewed some of the trial design and statistical approaches that might be adopted to address the particular challenges presented by a personalized medicine. Population-based and individual-based approaches to drug development were compared. Selection of suitable indications, study questions, study populations, and endpoints were identified as key areas for consideration when designing clinical trials with a “personalized medicine” goal. Dr. Nicholas Schork, Director of Research, Scripps Genomic Medicine Program, reviewed several statistical approaches that address the special challenges of personalized medicine trial designs. Dr. Steven Potkin, University of California, Irvine, presented his view of the implications of personalized medicine and how clinical practice may look in the future.
The ISCTM (www.isctm.org) was founded in 2004 to gather representatives from academic and clinical specialties, the pharmaceutical industry, and regulatory bodies to exchange ideas about important clinical and public-health challenges; to examine the development of novel treatments for major psychiatric and neuropsychiatric disorders; and to support advances in methods of evaluating such treatments that are scientifically sound, ethical, and feasible. To achieve this mission, ISCTM conducts two scientific meetings per year. The 6th Annual Scientific Meeting (including the National Mental Health Research-to-Policy Forum) will be held 22-24 February 2010, at The Fairmont, Washington D.C.
Contacts
ISCTM
Carlotta McKee, 615-383-7688
Executive Director
isctm@isctm.org
Baldessarini and Vieta Head Discussions on Improved Treatments for Bipolar Depression During ISCTM 5th Annual Meeting
Monday, November 9th, 2009March 13, 2009 10:42 AM Central Time
WASHINGTON–(BUSINESS WIRE)–A half-day symposium, chaired by Ross J. Baldessarini, MD, Harvard Medical School and Eduard Vieta, M.D., Ph.D., University of Barcelona, on development of improved treatments for bipolar depression was held on March 3, 2009, at the Annual Meeting of the International Society for CNS Clinical Trials and Methodology (ISCTM) in Arlington, VA. Other speakers were Joseph Calabrese, M.D., Case-Western University and Mauricio Tohen, M.D., Dr.P.H., University of Texas Health Science Center at San Antonio. Commentary and discussion were led by Charles Bowden, M.D., also of the University of Texas at San Antonio.
Interest in bipolar (manic-depressive) forms of depressive illness is growing greatly, along with recognition that standard treatments for unipolar major depressive disorder are much less effective for the short-term treatment of bipolar depression, and provide very limited protection against recurrences of depressions, compared to adult unipolar depressive disorders, as well as having substantial risk of inducing mania or other excited states. Patients with bipolar depression also have high rates of co-morbid abuse or alcohol or drugs as well as disability, and very high risk of suicide. Current treatment options include mood-stabilizing agents, notably lithium and certain anticonvulsants, and growing use of certain modern antipsychotic drugs originally developed to treat schizophrenia. Such treatments are sometimes used in complex combinations that often include antidepressants despite their limited efficacy. Since available treatments are less than ideal for this complex and rapidly changeable disorder, the symposium addressed options for improved treatments and novel methods for testing them. Further information regarding this session and others is available on the Society website.
The ISCTM (www.isctm.org) was founded in 2004 to gather representatives of academic and clinical specialties, the pharmaceutical industry, and regulatory bodies to exchange ideas about important clinical and public-health challenges, to examine the development of novel treatments for major psychiatric and neuropsychiatric disorders, and to support advances in methods of evaluating them that are scientifically sound, ethical, and feasible.
Contacts
ISCTM
Carlotta McKee, 615-383-7688
Executive Director