The role of regulatory drug submission evaluators in Canada is to critically assess both the data submitted and the sponsor's interpretation of the data in order to reach an evidence-, and context- based recommendation as to the potential benefits and potential harms (i.e., risks) associated with taking the drug under the proposed conditions of use. The purpose of this document is to outline the regulatory framework in which this assessment occurs, including: defining what “authorization to market a drug in Canada” means, in terms of the role of the sponsor, the responsibility of Health Canada in applying the Food and Drugs Act prior to and after marketing authorization, and the distinction between regulatory authorization versus physician authorization; highlighting organizational, process and legal factors within Health Canada related to authorization of clinical trials and authorization to market a drug; considerations during the review process, such as regulatory and scientific issues related to the drug, patient populations and trial designs; application of international guidelines, and decisions from other jurisdictions; regulatory realities regarding drug authorization, including the requirement for wording in the Product Monograph to accurately reflect the information currently available on the safe and effective use of a drug, and that hypothesis-confirming studies are essential to regulatory endorsement; current issues related to the review of therapies for dementia, such as assessing preventative treatments, and therapies that have symptomatic versus disease-modifying effects, statistical issues regarding missing data, and trial design issues.

In the past two decades there has been a tremendous effort among clinicians and searchers to improve the diagnostic criteria of the dementias on the basis of the differential neurological and neuropsychological profiles. This was an obligatory requirement for clinical trials and the development of treatments. Over the years it became rapidly evident that the cohorts of patients in studies had some degree of heterogeneity, making it difficult to interpret the results of some studies, particularly in the vascular dementias and the mild cognitive impairment (MCI) group. For example, many sub-types of the vascular group were included in clinical trials, such as the cortical strokes, the lacunar states and the diffuse white matter disease cases, and some of the patients might have had also mixed pathology. In addition, the standard DSM IV criteria for dementia no longer represent our present knowledge of the clinical profile of some of the dementias such as vascular dementia (VaD) and fronto-temporal dementia where the memory impairment is not necessarily the first requirement. To improve the validity of clinical trials and eventually help developing more appropriate treatments, we revised the present diagnostic criteria and made recommendations for some changes in the context of the 2nd Canadian Conference on the Development of Antidementia Therapies, held in 2004 and reviewed in the light of the recent literature as of early 2006. It is expected that in the near future, these dementia criteria for clinical trials will have to be revised again in order to include specific subtypes of the dementias as well as biomarkers, structural and functional imaging.

A great deal of progress has been made in the management of Alzheimer's disease and other dementias over the past 25 years. Much remains to be achieved, however. This article discusses some of the issues surrounding study design. In the absence of an accepted biological marker of progression, it is unlikely that a novel study design, such as randomized start or withdrawal, in itself could provide convincing evidence of disease modification. Biological markers will also be crucial in the development of therapies aimed at specific processes, and of immunotherapies.

The safety and efficacy of current symptomatic drugs for AD was established using parallel groups taking different doses of active drugs vs placebo over three to twelve months, whereas drugs with potential stabilizing/disease modifying effects are being tested by adding new compounds or placebo to standard symptomatic drugs over 12 to 18 months. Delaying progression to disease milestones may offer additional validity to these studies. It is unclear if biological and neuroimaging markers will add to the clinical evidence.

In the era of chronic disease, we are challenged to find therapies that provide symptomatic relief and ideally, alter the course of the underlying disease. In Alzheimer's disease (AD), these issues are complicated by the disease itself, which affects the subject's decision-making capacity for participation in the research. According to established ethical guidelines it is clear that individuals with impaired capacity may participate in research and their risk should be no greater than that which the individual would have in day to day activities with anticipation of benefits within that realm. Decision making processes are complex and involve proxies who themselves have biases about their loved one and the potential for participating in the research. Newer disease-modifying approaches such as immunotherapy have potential for affecting the course of the underlying disease but with greater risk of more significant side effects. Ideally the health care of the subjects is not disadvantaged by research participation. At the same time, trials of potentially riskier therapy are relevant in subjects with the disease. Research for subjects with AD must have appropriate safeguards in place to enable effective progress in innovative therapy for a vulnerable, often elderly population. Recommendations are made which could further our capacity to undertake ethical research in the AD population.

Clinical trials in persons with dementia bring into focus the ethical dilemmas frequently confronting the clinician-scientist. Despite the existence of various ethical guidelines, most with common underlying principles, few are specific to dementia. A particular difficulty is finding a balance between respect for the autonomy of the individual and the protection of vulnerable persons, while at the same time defining an acceptable risk/benefit ratio for the study. The availability of symptomatic treatments for Alzheimer's disease also now make it difficult to argue that withholding treatment from those in the placebo arm of a clinical trial fulfills one's duty to provide best care. Those conducting clinical trials must be knowledgeable about existing legislation and ethical guidelines in order to justify to themselves and others, the design of clinical trials and their risks. They must be prepared to educate patients and family members about dementia and research, determine each potential subject's competence to consent, and ensure that decisions about participation are in accordance with the best interests of the subject. Ethical conduct of clinical trials of new antidementia therapies will require that everyone involved understands the values and beliefs that guide their decision-making and the potentially conflicting roles facing the clinician-scientist.

Until recently, the gold standard for assessing the efficacy and effectiveness of new medications has been the placebocontrol randomized clinical trial (RCT). However, there are serious ethical concerns about placing patients on a placebo when effective treatments exist. Further, if a new agent is tested only against a placebo, there is no guarantee that it is more effective, or even as effective, as an existing agent. For these and other reasons, ethicists and regulatory bodies have said that, under these circumstances, new drugs should be tested against an active agent. There are three types of such trials: superiority, equivalence, and non-inferiority. In superiority trials, the goal is to establish that the new drug is better (i.e., more effective, or with a more benign side-effect profile) than the standard. Because such trials require much larger sample sizes than placebo-control studies, and are rarely required to bring a drug onto market, they are rarely done. In equivalence trials, the aim is to show that the new and standard agents have similar degrees of effectiveness or adverse events. Due to sample size requirements, most studies of new drugs are non-inferiority trials, in which it is sufficient to demonstrate that the new drug is not significantly worse than the existing ones. However, there are methodological concerns with equivalence and non-inferiority trials, including (a) an inability to determine if the drugs were equally good or equally bad; (b) poorly executed trials with low power can be mistaken for “proving” equivalence or non-inferiority; (c) the equivalence interval is arbitrary; (d) successive non-inferiority trials may lead to a gradual reduction in effectiveness; and (e) often larger trials are necessary. The paper also discusses “add on trials.” It is recommended that, even when existing drugs exist, trials should consist of at least three arms, one of which is a placebo. This paper briefly considers the ethics of placebo, and conditions are stated under which such studies can be conducted.

The Cognitive section of the Alzheimer's Disease Assessment Scale (ADAS-Cog) remains the most widely used cognitive measure in dementia trials although it does not assess attention, executive function, or agnosia. Designed for use in Alzheimer's disease (AD), it may not be ideal in assessing patients with other diagnoses. The ADAS-Cog differentiates between AD patients, patients with Mild Cognitive Impairment, and normal controls. It has been used in trials of drugs for vascular and mixed dementia and dementia with Lewy bodies. It is not clear that the ADAS-Cog is adequate for assessing cognition in frontotemporal dementia. Well-validated aphasia batteries, such as the Western Aphasia Battery, can be used to assess language. Brief tests of frontal function such as the Frontal Assessment Battery or the Executive Interview might be useful additions in frontotemporal dementia trials. The most widely used assessment tool for patients with advanced dementia is the Severe Impairment Battery. The domains tested are analogous to those assessed by the ADAS-Cog. The Mini-Mental State Exam and the Modified Mini-Mental State Examination are useful in stratifying patients for trial entry. Cognitive measures better tailored to the diseases in question are needed for non-Alzheimer dementias.

Functional assessment refers to the evaluation of performance in basic activities of daily living, instrumental activities of daily living, professional duties, and hobbies. This assessment is particularly relevant in the evaluation of cognitive impairment. In fact, functional decline represents a core feature of dementia according to the DSM-IV criteria. Clinically, functional deterioration represents a diagnostic marker, can be used to chart the course of the disease, and as a prognostic marker as it contributes significantly to caregiver burden and institutionalization. For all these reasons, functional assessment has been widely used as an outcome measure in intervention trials of Alzheimer disease (AD). Appropriate function assessment scales have been developed for use in clinical trials of AD. Studies have shown that functional decline benefits from pharmacological interventions in AD and some other cognitive syndromes. This benefit translates into a stabilization ranging between 6 to 12 months compared to a gradual deterioration in the placebo group. There is rarely reversibility for IADL's lost. There are no functional scales specifically designed for assessment of subjects with non-AD cognitive impairment. Scales specifically developed for Mild Cognitive Impairment and other dementias are needed.

The use of judgment-based global measures of clinical treatment effects has a long history in the regulatory approval of drugs for the treatment of dementia. This paper reviews current use of these measures, noting several practical difficulties with their implementation. Importantly, global measures have usually yielded general estimates of drug effects similar to psychometric test batteries, even though correlations between global and psychometric measures at the individual patient level is modest. Like psychometric tests, global measures can tell us that some clinically detectable effect is present but often yield only limited evidence about what those effects might be. Steps should be taken to improve the specificity of treatment effect description and to incorporate patient/caregiver preferences in global measures about disease treatment in dementia.

There is a growing consensus that quality of life (QOL) is an important outcome for assessing the effectiveness of interventions for dementia, but there is no agreement about how to best measure it. Various approaches to QOL assessment have been employed to measure the QOL of persons with dementia, including patient self-report, caregiver proxy report and observational assessment by trained observers. Furthermore, several dementia-specific measures of QOL have been developed, and several generic measures of QOL have been used to assess QOL in dementia. However, to date, QOL has rarely been included as an outcome measure in clinical trials of pharmacotherapy for dementia. This manuscript reviews the current state of knowledge about QOL assessment in dementia.

This new section to the guidelines was added due to the recognition that clinical milestones are useful indices of the progression of dementia in patients with Alzheimer's disease and could help in the development of stage-specific targeted therapy. This review specifically looks at clinical milestones that could be used in clinical trials, such as global function, function, behaviour, caregiver burden, and quality of life milestones. It also addresses the possible use of biological and surrogate markers for use as milestones - which may eventually replace clinical milestones. It concludes that current definitions of dementia must be broadened beyond cognition alone to include some of the domains listed.

Neuropsychiatric symptoms (mood, psychotic, and behavioural) are very common in dementia and do not necessarily correlate well with other measures of cognition. However, these symptoms are of great importance, as they are a major source of excess disability, patient distress and caregiver burden and have great impact on the level of care required, and the associated costs. This paper is a review of the most useful outcome measures for behaviour and mood symptoms. Investigators who require a comprehensive instrument to measure neuropsychiatric symptoms in studies of patients with dementia should consider using the Neuropsychiatric Inventory (NPI), the Behavior Rating Scale for Dementia of the Consortium to Establish a Registry for Alzheimer's Disease (CERADBRSD) or, possibly, the Behavioral Pathology in Alzheimer's Disease Scale (BEHAVE-AD). The Cornell Scale for Depression in Dementia and the Dementia Mood Assessment Scale (DMAS) are recommended for evaluating depressive symptoms and the Cohen-Mansfield Agitation Inventory (CMAI) is very useful for evaluating the full range of agitation symptoms.

Biomarkers are required to improve our diagnostic sensitivity and specificity and to monitor the biological activity of the Alzheimer’s disease (AD) in terms of the burden of neural involvement and the tempo of disease progression. Biomarkers will initially supplement our more traditional neuropsychological and imaging markers but may eventually evolve into useful surrogate endpoints in AD research. These markers may also provide important mechanistic clues to the pharmacological action of anti-dementia compounds. At this point, the combination of elevated cerebrospinal fluid phosphorylated TAU (CSF p-TAU) proteins and low CSF A²1-42 are the only biomarkers with the sensitivity and specificity to serve as useful diagnostic biomarkers capable of distinguishing AD from other dementias in the early stages. Advances in non CSF tests is urgently required. Markers assessing the progression of disease do not necessarily require the same high disease specificity as diagnostic markers, but need to be sensitive to changes in disease state. At present, candidate markers fall under four main biological rationales: 1. Specific markers of AD neuropathology; 2. Non-specific markers of neural degeneration; 3. Markers of oxidative stress; 4. Markers of neural inflammation. It is foreseeable that a panel of such markers might prove advantageous. It will be important to develop “non-invasive “ markers utilizing readily obtainable tissue samples such as serum or urine to monitor disease progression (or hopefully regression). Repeated sampling would allow for comparison with traditional neuropsychological and imaging measures. The assays themselves will need to be reproducible, reliable and relatively inexpensive. Unfortunately, these biomarkers are in the formative stages of testing and results at present are inconclusive. To facilitate biomarker development in the future it would be highly advantageous to begin to collect and store biological specimens as an adjunct to current research in AD.

There are five potential major roles for neuroimaging with respect to dementia; 1) as a cognitive neuroscience research tool, 2) for prediction of which normal or slightly impaired individuals will develop dementia and over what time frame, 3) for early diagnosis of Alzheimer's disease (AD) in demented individuals, (sensitivity) and separation of AD from other forms of dementia (specificity), 4) for monitoring of disease progression, and 5) for monitoring response to therapies. Focusing on the last role, no single imaging approach is yet ideal, as all trade-off speed, cost, and accuracy. Functional imaging (SPECT and PET) is best suited to tracking symptomatic therapy response, and anatomic (MRI volumetric) imaging or amyloid PET are more suited to reflect dementia modulation studies. The potential for imaging with respect to pharmacological studies of dementia - to provide surrogate markers for drug studies, to improve diagnosis, to speed evaluation of outcomes, and to decrease sample sizes - is huge. At the present time, however, no single measure has sufficient proven reliability, replicability, or robustness, to replace clinical primary outcome measures.

Prevention in Alzheimer's disease and other dementias (AD/dementia) is defined on the basis of clinical states and their expressed symptoms. Primary prevention refers to delaying the development of the full-blown state of clinically expressed disease in normal individuals. Current primary prevention research is driven by evidence of AD/dementia protective factors that have emerged from epidemiological studies. The first randomized controlled trials (RCTs) of primary AD/dementia prevention have been designed to test the efficacy and safety of NSAIDs, hormonal therapy, antihypertensive drugs and antioxidants. The experience of these trials has indicated safety concerns as a key issue and highlighted significant design challenges in this type of research. These trials have required large sample sizes and unsustainable costs. There should be consideration given in future trials to enriching study samples with risk factors to increase progression rates to AD/dementia. Innovative strategies will also be needed to recruit and retain subjects given the long follow-up periods, modest perceived benefit and the potential for the risk-benefit ratio to change during the trial. It is foreseeable that regulatory authorities will be presented with primary prevention RCTs for approval and labelling, and that criteria to evaluate such evidence still need to be developed.

The status of Mild Cognitive Impairment (MCI) as a valid construct is controversial. The term encompasses people with heterogeneous clinical profiles, and invites sub-classifications that still require validation. Still, much evidence suggests that, properly selected, many people with MCI - especially Amnestic MCI - are at a high risk of dementia. This paper considers the validity of the construct of MCI as a high-risk state for progression and a target for treatment. We conclude that the status of MCI as an entity remains controversial. On the one hand, it can be argued that the careful section of cases at high risk of developing dementia means that it is a valid target, with the goal being the prevention of dementia. Advocates of this view see a linear progression that they are trying to arrest, but studies have yet to show that this can be done. On the other hand, it can be argued that the patients who progressed did not develop dementia: they actually had a very early form of it. By this view, people without the progressive form will be needlessly exposed to antidementia drugs, and the others should be treated anyway. Why some people progress and others do not is not clear, but the variable rates of progression - between clinic-based and population-based samples and between very similar clinical trials with slightly different inclusion criteria - suggests that MCI is a heterogeneous entity. The phenomenon of slowing or non-progression itself should be investigated, and such investigations likely should extend to people now classified as having mild dementia.

Over the last two decades, numerous studies have been conducted on subjects with mild to moderate Alzheimer's disease. The objective of this paper was to review concerns raised in the literature about the design and methodology of these clinical trials and to make recommendations to deal with the limitations identified. Concerns raised in the literature include the following: undue focus on statistical rather than clinical significance; the need for further pharmacoeconomic evaluations; the nonrepresentativeness of the study populations; perceived inadequacies in the direct-comparison studies conducted to date; the limitations of open-label extension studies; the inability of standard psychometric tools to document all the relevant treatment effects; the ethics of placebo-controlled trials; and, problems caused by the actions of the regulatory authorities. Recommendations are made to deal with the issues raised.

Moderate to severe Alzheimer's disease (AD) is characterized by increasing cognitive, functional, and behavioural dysfunction that results in increased caregiver burden and, eventually, complete dependence. Despite its significance as a societal health problem, there are few treatment trials of cognitive enhancers or disease modifying agents for this stage of illness. Studies suggest the cholinesterase inhibitors, especially donepezil, may provide benefit. Several studies provide support for the use of the NMDA receptor antagonist memantine as monotherapy or added to a cholinesterase inhibitor for moderate to severe AD. While there are no published guidelines for the treatment of moderate to severe AD, these studies do provide guidance for recommendations for study design and outcome measures. Such studies are urgently needed.