Can J Neurol Sci
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Until recently, the gold standard for assessing the efficacy and effectiveness of new medications has been the placebo-control 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. ⋯ 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.
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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. ⋯ 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.
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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.