Comparison of Treatment Effects Between US and Non-US Study Sites in Multiregional Alzheimer Disease Clinical Trials.

BACKGROUND: Conducting clinical trials across multiple regions of the world has become common practice. A multiregional clinical trial (MRCT) presents opportunities as well as challenges. However, regional differences of treatment effects appear in many MRCTs, which make the interpretation of clinical trial results difficult and presents challenges for clinical trial design. Alzheimer disease (AD) is a progressive neurodegenerative disorder that affects approximately 5 million people in the United States and is the sixth leading cause of death in the country. In 2014, AD cost the United States $214 billion, and the cost is expected to rise to $1.2 trillion by 2050. METHODS: In this article, we utilize data from New Drug Applications (NDAs) that have been approved for the treatment of AD to study whether there are differences in treatment effect between US and non-US study sites. Using an analysis of covariance (ANCOVA) model and forest plot, we analyze the treatment difference by region (US and non-US) from 3 separate perspectives: by region for each trial, by region for each endpoint, and by region and trial for each endpoint. RESULTS: Overall, the analyses indicate that treatment effects in clinical trials for AD are generally in the expected direction in both US and non-US sites. There was no clear evidence of heterogeneity in treatment effects between US and non-US sites. CONCLUSIONS: It appears that there is no clear evidence to suggest that MRCTs should not be used to study AD.

Clinical Spectrum of Hereditary Spastic Paraplegia in Children: A study of 74 cases.

OBJECTIVES: The aim of the study was to explore the spectrum of hereditary spastic paraplegia (HSP) in children in Oman. METHODS: This retrospective study was carried out between January 1994 and August 2011 on children with delayed development, gait disorders and motor handicaps, with signs of symmetrical pyramidal tract involvement. A detailed perinatal and family history, including the age of onset of symptoms, was recorded. The children were labelled as having either the pure or complicated form of HSP based on the established diagnostic criteria. In families with more than one affected child, parents and all other siblings were also examined. RESULTS: Within the study, 74 children from 31 families were diagnosed with HSP. Parental consanguinity was seen in 91% of cases, with 44 children (59.4%) experiencing onset of the disease under one year of age. Complicated HSP was the most common type, seen in 81.1%. Speech involvement, mental retardation, and epilepsy were the most common associated abnormalities. Nonspecific white matter changes and corpus callosum abnormalities were noted in 24.3% of cases on magnetic resonance imaging. CONCLUSION: The study described clinical features of 74 children with HSP. Autosomal recessive complicated HSP was seen in 81.1% of cases.

The evaluation of disease modifying therapies in Alzheimer's disease: a regulatory viewpoint.

Several drugs have received marketing approval in this country for the treatment of dementia of the Alzheimer's type. Their approval has been based on clinical trial designs that do not permit a distinction to be made between an effect of the drug on the symptoms of that disease, and an effect on the pathophysiological mechanisms that underlie that disorder. The latter effect has been referred to as 'disease-modifying.'In recent years there has been considerable interest in developing disease-modifying treatments for Alzheimer's disease (AD), using either specific clinical designs, or surrogate markers, such as brain imaging modalities. This paper outlines the regulatory framework governing how the Food and Drug Administration addresses new drug claims, the current basis for approving drugs for the treatment of AD, clinical trial designs that have been proposed as a means of demonstrating disease-modifying effects, a general and regulatory background to the use of surrogate markers in drug development, and, finally, views about the possible role of surrogate markers, especially brain imaging, as outcome measures in clinical trials intended to produce disease-modifying effects in Alzheimer's Disease.

Regulatory aspects of vascular dementia in the United States.

There is significant interest in the development of new drugs to treat vascular dementia. However, before US approval of new drugs for this entity is possible, certain issues with regulatory implications need to be addressed. Is vascular dementia a distinct clinical syndrome with valid diagnostic criteria? Can this entity be distinguished from Alzheimer's disease (AD) and other causes of dementia? What design features are important for clinical trials in this disorder? The US Food and Drug Administration (FDA) convened a special meeting of the Peripheral and Central Nervous System Advisory Committee in an attempt to answer these questions. The conclusions from this meeting indicate that vascular dementia (VaD) is a pathologically heterogeneous disorder but appears to be reasonably distinguishable from AD dementia. The NINDS-AIREN diagnostic criteria are suitable as entry criteria for vascular dementia trials. Trials should be similar in duration to AD dementia trials and should employ a dual outcome strategy (cognitive + global/functional measures). For drugs that are believed to have a disease-modifying effect, clinical trials should study specific vascular dementia subtypes and would need to employ substantially different designs from those used currently. The term "vascular dementia" may not be entirely appropriate to describe this population.