Study design considerations: Conducting global clinical trials in early Alzheimer's disease

Abstract

An increasing number of Alzheimer's disease (AD) clinical trials are being conducted in countries in which such trials have infrequently, if ever, been conducted. The infrastructure for conducting trials in many of these regions is not well developed, leading to particular challenges in collection of biomarkers, which are becoming increasingly important in trials in early AD. Linguistic and cultural differences make scale translation, adaptation, validation and implementation across countries and regions difficult. In addition, multiple translations and versions of scales and differences in their administration increase variability and thus decrease the chance of detecting a signal. These issues are magnified in trials in early AD, where detecting subtle neuropsychological deficits is even more challenging. Two additional significant factors for global AD research include: 1) Differing regulatory authority requirements resulting in the need for repeat studies to satisfy diverse regulatory requirements in different parts of the world; and 2) reimbursement and access may be limited due to different data requirements for country specific economic evaluations. While standardization of biochemical assays and neuroimaging protocols have recently been undertaken, there remains a pressing need for standardization of clinical measures (including translation, linguistic and cultural validation and administration). In addition, a global consensus on regulatory requirements for approval of drugs for the treatment of early AD and identification of universally accepted variables from a cost-effectiveness or value perspective would have significant impact on advancing drug development in early AD.

Early detection and intervention in Alzheimer’s disease (AD) holds the greatest potential for any one individual and the greatest good for the greatest number of people given the global epidemic nature of the disease (1). The ability to prevent the progression of AD in its early stages is a realistic goal given the potential outcomes of current and near term research. An immediate issue is ensuring that our research is inclusive of populations worldwide.

The majority of clinical trials of drugs for the treatment of Alzheimer’s disease have been conducted in western countries and regions. As the Alzheimer’s disease epidemic continues to grow in direct proportion to the aging of the world population, there is increasing recognition of the large projected number of cases, especially in highly populated developing nations. The global impact of the disease in combination with the large number of new compounds in development for the treatment of Alzheimer’s disease (2) results in an urgent need for more patients in a broader range of populations worldwide to enter clinical trials. In response, an increasing number of AD clinical trials are being conducted in countries in which such trials have infrequently, if ever, been conducted. This situation has raised multiple challenges. To address these challenges approaches centering on standardization of methods as well as addressing the differences in regulatory and reimbursement requirements can expedite the availability of treatments.

The Challenges

Infrastructure and technology

The infrastructure for conducting clinical trials in many regions is not well developed. This ranges from more basic issues such as internet availability for electronic data capture to technological differences in collection of biomarkers and neuroimaging capabilities. This includes handling of biofluids (e.g., refrigeration, centrifugation), availability and differences in scanning equipment, and differing standards of interpretation. The latter has been addressed through the use of centralized reading. However, technological disparities remain and will become an increasing issue as more trials are conducted in an early AD population and the role of biomarkers becomes increasingly important.

Cultures and linguistics

Measuring cognitive, behavioral and functional changes in varying populations and cultures is an increasing technical concern as clinical trials are performed in a growing number of countries (3, 4). This has become even more apparent as the limitations of the scales, even within individual cultures and languages, have become increasingly evident (5). Moreover, as clinical trials move into earlier AD populations, the difficulties in detecting and measuring more subtle neuropsychological deficits become even more challenging. Linguistic and cultural differences make scale translation, adaptation, validation and implementation across countries and regions difficult (4). Moreover, multiple translations and versions of scales and differences in their administration both across countries and even within countries (4), often as implemented by different sponsors, increase variability and thus decrease the chance of detecting a signal. While some regions have successfully harmonized some of the neuropsychological assessments in standard use (3), this has not occurred across most regions nor for most of the scales typically employed in trials. There remains a pressing need for agreement on clinical measures employed in trials, including translation, linguistic and cultural validation, and administration.

As a parallel issue, cultural differences have an impact on the ability to collect biological fluids. For example, cerebrospinal fluid and larger quantities of blood may be difficult to collect in certain cultures (4).

Regulatory and reimbursement issues

Other challenges to conducting global clinical trials include differing regulatory and reimbursement authorities’ requirements (6, 7). Some regulatory bodies now require that a minimum number of subjects studied are from the region or country in which the sponsor is seeking approval (8). In addition, the requirements for approval, including study design and outcome measures, may differ between regions (6). In addition, as the field moves toward trials in early AD, the regulatory requirements for demonstrating change on measurements of cognition and function may become insurmountable in this population where symptoms may be minimal and difficult to demonstrate using clinical scales (9). Finally, even if a drug receives regulatory approval in a particular region, reimbursement and access may be limited due to different data requirements for country specific economic evaluations (7).

A Call for Harmonization: The need for collaborative initiatives across industry and academia

The need for globally conducted clinical trials in early Alzheimer’s disease is now clearly pressing. The field has addressed differences in interpretation of imaging in multicenter trials through what is now standard use of centralized reading. The need for biomarkers (10) and standardization in the collection of imaging and biofluids is being addressed, most notably in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (11, 12). This project has catalyzed similar initiatives in other regions which are using the same standards of biomarker collection and interpretation so that results can be ultimately pooled or compared (13). However efforts to harmonize clinical assessments and regulatory guidance have not progressed as quickly.

Ideally, a collaborative initiative across industry and academic sponsors such as in ADNI, would be undertaken (14) aimed at achieving universal use of agreed upon, validated, country specific adaptations of scales (including linguistic, semantic and cultural properties); as well as standardized implementation, including training, instruction, data capture and scoring. In addition, the conduct of studies should be centralized to the greatest possible extent, including centralizing investigators’ meetings and training; implementing standard recertification procedures; centralizing scoring of outcome measures, reading/interpretation of labs; and rating surveillance (15).

The ultimate challenge: Availability and access

Attainment of a truly global consensus on regulatory requirements for approval of drugs for the treatment of early AD, and clear definition of the requirements to make a potential claim would have significant impact on advancing drug development. Currently, significant additional resources are required to repeat studies based on the need to vary endpoints, populations, trial design or analyses to satisfy diverse regulatory requirements in different parts of the world (16). A similar need exists to identify universally accepted variables from a cost-effectiveness or value perspective (e.g., quality of life, caregiver burden, pharmacoeconomic endpoints) so that studies can be designed with these additional parameters in mind (7).

The growing population of aging citizens globally presents a monumental task: to develop and bring to market cost effective therapies for the prevention and treatment of AD and related dementias in both the developed and the developing world. If this task is to be successfully accomplished in the limited time available to us before a major epidemic is upon us, it must be done collaboratively and efficiently. The issues raised here and the methods to address the major challenges before us represent a path forward to more swiftly advance the discussion and subsequent initiatives. The task is urgent; the consequences of our success or our failure will be great.