Commentary on “A roadmap for the prevention of dementia II. Leon Thal Symposium 2008.” Facilitating Alzheimer's disease drug development in the United States

Therapeutic research of Alzheimer's disease (AD) is on the brink of a major advance. The field is poised to add effective disease-modifying treatments to our current symptomatic agents. The basic scientific understanding of AD pathophysiology has yielded a number of exceedingly promising targets for intervention, with many drugs now in various phases of clinical testing. Whether we reach a breakthrough within 5 or 15 years will be determined by the national will. In addition to financial support (specifically, funding by the National Institutes of Health for AD translational research), several concrete steps will facilitate progress toward bringing the next generation of therapeutics to the market. These steps are related to some important issues specific to the development of disease-modifying AD treatments, as well as some broader clinical research issues. A diagnosis of AD should indicate the presence of neurobiological abnormalities that, if unchecked, will eventually lead to dementia. At present, diagnostic criteria require the presence of dementia [1]. But we now have tools that allow the documentation of reduction in cerebral metabolic rate [2], amyloid and tau dysregulation [3], amyloid deposition in the brain [4], and regional brain atrophy [5], many years before the appearance of the functional impairments of dementia. Further, we can measure subtle cognitive decline many years before clinically important impairment occurs [6]. Based on observations regarding the prevalence of brain amyloid deposition and mild cognitive decline in the nondemented elderly, we can estimate that the number of cases of "neurobiological AD" is at least 2–3 times larger than the number of cases of clinical AD according to current criteria. In other words, there are now at least 10–15 million people in the United States with AD pathology, though only about 5 million are demented. Appreciation of the "true" prevalence of AD will encourage a more reasonable allocation of resources. But more importantly, the millions of people with early AD neurobiology represent the proper target population for effective disease-modifying interventions. The recently proposed research criteria for AD serve as an excellent start in the process of adjusting diagnoses based on our growing understanding of the neurobiology of AD [7]. Disease-modifying treatments target AD neurobiology rather than clinical symptoms, and for significant efficacy in altering clinical trajectories, such treatments should be initiated years before the onset of dementia. If drug studies are limited to dementia patients, they may be doomed to failure (or very limited success). We must facilitate the testing of drugs in the predementia stage, perhaps in the asymptomatic stage. Hence we must adjust the current criteria for drug approval. At present, an AD drug must be shown to exert a favorable influence on cognition and global clinical or functional status. Early in AD neurobiology, when symptoms are minimal or absent and function is normal, it cannot be possible to influence cognition and functional status favorably in a workable period of time. Therefore, the definition of the disease must be moved back to encompass early stages of diagnosis, and a regulatory pathway, including surrogate markers of neurobiology, must be developed. A realistic approach to the validation of AD surrogates must be adopted by the field and the Food and Drug Administration. The necessary methodology will require extensive efforts to develop usable biochemical and imaging biomarkers of AD neurobiology, link those biomarkers to cognitive, behavioral, and functional aspects of the disease, and establish appropriate analytical tools to demonstrate drug efficacy. No single company, institution, or even sector can readily accomplish this. Precompetitive collaboration was established in efforts such as the Alzheimer's Disease Neuroimaging Initiative [8] (funded jointly by the National Institutes of Health and the pharmaceutical industry, with industry, academic, and regulatory collaborators). This type of collaboration must be expanded and intensified in the near future, to yield workable solutions to today's trial-design conundrums. The number of AD subjects and families required for enrollment in current trials is many-fold higher than just a couple of years ago. The Elan/Wyeth Bapineuzumab Program alone requires 4000 subjects. This increase in subjects needed reflects not only the growing number of promising treatment strategies (active and passive immunotherapy, γ-secretase inhibition/modulation, β-secretase inhibition, anti-aggregation agents, mitochondrial stabilizers, and neuroprotectants), which is very good news, but also the huge trial size and length required for the development of disease-modification drugs. We must not let unmet trial-recruitment needs create a bottleneck in AD drug development. To avoid this, a national drive to broaden awareness of the need for widespread clinical research participation, as well as awareness of the altruistic rewards of such activity, should be undertaken. The healthcare professions, government (the White House, the Surgeon General, and Congress), the entertainment world, and media resources must all be brought to bear. A national registry of subjects and families affected by (or at risk for) AD should be one component of this effort. This would serve multiple purposes, including facilitation of communication regarding the disease, its current treatment and research developments, and information regarding clinical trial opportunities. It is possible to establish such a system, with appropriate attention to privacy concerns. It may be feasible to make use of the growing commitment to electronic medical-record systems (which might facilitate invitations to individuals to join a registry, and if consent is provided, the automated transfer of relevant information into the registry). Greater participation in trials also requires a stronger AD trial infrastructure. The number of qualified trial sites in the United States (and internationally) is insufficient for current needs. Out of necessity, the largest drug studies are being conducted at academic, commercial, and private-practice sites lacking in appropriate trial methodology training and resources. The result will likely be an increase in subject heterogeneity, measurement variance, and dropout rates; this will drastically increase the chance that an effective drug will fail in clinical trials. To strengthen our clinical performance sites, we must improve the training and retention of investigators, provide infrastructure support to sites, increase site reimbursement rates for subject enrollment, and strengthen and expand national trial organizations such as the Alzheimer's Disease Cooperative Study [9]. AD clinical trials currently in progress range in size from 1–270 sites. For large multicenter trials, an enormous effort is required to obtain local institutional review board (IRB) approval at each participating site. Whereas commercial and private-practice sites may have the option of utilizing private central IRBs, academic sites must obtain individual review and approval at each institution. This means that a trial protocol and consent form is independently reviewed, in exhaustive detail, by dozens of committees. The time, effort, and expense of these redundant reviews (and the endless "wordsmithing" of consent forms), which must be repeated with each trial amendment, are enormous and discouraging. A single, national IRB, with appropriate expert representation, would provide more meaningful oversight at a small fraction of the effort. The risks and costs of investing in AD therapeutics can deter large and small companies alike. The potential payoff in societal gains is of course enormous, but we must assure that corporate investment is adequately rewarded. Because the development timeline in this field is so long, adjustment to the protections of intellectual property value are necessary. For example, an extension of the period of market exclusivity for first-in-class AD drugs may be required. None of these seven items requires a huge financial investment. They can all be readily accomplished with an appropriate national commitment to the development of effective prevention and treatment for AD. No healthcare investment in the United States will have a greater payoff.