Exciting advances have been made recently in understanding the mechanistic underpinnings of aging. Mounting evidence suggests that progression of aging changes can be modulated. Interventions that extend health span and lifespan in model organisms have been developed. The time is approaching for translation of these interventions into clinical treatments. By targeting fundamental aging mechanisms, it may be possible to delay, prevent, or alleviate chronic diseases as a group, rather than individually, and enhance health span. Such a compression of morbidity would have profound clinical and economic benefits, with reductions in life-years spent with chronic disease and age-related dysfunction. However, barriers remain, including lack of clinical and regulatory paradigms for translating agents that target fundamental aging processes into clinical interventions, and a shortage of personnel trained to do so. Here we consider research findings that support the potential value of translational aging research and strategies to move these findings from bench to bedside.

A new therapy that uses the patient's own blood to cure blood cancers (leukaemias) is the focus of this chapter. The history of its detection and diagnosis is related, along with the long and arduous search for effective treatment, arriving at successful employment of bone marrow transplantation in the later twentieth century. More recent developments in chemotherapy are reviewed, leading to a contemporary account of the encouraging progress with T-cell therapies.

As vaccines are complex technologies that interact with the human body, their development is overseen by regulators in the administrative state. Countries structure the review of pharmaceutical products according to domestic rules and institutional design. As such, vaccines are reviewed as biologic products by regulatory authorities at the domestic level, such as the Therapeutic Goods Administration in Australia or the Pharmaceutical and Medical Devices Agency in Japan. The national basis of vaccine regulation inevitably leads to country-specific processes and timelines and may in some cases lead to different decisions.

We incorporate the perspectives of research participants in a clinical trial of DBS for TBI about investigator and sponsor responsibilities with respect to posttrial access to a functioning embedded medical device. We argue that investigators owe a duty of transparency about posttrial access to device maintenance, upgrades, or removal as part of an ongoing informed consent process.

The COVID-19 pandemic caused enormous disruption of clinical, research, and academic services around the world. This chapter focuses on the impact of COVID-19 on clinical trials and reflects upon the various measures taken to continue research work while minimizing risk to participants. Through careful observations, we conclude that it is imperative to continue Alzheimer’s disease (AD) drug development programs. With proper infection prevention protocols and precautions in place, it is possible to preserve the safety of both study participants, and investigators/research staff while moving forward with essential drug development processes for the benefit of study participants, and patients in general. Such protocols, once perfected, need to become a part of all institutional review boards and study protocols in order to avoid any loss or delay of essential work in the future.

Phase 2 in drug development is a crucial phase that can make or break success. The goals in Phase 2 are to determine safety, dosage and efficacy. In this chapter elements of planning, design, biomarker use and clinical outcomes are highlighted and some good and bad examples are given, emphasizing the importance of conducting a proper Phase 2.

Animal model systems play a fundamental role in the development and evaluation of novel treatments for Alzheimer’s disease (AD). The examination of safety and tolerability in animal models is a necessary first step prior to any human clinical trials. Equally important, preclinical testing of novel therapeutics in disease relevant models is required for the determination if a potential therapeutic should advance. There are a number of important considerations in the preclinical workflow that range from selection of the most appropriate animal model related to drug mechanism of action, as well as what AD-relevant measures are to be evaluated to determine if a candidate therapy should advance. In this chapter we highlight the process of preclinical animal model testing for novel therapeutics in AD, as well as detail several of the models utilized and the measures relevant to AD. We also include the emerging approaches to provide better AD animal models (MODEL-AD) as well as emerging approaches to refine the process of identifying new treatments (TREAT-AD).

Alzheimer’s disease (AD) drug development is a complex process that proceeds from identification of a biological target; to testing of candidate therapies in in vitro assays; assessment of efficacy in animal models and assessment of safety in several animal species; clinical testing in humans in Phase1, Phase 2, and Phase 3 clinical trials; regulatory review by agencies in all countries in which the drug might be marketed; and eventual commercialization. This process requires more than a decade to accomplish. The process involves substantial infrastructure resources; multiple stakeholders; and funding from a variety sources along the developmental pathway. This is the complex ecosystem that supports AD drug development.

The National Institutes of Health (NIH) is the largest funder of Alzheimer’s disease and related demententias (AD/ADRD) research in the world. The National Institute on Aging (NIA), part of the NIH, leads the federal effort on AD/ADRD research. Since 2005 the NIA has been developing a robust translational research program for the treatment and prevention of AD dementia. In 2011, the National Alzheimer’s Project Act became law and ordered the creation of a National Plan to Address Alzheimer’s Disease. The National Plan was first released in 2012 and the first goal of the plan is to find effective ways to treat or prevent dementia by 2025. Since the first the release of the first National Plan in 2012, NIA’s funding for AD/ADRD research has steadily increased, allowing continued expansion and diversification of the drug development portfolio and the development of translational infrastructure programs to accelerate the discovery of effective therapies.

While Alzheimer’s disease (AD) remains one of the very few common chronic diseases of aging and old age without any effective treatments to slow or prevent the illness, an historical perspective can provide the context for why this is true. The same historical perspective demonstrates that this lag is primarily a frame shift in time, rather than due to excess difficulties in developing drugs for the disease. Indeed, the historical perspective suggests that today, we are “right on time” for an explosion in new drugs for the disease after 40 years of rapid progress in basic and clinical research. The first drugs (cholinergic agents) for AD were approved after only about 15-20 years of research in the field, including the time needed for basic discovery, clinical development and regulatory approval.  Today, after 40 years of AD research, many disease-modifying drugs are in clinical development. Considering that cancer, diabetes and hypertension research began more than 80-100 years ago, the rapid progress in AD research can actually be viewed as impressive progress.

Alzheimer’s disease (AD) is a public health challenge that grows in urgency every year. As the world’s largest dedicated voluntary health organization to AD and related dementia (ADRD), the Alzheimer’s Association has a vision of a world without AD and ADRD. In addition to providing care and support in communities across the United States and actively pursuing advocacy for federal research support and community needs,it is committed to advancing vital research toward methods of treatment, prevention, and a cure. In addition to financial support to researchers worldwide, it promotes the sharing of knowledge and data, gathering key stakeholders form the field, including academia, federal, non-profit and industry to advance research (such as through the Alzheimer’s Association International Conference) and accelerating clinical trial research though Alzheimer’s Association TrialMatc. The Association’s funding expands the full spectrum of research, with focused funding on drug development and early-phase human trials.

The path to approvability of drugs created for Alzheimer’s disease (AD) dementia, mild cognitive impairment, or associated symptoms of AD is long and expensive, involving the study sponsor, the registration authorities, a clinical research organization, and the performance site. The key to successful AD trials is the performance site, the individual investigators, the recruited subjects, and the quality of the data generated. Performance sites include academic medical centers, a division within a large multi-specialty group, and for-profit clinical trial companies. All performance sites have common elements. These include the staff (investigator, coordinator, rater/neuropsychologist, and manager), access to study participants for enrollment, appropriate training of staff, regulatory oversight (investigational review board ), and the ancillary services. Types of studies that are available include therapeutic (medication or device), longitudinal observational, and imaging. Different types of studies have different requirements for staff or infrastructure, some easy to deploy, others not. In this chapter we will describe the elements of a successful AD clinical trial site.

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a longitudinal, observational study initiated in 2004 with the aim to develop and validate biomarkers for Alzheimer’s disease (AD) trials. From its inception, ADNI has been a model of a public–private partnership, with industry partners involved not only through financial support but in a guidance capacity. Through the development of standardized methods, ADNI has collected imaging and fluid biomarker data from cognitively normal, early and late mild cognitive impairment, and AD participants which is available to qualified researchers without embargo. Moreover, these methods have been incorporated into companion studies worldwide. The data that have been collected have provided important insights into the progression of AD pathology over time, assists in understanding which biomarkers may be most useful in clinical trials and have facilitated the design of studies of disease-modifying therapies.

Frontotemporal lobar degeneration (FTLD), a major cause of dementia worldwide, is an unrelenting and ultimately fatal set of pathological processes without any approved disease-modifying therapies. Clinical trial development in FTLD has previously been challenging, due to its pathological heterogeneity aand the clinical heterogeneity of frontotemporal dementia (FTD) and other clinical syndromes that arise from FTLD. Advances in FTLD basic science research have recently translated into a growing field of FTLD clinical trial development, with a particular focus on therapies tailored to distinct clinical syndromes with the highest specificity for particular FTLD pathophysiologies. The expansion of FTLD clinical programs has been fostered by a variety of advocacy groups and a number of large multi-site clinical research consortia, the latter of which have advanced the investigation of fluid biomarkers and clinical and neuroimaging measures for use in future clinical trials. This chapter covers the unique considerations of clinical trials in patients with FTLD pathology and review previous and current clinical trial programs investigating disease-modifying therapies targeting FTLD.