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U.S. FDA Recent Draft Guidance for Drug Development of Early Alzheimer's Disease
U.S FDA Recent Draft Guidance for Drug Development of Early Alzheimer's Disease
- 글 이희민(Heemin Rhee)
· 2011~現 Health Research International 대표
· 現 한국보건산업진흥원 GPKOL 위원(임상, R&D기획 분야)
· 1973~1976 위스콘신 의과대학(University of Wisconsin Medical School), 약리학 박사 후 과정
· 1970~1973 오하이오 주립대 의과대학, 약리학 박사
In Feb. 2018, the U.S. FDA published this guidance document for the purpose of feedback through the comments and suggestions from the relevant organizations and readers. However, I would like to share the guide with Korean readers and sponsors for the reference of their appropriate pharmaceutical discovery and development. The readers can respond within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to https://www.regulations.gov. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. If you have any questions regarding this draft document, contact (CDER) Billy Dunn at 301-796-2250 or (CBER) Office of Communication, Outreach, and Development at 800-835-4709 or 240-402- 8010. This is an update of the draft guidance for industry ”Alzheimer’s Disease: Developing Drugs for the Treatment of Early Stage Disease issued in February 2013”.
Amyloid beta (Aβ)
Alzheimer’s disease (AD)
Center for Biologics Evaluation and Research (CBER)
Center for Drug Evaluation and Research (CDER)
Center for Devices and Radiological Health (CDRH)
Clinical Trial (CT)
Food and Drug Administration (FDA)
Neurofibrillary Tangles (NFTs)
Office of Tissues and Advanced Therapies (OTAT)
Parkinson’s Disease (PD)
Type 2 diabetes (T2DM)
The primary purpose of this guidance is to assist sponsors in the clinical development of drugs for the treatment of the stages of sporadic Alzheimer’s disease (AD) that occur before the onset of overt dementia, which will be collectively referred to as early AD, though it is recognized that patients with later stage early AD and patients with AD in the earliest stages of dementia may not differ significantly.
This guidance is intended to serve as a focus for continued discussions among representatives of the U.S. FDA Division of Neurology Products in the CDER or the Office of Tissues and Advanced Therapies (OTAT) in the CBER, as pharmaceutical sponsors, the scientific community, and the public are working together. The design of clinical trials (CTs) that are specifically focused on the treatment of patients with AD who have developed overt dementia, or any of the autosomal dominant forms of AD, is not discussed, although some of the principles in this guidance may be pertinent.
The most common form of dementia, Alzheimer disease (AD) affects approx. 5.3 million people in the U. S. alone, and that number is projected to reach 13.8 million by the year 2050. A larger number of individuals have decreased cognitive function, which frequently evolves into full-blown dementia. The World Health Organization’s review in 2000 on the Global Burden of Dementia, which was an integrative analysis of 47 surveys across 17 countries, suggested that approximate rates for dementia from any cause are under 1% in persons aged 60-69 years, rising to about 39% in persons 90-95 years old. The prevalence doubles with every 5 years of age within that range, with few differences taking into account secular changes, age, gender, or place of living.
Neuropathological alterations in AD patients such as accumulation of amyloid beta (Aβ) and neurofibrillary tangles (NT) are well known, which may be the result of AD manifestation rather than the causes of the diseases. Accumulating evidence also indicates a role for metabolic dysfunction in the pathogenesis of AD. Type 2 Diabetes Mellitus (T2DM) increases the risk of developing AD, and several postmortem analyses have found evidence of insulin resistance in the AD brain. Thus, insulin-based therapies have emerged as potential strategies to slow down the cognitive decline in AD.
Eli Lilly Company tried three times to produce pivotal evidence that solanezumab could influence the course of the disease by clearing amyloid β, but, unfortunately not successful. The company now has sola in a study to see if it can prevent the disease in at-risk patients. Merck’s Beta-secretase 1 (BACE1) drug verubecestat, which moves upstream in the biology of developing amyloid β. It has now failed in both mild-to-moderate as well as prodromal patients. Indeed, numerous organizations have been poured incredible resources for the discovery and development of safe and effective drug products for AD and dementia. Products may be beneficial in slow down the neurodegenerative process, but ideal treatment agents will not be available until we know the precise molecular mechanism of AD and/or dementia, for which the U.S. FDA upgrades its guidance frequently for the industry.
Historically, the use of clinical criteria that defined later stages of AD, after the onset of overt dementia, was processed for enrollment into CTs. Accordingly, patients included in these trials exhibited both the cognitive changes typical of clinically evident AD and the degree of functional impairment associated with overt dementia. Drugs that were approved for dementia during that time were evaluated in that context. Studies supporting approval of those drugs used a co-primary approach to assessment of cognitive and functional (or global) measures.
This approach ensured both that a clinically meaningful effect was established by a demonstration of benefit on the functional measure and that the observed functional benefit was accompanied by an effect on the core symptoms of the disease as measured by the cognitive assessment.
The co-primary endpoint approach was used, in part, because the cognitive assessments used in the studies were not considered inherently clinically meaningful. Such assessments typically measure the cognitive deficits of AD through the use of highly sensitive formalized measures of neuropsychological performance that are capable of discriminating small changes of uncertain independent clinical meaningfulness.
This historical dichotomy of functional and cognitive assessments has led to common use of the terms cognition andfunction with respect to outcome assessment in AD CTs, with the implication that an effect on cognition is non-meaningful unless accompanied by a benefit on an independent endpoint assessing function in a meaningful manner. The FDA rejects this dichotomy and finds such usage inappropriate, because it implies that an effect on cognition itself, regardless of the nature of the observed effect and the manner in which it is assessed, cannot be clinically meaningful. This is certainly not the case.
Cognition, in its entirety, encompassing all its constituent processes and domains, is most certainly meaningful in terms of daily function. Although small changes in various cognitive domains may be detected using sensitive neuropsychological tests that are capable of detecting changes of uncertain clinical meaningfulness, more marked cognitive changes may represent impairment that is clearly clinically meaningful.
It follows, in concept, that cognitive changes of particular character, perhaps defined by magnitude or breadth of effect(s), may represent clinically meaningful benefit. The issue of concern with regard to considering the meaningfulness of cognitive measurements is the method of assessment, not the entity of cognition itself, especially for cognition taken as a whole. In short, cognition is meaningful, but when measured using conventional approaches with sensitive tools directed at particular domains, the meaningfulness of measured changes may not be apparent.
As the scientific understanding of AD has evolved, efforts have been made to incorporate in CTs, to varying degrees, the use of biomarkers reflecting underlying AD pathophysiological changes and the enrollment of patients with AD at earlier stages of the disease, stages in which there may be no functional impairment or even no detectable clinical abnormality. These efforts are particularly important because of the opportunity to intervene very early in the disease process that AD provides, given the development of characteristic pathophysiological changes that greatly precede the development of clinically evident findings and the slowly progressive course of AD.
It is obvious that delaying, or, preferably, halting or reversing, the pathophysiological process that will lead to the initial clinical deficits of AD is the ultimate goal of presymptomatic intervention, and treatment directed at this goal must begin before there are overt clinical symptoms. This opportunity carries with it the need to understand the optimum manner, in which to assess treatment benefit in these earlier stages of disease.
Diagnostic Criteria for Early Alzheimer's Disease
Eligibility for enrollment in efficacy trials in AD, including early AD, should be based on current consensus diagnostic criteria, with a focus on objective tests and, when appropriate, history and physical examination, to determine the presence or likely presence of AD, and to exclude other conditions that can mimic AD. FDA supports and endorses the use of diagnostic criteria that are based on a contemporary understanding of the pathophysiology and evolution of AD.
The characteristic pathophysiological changes of AD greatly precede the development of clinically evident findings and progress as a continuous disease process through stages defined initially only by those pathophysiological changes and then by the development of subtle abnormalities, detectable using sensitive neuropsychological measures. These are followed by the development of more apparent cognitive abnormalities, accompanied by initially mild and then more severe functional impairment. In part because of failures of CTs intended to alter disease progression in later stages of AD, there is an increased focus on evaluating drug treatments for AD in the earliest stages of the disease.
Diagnostic criteria that reliably define a population with early AD, including the earliest stages characterized only by pathophysiological changes, are suited to the evaluation of drugs intended to delay or prevent the emergence of overt symptoms. Important findings applicable to the categorization of AD along its continuum of progression include the presence of pathophysiological changes as measured by biomarkers, the presence or absence of detectable abnormalities on sensitive neuropsychological measures, and the presence or absence of functional impairment manifested as meaningful daily life impact that present with subjective complaints or reliable observer reports.
Although FDA recognizes that variations in the selection and application of clinical characteristics and biomarkers may lead to the identification of patients who are at somewhat different stages of a progressive disease process, the following categories are conceptually useful for the design and evaluation of clinical trials in different stages of AD:
Stage 1: Patients with characteristic pathophysiologic changes of AD but no evidence of clinical impact. These patients are truly asymptomatic with no subjective complaint, functional impairment, or detectable abnormalities on sensitive neuropsychological measures. The characteristic pathophysiologic changes are typically demonstrated by assessment of various biomarkers.
Stage 2: Patients with characteristic pathophysiologic changes of AD and subtle detectable abnormalities on sensitive neuropsychological measures, but no functional impairment. The emergence of subtle functional impairment signals a transition to Stage 3.
Stage 3: Patients with characteristic pathophysiologic changes of AD, subtle or more apparent detectable abnormalities on sensitive neuropsychological measures, and mild but detectable functional impairment. The functional impairment in this stage is not severe enough to warrant a diagnosis of overt dementia.
Stage 4: Patients with overt dementia. This diagnosis is made as functional impairment worsens from that seen in Stage 3. This stage may be refined into additional categories (e.g., Stages 4, 5, and 6, corresponding with mild, moderate, and severe dementia) but a discussion of these disease stages is not the focus of this guidance. It is vital to distinguish accurately these conceptual categories, even in the presence of a single continuous disease process, to allow and inform appropriate outcome measure selection.
In descriptions of studies, both proposed and completed, sponsors should identify both the stage of AD defined for study eligibility and enrollment and the stage of AD anticipated for the majority of the enrolled patient population at the time of primary outcome assessment. It is reasonable to expect that biomarker evidence of disease will play a role in the reliable identification of patients in trials of early AD. Indeed, it is unusual to encounter a proposed CT that does not include in the enrollment criteria biomarker evidence of disease. If this evidence could be needed to adequately define the anticipated indicated population, we encourage sponsors to engage early in development with the Division of Neurology Products, OTAT, or the Center for Devices and Radiological Health (CDRH) as appropriate, at FDA to discuss the potential need for the co-development of a companion diagnostic device.
5a. Clinical Endpoints for Early AD Trials in Stage 3 Patients
Early AD patients approaching the onset of overt dementia (Stage 3 patients) are likely to have relatively mild but noticeable impairments in their daily functioning. Although studies in this stage of disease will generally include sensitive measures of neuropsychological performance of uncertain independent clinical meaningfulness, it is important to demonstrate that a drug favorably affects these functional deficits.
Many of the assessment tools typically used to measure functional impairment in patients with overt dementia may not be suitable for use in these early stage patients. Ideally, the outcome measure used in this stage of disease will provide an assessment of meaningful cognitive function. An integrated scale that adequately and meaningfully assesses both daily function and cognitive effects in early AD patients is acceptable as a single primary efficacy outcome measure.
5b. Clinical Endpoints for Early AD Trials in Stage 2 Patients
In patients in the earliest clinical stages of AD (Stage 2 patients), where only subtle cognitive deficits detected on sensitive measures of neuropsychological performance are present, and there is no evidence of functional impairment, it may be difficult to establish a clinically meaningful effect on those subtle cognitive deficits during the course of a trial of reasonable duration. Nonetheless, a possible approach is to conduct a study of sufficient duration to allow the evaluation of the measures discussed above for Stage 3 patients. As patients transition to Stage 3 during participation in the trial, the principles applicable to outcome assessment for Stage 3 would apply.
Alternatively, and in view of the rapidly and continually expanding body of knowledge concerning AD, FDA will consider strongly justified arguments that a persuasive effect on sensitive measures of neuropsychological performance may provide adequate support for a marketing approval. Given the panoply of available neuropsychological tests, a pattern of putatively beneficial effects demonstrated across multiple individual tests would increase the persuasiveness of the finding; conversely, a finding on a single test unsupported by consistent findings on other tests would be less persuasive. A large magnitude of effect on sensitive measures of neuropsychological performance may also increase their persuasiveness. It would generally be expected that such arguments would be supported by similarly persuasive effects on the characteristic pathophysiologic changes of AD, as discussed below for Stage 1 patients.
Importantly, such arguments should be predicated on the certainty of diagnosis of enrolled patients, the certainty of their future clinical course, and the certainty of the relationship of the observed effects on sensitive measures of neuropsychological performance and characteristic pathophysiologic changes to the evolution of more severe cognitive deficits and functional impairment. Whether such arguments, if convincing, would support full approval (i.e., the cognitive effects were found to be inherently clinically meaningful, either on face or because they reliably and inevitably are associated with functional benefit later in the course of the disease) or accelerated approval (i.e., the cognitive effects were found to be reasonably likely to predict clinical benefit, with a post-approval requirement for a study to confirm the predicted clinical benefit) would be a matter of detailed consideration. Sponsors considering these issues should discuss their plans with FDA early in development. Evolution of the scientific understanding of AD may also influence these considerations.
5c. Endpoints for Early AD Trials in Stage 1 Patients
Because it is highly desirable to intervene as early as possible in AD, it follows that patients with characteristic pathophysiologic changes of AD but no subjective complaint, functional impairment, or detectable abnormalities on sensitive neuropsychological measures (Stage 1 patients) are an important target for clinical trials. A clinically meaningful benefit cannot be measured in these patients because there is no clinical impairment to assess (assuming that the duration of a trial is not sufficient to observe and assess the development of clinical impairment during the conduct of the trial).
In Stage 1 patients, an effect on the characteristic pathophysiologic changes of AD, as demonstrated by an effect on various biomarkers, may be measured. Such an effect, analyzed as a primary efficacy measure, may, in principle, serve as the basis for an accelerated approval (i.e., the biomarker effects would be found to be reasonably likely to predict clinical benefit, with a post-approval requirement for a study to confirm the predicted clinical benefit). As with the use of neuropsychological tests, a pattern of treatment effects seen across multiple individual biomarker measures would increase the persuasiveness of the putative effect.
Although the issues and approaches discussed above for Stage 2 patients are relevant for Stage 1 patients, there is unfortunately at present no sufficiently reliable evidence that any observed treatment effect on such biomarker measures would be reasonably likely to predict clinical benefit (the standard for accelerated approval), despite a great deal of research interest in understanding the role of biomarkers in AD. FDA strongly supports and encourages continued research in this area and stresses its potential importance in the successful development of effective treatments appropriate for use in the earliest stages of AD. Precompetitive structured sharing across the AD scientific community of rigorously collected standardized data is a crucial component of this research.
While research pursues the development of evidence sufficient to support the use of biomarker measures as the primary evidence supporting an accelerated approval, or perhaps a full approval if the fundamental understanding of AD evolves sufficiently to establish surrogacy, a possible approach to Stage 1 patients might be to conduct a study of sufficient duration to allow the evaluation of the measures discussed above for Stage 2 patients. As patients transition to Stage 2 during participation in the trial, the principles applicable to outcome assessment for Stage 2 would apply.
5d Time-to-Event Analysis
The use of a time-to-event survival analysis approach (e.g., time to the occurrence of a clinically meaningful event during the progressive course of AD, such as the occurrence of some degree of meaningful impairment of daily function) would be an acceptable primary efficacy measure in CTs in early AD. Sponsors considering such an approach should discuss their plans with FDA early in development.
5e Assessment of Disease Course
Although the demonstration of a substantial clinically meaningful treatment effect of any sort is of paramount importance, this may not be feasible in a clinical trial of reasonable duration, especially very early in the course of the disease, and clinical trials in early stage disease will usually be intended to provide evidence that a drug has permanently altered the course of AD through a direct effect on the underlying disease pathophysiology, an effect that persists in the absence of continued exposure to the drug.
A randomized-start or randomized-withdrawal trial design (with clinical outcome measures) is the most convincing approach to demonstrating a persistent effect on disease course. Generally, a randomized-start design would be most appropriate for use in AD. In this study design, patients are randomized to drug and placebo, and at some point, placebo patients are crossed over to active treatment.
If patients in the trial who were initially on placebo and then assigned to active treatment fail to catch up (after a reasonable period of time) to patients who received active treatment for the entire duration of the trial, a persistent treatment effect on disease course would have been shown. Assessment of various biomarkers may provide supportive evidence for a drug that has an established clinically meaningful benefit, but the effects on biomarkers in AD are not sufficiently well understood to provide evidence of a persistent effect on disease course.
There is no consensus as to particular biomarkers that would be appropriate to support clinical findings in trials in early AD. For this reason, sponsors at present have insufficient information on which to base a hierarchical structuring of a series of biomarkers as secondary outcome measures in their trial designs. Sponsors are therefore encouraged to analyze the results of these biomarkers independently, though in a prespecified fashion, with the understanding that these findings will be interpreted in the context of the state of the scientific evidence at the time of a future marketing application.
Summary and Conclusions
The draft guidance was appeared after a meeting of the Washington, D.C.-based Alzheimer’s Association research group, which was discussing how you might be able to use a mix of markers for amyloid β and tau along neurodegenerative markers to identify patients who could be enrolled at a very early point in the disease. We need to figure out ways to do measurements better, sensitive to earlier stages of the disease, looking at cognition and function for more sensitive ways of doing it, particularly need to identify the stages of AD patients for their appropriate clinical trials. In any cases, sponsors should identify both the stage of AD defined for study eligibility and enrollment and the stage of AD anticipated for the majority of the enrolled patient population at the time of primary outcome assessment.
If the sponsors find a clear beneficial clinical effects for the selected subject, they should apply for an accelerated approval. Sponsors considering these issues should discuss their plans with FDA early in development. Evolution of the scientific understanding of AD may also influence these considerations. Because of importance of early AD intervention, patients with characteristic pathophysiologic changes of AD but no subjective complaint, functional impairment, or detectable abnormalities on sensitive neuropsychological measures (Stage 1 patients) are a critical clinical target, although a clinically meaningful benefit may not be measured in these patients.
The cognitive effects are also meaningful because they reliably are associated with functional benefit later in the course of the disease or accelerated approval with a post-approval requirement for a study to confirm the predicted clinical benefit. Most of all, accurate elucidation of AD pathologic molecular mechanism is critical to devise safe and effective drug products as the FDA strongly supports and encourages continued research in this area and stresses its potential importance in the successful development of effective treatments appropriate for use in the earliest stages of AD.
Oxidative stress is believed to be a critical factor in normal aging and in neurodegenerative diseases such as AD, PD and amyotrophic lateral sclerosis (ALS). Formation of free carbonyls and thiobarbituric acid-reactive products, an index of oxidative damage, are significantly increased in AD brain tissue compared with age-matched controls. Plaques and tangles display immunoreactivity to antioxidant enzymes. Recent findings also indicate that the composition of gut microbiomes microbes could influence the number and size of the amyloid plaques characteristic of AD possibly by affecting brain inflammation, although the focus of the guides is on the clinical studies for the early AD patients. While research should pursue the development of evidence sufficient to support the use of biomarker measures as the primary evidence supporting an accelerated approval through accurate determination of molecular mechanism of the AD and other related neurodegenerative diseases.
1. Multiple Endpoints in Clinical Trials Guidance for Industry http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
2. National Institutes of Health-Alzheimer’s Disease and Related Disorders Association (NIH-ADRDA)American Psychiatric Association, in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5); and the Consortium to Establish a Registry in Alzheimer’s Disease (CERAD).
3. Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
4. Bereczki, E. et al. Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach. Brainhttps://doi.org/10.1093/brain/awx352 (2018)
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