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Throughout the development of new drugs in the field of Alzheimer’s disease (AD), the high failure rate in clinical trials is prohibitive. There are many reasons for this. The core problem is not enough awareness of AD itself. Therefore, we need to adjust the cognition of AD from all angles. FDA released a new guide in February 15, 2018, “Early Alzheimer ‘s Disease: Developing Drugs for Treatment,” and obviously, for AD this stubborn disease, FDA is determined to reorganize the mood and adjust the route, the more difficult and the more forward!
The progress of AD is a continuous process from light to heavy. At the early stage of AD, the patient might not have any clinical symptoms, but in fact, there were characteristic pathophysiological changes in vivo. At this stage, subtle abnormalities can be found through sensitive neuropsychological tests. When the patient’s AD course continues to increase, there will be more obvious cognitive abnormalities, accompanied by mild to severe functional impairment.
In FDA’s new guide, it also reflects the latest cognition of FDA on the development of new AD drugs.
1. the failure rate of the new drugs for the treatment of advanced Alzheimer’s disease is too high, which makes the biopharmaceutical enterprises take advantage of the advantage and avoid harm, and turn to the development of the treatment drugs for the early AD. Based on this reality, FDA recommends that the course of disease targeted by AD drugs be adjusted to an early stage.
In the past, the AD subjects recruited by clinical trials were usually later patients, those with AD patients with typical AD cognitive changes and functional impairment symptoms associated with dementia. However, with the continuous deepening of the scientific understanding of AD, it is found that the characteristic pathophysiological changes of AD are much earlier than the appearance of obvious clinical symptoms, and the disease of AD is progressed slowly. Therefore, it is very important to intervene in AD at the early stage of disease. The following approaches have emerged in current clinical research:
Biomarkers that reflect the potential pathophysiological changes of AD to varying degrees are used.
Early AD patients were recruited as clinical subjects.
Patients who had not yet had functional impairment or were temporarily unable to detect clinical abnormalities were recruited as subjects.

2. there is a different understanding of the clinical significance of cognitive assessment.
In the past AD clinical trials, the use of cognitive and functional (or overall) indicators is usually used as the main end point of the evaluation of cognitive and functional (or overall) indicators due to the fact that the use of cognitive evaluation indicators is not of intrinsic clinical significance. This method of joint evaluation of cognitive and functional indicators can not only ensure that the benefit of the evaluation of functional indicators can be used to establish the role of clinical significance, but also to ensure that the AD core symptoms tested by cognitive indicators benefit from functional indicators.
This method of dividing the evaluation index into two is commonly used in the AD clinical effectiveness evaluation, but it also suggests that the only cognitive improvement effect is considered meaningless, unless the benefit of functional indicators with independent end-point evaluation is also associated with it.
But FDA is currently in the new guide that a sensitive neuropsychological test can be used to detect subtle changes in cognitive aspects. More significant cognitive changes may represent significant clinical damage, and the cognitive changes of special features (size or amplitude of action) may also represent clinical significance. Benefit.
From this we can see that the controversy about cognitive evaluation is mainly the evaluation method, not the “cognition” itself, especially for the overall cognition. In short, cognition is meaningful, but the significance of testing changes may be less obvious when it is tested using traditional methods and sensitive means for specific aspects.
To sum up, the practice of delaying, stopping, or reversing the pathophysiological process of Alzheimer’s disease must begin before the patient has obvious clinical symptoms, which requires us to understand how to evaluate the benefit of treatment at the early stage of Alzheimer’s disease. This is also the background and significance of the introduction of this guide.
Introduction to the guide content
1. guidelines for the purpose
This guide aims to help applicants develop clinical drugs for sporadic Alzheimer’s disease (AD), which is known as early AD in this guide, before the onset of obvious dementia. But it does not include specific discussions on clinical trials designed for patients with dementia or any autosomal dominant AD.
This guideline has revised the draft guidelines for Alzheimer’s disease issued in February 2013. This revision is related to FDA’s current idea of selecting early AD patients for clinical trials and the choice of clinical trial endpoints.

2. guidelines for the diagnosis of early Alzheimer’s disease
The qualification of Alzheimer’s disease effectiveness test (including early AD) should be based on the current consensus diagnostic criteria. The emphasis is on objective evaluation, and in appropriate cases, medical history and physical examination are carried out to determine the existence or possible existence of AD and to exclude other symptoms similar to that of AD.
FDA supports and endorses the use of modern understanding based on AD pathophysiology and disease progression as diagnostic criteria. Diagnostic criteria for only the earliest AD population characterized by pathophysiological changes are applicable to evaluating drugs that delay or prevent more obvious symptoms.
Important findings applicable to AD classification of continuous progress include:
Biomarkers were tested for pathophysiological changes.
Is there a detection abnormality in sensitive neuropsychological tests?
Are there any functional impairments that affect subjective daily life or subjective observation or report?
Although FDA recognizes the differences in clinical features and biomarkers selection and application, it can identify certain stages of the progressive disease process that patients are in. Although the classification of the following AD stages is not the focus of this guideline, it is of reference significance for the design and evaluation of clinical trials.

It is reasonable to expect AD biomarkers to play a role in early AD patients. In fact, clinical trials that do not include biomarkers in inclusion criteria are not common. If these evidence is needed to fully identify the expected population, applicants should be encouraged to communicate with the neuroscience products department, OTAT or equipment and radiation health center as soon as possible, and discuss with FDA the potential needs for co development of supporting diagnostic equipment.
3. observation index

4. time – event analysis
The use of time event survival analysis (the time for the occurrence of clinical events in the process of AD, for example, to a certain degree of impairment of daily function) will be an acceptable evaluation method for early AD in effective clinical trials.
Applicants who consider adopting this approach should discuss development plans with FDA at the early stage of development.
5. evaluation of disease process
Although it is essential to demonstrate the clinical therapeutic effect, it may not be feasible in clinical trials at the early stage of the disease.
Clinical trials of early AD are usually designed to provide evidence that drugs can permanently alter the course of AD by directly acting on the pathophysiology of the potential disease, which still exists without persistent drug exposure.
Generally speaking, random initial design is most suitable for use in AD. In the design of the study, patients were randomly assigned to drugs and placebo, and at some point, the placebo patients were cross actively treated. If the patients in the trial were initially given a placebo, and then the patients who were assigned to the active treatment failed (after a reasonable period of time) to receive active treatment during the whole period of the trial, the patients who had been treated with positive treatment had shown sustained treatment for the disease process.
The evaluation of various biomarkers may provide supportive evidence for the identified benefiting drugs that have clinical significance, but if the role of biomarkers in AD is not fully understood, evidence of the continuous impact of the disease process can not be provided. At present, there is no consensus on whether specific biomarkers in the early stage of AD support clinical research. For this reason, the applicant does not have enough information to establish a series of hierarchical biomarkers as a secondary outcome indicator in clinical trial design. Therefore, applicants are encouraged to analyze the results independently of these biomarkers, although in a predetermined way the understanding of these discoveries will be explained in the state of scientific evidence at the time of the application.

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