Contributed by: Dennis Fortier, President, Medical Care Corporation
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There has been a lot of press recently about diagnostic tests for Alzheimer's disease including this piece from Examiner.com that has garnered a lot of attention today. Digesting this news requires a broad perspective on the problem.
Physicians will tell you that solving a medical problem involves three distinct steps:
First you need to recognize that a problem exists. This is often a simple task when clear symptoms are present. Other times however, symptoms are vague and a physician must take steps to determine whether or not a legitimate health concern is at hand.
Second, you must diagnose the problem. If the symptom is blurry vision, for example, the physician must diagnose the root cause of the problem because a care plan for diabetes is much different then a care plan for a scratched cornea.
Third, the physician must select the appropriate care plan and oversee its administration.
When all three steps have clear guidelines that lead to successful clinical outcomes, physicians generally deliver fantastic medical care. When one or more of these three steps is uncertain, standards of care tend to vary from good to less good. In the case of Alzheimer's disease, it turns out that all three steps have some uncertainty.
Early stage Alzheimer's disease has generally vague symptoms usually including subtle memory loss. This is challenging for physicians because many adults, a large percentage of whom are perfectly healthy, sense that their memory is not as sharp as it may have been in the past. The difficulty in sorting the healthy from the unhealthy leads to a delay in meaningful intervention.
Once a physician decides a problem is present, the diagnostic process for AD is perceived as uncertain based on the over-emphasized fact that autopsy is the only certain approach. Importantly, any physician following the NINDS-ADRDA diagnostic guidelines can accurately diagnose AD and other problems on a consistent basis (but this is not well understood by most primary care physicians). Finally, current treatment options are considered uncertain given the variability with which patients respond. Some patients seem to respond while others do not. Overall, there is a lot of uncertainty around this disease.
The primary point of this post is that stories like the one referenced above can only be appreciated in the context of the full continuum of clinical steps to identify, diagnose, and treat Alzheimer's disease. While an accurate diagnostic test will be a welcomed advance, the problem is quite complex and such a test will have limited impact until we can sure up all three steps in the care process.
How Drugs get Approvd by the FDA
Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego.
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Before a drug can be approved for use by patients, there is a set of clinical tests that must be performed. There is the Pre-Clinical Research Stage. Here the drug is synthesized and purified. Animal tests are performed, and institutional review boards assess the studies and make recommendations on how to proceed. If the recommendations are positive, then an application to the FDA occurs and clinical tests in humans may begin.
Phase 1: Clinical studies in this phase represent the first time that an Investigational New Drug (IND) is tested on humans, either healthy volunteers or patients. The purpose of these studies is to look at the metabolism and any potential side effects of the drug in humans. Phase 1 studies are usually conducted on 20 to 80 subjects and are therefore concerned with safety and tolerability.
Phase 2: The purpose of phase 2 is to determine the efficacy of a drug to treat patients with a specific disease or condition, as well as learn about common short-term side effects or risks. These studies are conducted on a larger scale than phase 1 studies and typically involve several hundred patients.
Phase 3: These trials provide even more information about the effects and safety of the drug, and more importantly assess the efficacy or the drugs ability to treat the disease. Phase 3 studies generally involve several hundred to several thousand people and can last from months to a couple of years. These trials are almost always double-blind and placebo controlled. This means that neither the subjects nor the researchers know who is getting the investigational drug versus placebo (or sugar pill).
There are several checks and balances in the process of clinical trials; among them is the use of institutional review boards (IRBs) and advisory committees. IRBs are designed to protect the rights and welfare of people participating in clinical trials both before and during the trials. IRB's are made up of a group of at least five experts and lay people with diverse backgrounds to provide a complete review of clinical proceedings. Also, clinical trials are monitored for their entire duration by study monitors and safety monitoring boards that follow subjects in real time as trials progress.
The Application Process:
Once a trial is complete, or closed, the data is then analyzed by statisticians and researchers to look for efficacy. Since many trials are multi-center, this process can take many months, the results of which are eventually submitted in a formal application to the FDA for final approval. This New Drug Application (NDA) must include results and analyses from tests of the drug on both animals and humans. The NDA must provide enough detailed information for FDA reviewers to make several critical decisions. The result of the study must show whether the drug is safe and effective and whether its benefits outweigh its risks.
The process of developing and testing a new drug is a lengthy one. The FDA estimates that it takes a little over 8 years to test a drug, including early laboratory and animal testing, before there is final approval for use by patients.
FDA Approval
The FDA's decision whether to approve a new drug for marketing comes down to answering two questions:
1. Do the results of blinded, placebo-controlled studies provide substantial evidence of its effectiveness?
2. Do the results show that the product is safe under the explicit conditions of use in the proposed labeling? Here "safe" is a relative term; it means that the benefits of the drug appear to outweigh its risks.
When the review is complete, the FDA writes to the applicant to say the drug is either approved for marketing, is "approvable," provided minor changes are made, or is not approvable because of major problems.
___________________________________________
Before a drug can be approved for use by patients, there is a set of clinical tests that must be performed. There is the Pre-Clinical Research Stage. Here the drug is synthesized and purified. Animal tests are performed, and institutional review boards assess the studies and make recommendations on how to proceed. If the recommendations are positive, then an application to the FDA occurs and clinical tests in humans may begin.
Phase 1: Clinical studies in this phase represent the first time that an Investigational New Drug (IND) is tested on humans, either healthy volunteers or patients. The purpose of these studies is to look at the metabolism and any potential side effects of the drug in humans. Phase 1 studies are usually conducted on 20 to 80 subjects and are therefore concerned with safety and tolerability.
Phase 2: The purpose of phase 2 is to determine the efficacy of a drug to treat patients with a specific disease or condition, as well as learn about common short-term side effects or risks. These studies are conducted on a larger scale than phase 1 studies and typically involve several hundred patients.
Phase 3: These trials provide even more information about the effects and safety of the drug, and more importantly assess the efficacy or the drugs ability to treat the disease. Phase 3 studies generally involve several hundred to several thousand people and can last from months to a couple of years. These trials are almost always double-blind and placebo controlled. This means that neither the subjects nor the researchers know who is getting the investigational drug versus placebo (or sugar pill).
There are several checks and balances in the process of clinical trials; among them is the use of institutional review boards (IRBs) and advisory committees. IRBs are designed to protect the rights and welfare of people participating in clinical trials both before and during the trials. IRB's are made up of a group of at least five experts and lay people with diverse backgrounds to provide a complete review of clinical proceedings. Also, clinical trials are monitored for their entire duration by study monitors and safety monitoring boards that follow subjects in real time as trials progress.
The Application Process:
Once a trial is complete, or closed, the data is then analyzed by statisticians and researchers to look for efficacy. Since many trials are multi-center, this process can take many months, the results of which are eventually submitted in a formal application to the FDA for final approval. This New Drug Application (NDA) must include results and analyses from tests of the drug on both animals and humans. The NDA must provide enough detailed information for FDA reviewers to make several critical decisions. The result of the study must show whether the drug is safe and effective and whether its benefits outweigh its risks.
The process of developing and testing a new drug is a lengthy one. The FDA estimates that it takes a little over 8 years to test a drug, including early laboratory and animal testing, before there is final approval for use by patients.
FDA Approval
The FDA's decision whether to approve a new drug for marketing comes down to answering two questions:
1. Do the results of blinded, placebo-controlled studies provide substantial evidence of its effectiveness?
2. Do the results show that the product is safe under the explicit conditions of use in the proposed labeling? Here "safe" is a relative term; it means that the benefits of the drug appear to outweigh its risks.
When the review is complete, the FDA writes to the applicant to say the drug is either approved for marketing, is "approvable," provided minor changes are made, or is not approvable because of major problems.
Preventing Alzheimer's Disease
Contributed by: Dennis Fortier, President, Medical Care Corporation
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The March 27 issue of Alzheimer's & Dementia, the journal of the National Alzheimer's Association, is dedicated to the notion of preventing Alzheimer's disease. In a tone-setting editorial (Prevent Alzheimer's disease by 2020: A national strategic goal), authors Zaven S. Khachaturian and Ara S. Khachaturian outline a road map to achieve this important national goal.
While the looming specter of rising dementia prevalence is daunting, it is clear that coordination of resources and well-directed funding could catalyze a more efficient discovery process and accelerate advances in this field. Success will require resources, infrastructure, and central governance of a process that integrates several legacy research efforts currently underway. The author's vision is broad but tangible, comparing the goal of preventing this disease in the next decade to a similarly spectacular scientific feat accomplished by an earlier generation that put a man on the moon with the Apollo Space program.
Overall, it is an article that breeds hope through its comprehensive consideration of both the problem and the solution. Several, more focused perspectives are offered by luminaries in the field with insight on some specific element of this multi-faceted problem. Taken together in the full issue, these perspectives paint a clear and plausible picture of how we can indeed, prevent Alzheimer's disease by 2020.
________________________________________________
The March 27 issue of Alzheimer's & Dementia, the journal of the National Alzheimer's Association, is dedicated to the notion of preventing Alzheimer's disease. In a tone-setting editorial (Prevent Alzheimer's disease by 2020: A national strategic goal), authors Zaven S. Khachaturian and Ara S. Khachaturian outline a road map to achieve this important national goal.
While the looming specter of rising dementia prevalence is daunting, it is clear that coordination of resources and well-directed funding could catalyze a more efficient discovery process and accelerate advances in this field. Success will require resources, infrastructure, and central governance of a process that integrates several legacy research efforts currently underway. The author's vision is broad but tangible, comparing the goal of preventing this disease in the next decade to a similarly spectacular scientific feat accomplished by an earlier generation that put a man on the moon with the Apollo Space program.
Overall, it is an article that breeds hope through its comprehensive consideration of both the problem and the solution. Several, more focused perspectives are offered by luminaries in the field with insight on some specific element of this multi-faceted problem. Taken together in the full issue, these perspectives paint a clear and plausible picture of how we can indeed, prevent Alzheimer's disease by 2020.
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