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Webinar Transcript: Draft Guidance For Industry On Alzheimer’s Disease: Developing Drugs For The Treatment Of Early Stage Disease

Transcript from FDA Webinar: Draft Guidance For Industry On Alzheimer’s disease: Developing Drugs for the Treatment of Early Stage Disease; Availability - March 28, 2013

Good afternoon; I am here with the FDA, I would like to welcome you to the webinar, Early Alzheimer's Disease, it is one of the most devastating challenges to our society today. The clinical and biological markers, which play a critical role in medical development. To discuss this I am delighted to present with the summarizing of the contents Afterwards there will be a session of public questions and answers, submit the questions to the docket as well, just to make sure that they are all systematically reviewed by FDA. And now I would like to welcome Nicholas A. Kozauer, MD.

Welcome, I’m Nicholas A. Kozauer, MD. I will start off the webinar with a presentation, before I begin it is worth mentioning it is a five it is a 5 1/2 page concise document. My presentation will be brief, which will leave time for questions at the end. I would like to start with some background, with context to the role it will play. I would like to walk through the diagnosis and how it is made in the trial element. I would like to talk about clinical endpoints, and then finish with two topics which are closely intertwined, which are biomarkers, and how does perfect of the underlying progression of the disease process. Or the disease modification. Then I will end with a summary. That should leave plenty time of for questions.
I want to be clear to point out this is a draft guide, it is to generate feedback and comments. It was released February 7th. There is a 60 day period for open date comment, which ends on April 9. As we go forward, the people who are interested in commenting, there is the website, www.regulations.gov. There will be a comment box to submit comments. I think the best place to start, is with the disease itself, to do this I would rely on a very frequently cited figure that comes out from a publication by the Mayo Clinic published in 2010, it is a theoretical model. For the purpose of this presentation it will serve very well. This is a model of the progression of Alzheimer's disease or co--- disease. We are looking at the clinical state of the patient at the bottom, pathology is accruing, they are asymptomatic. They have other names as well, MCI, where they begin to emerge, you then enter in the dementia state. This is what we think of when we think of the disease. When I say markers, I go through left to right , it changes the accumulation of abnormal protein, that happens long before systems emerge, it is followed by a neural injury, when brain structure is affected enough, you begin to see as time goes on cognition will be affected. You will see it in day-to-day clinical functioning, and then you will be able to make a dementia diagnosis. Why is this model relevant for guidance? It turns out all the studies over the decade or so, that evaluate drugs, and refer to them as drugs, -- all the drugs that have been tested, and thought to have of progression on the disease process, has been tested in the dementia stage. We have multiple examples from those trials, where they have been disappointing. One of the theories on why it might be the case, it was too late in the disease process. The damage was done. It was too late to have a clinical meaningful assessment. If the treatment was earlier, the patient  may have more benefit from it. It is working through early trials, it is the early stages, -- it is required that the framework -- novelty framework is required. Before I leave this figure entirely, -- regulatory Frager Merck -- framework. Before I leave this entirely, for our purposes we are not referring to patients with dementia, and not displaying the disease occurring in their brain, the dementia patients are what we are referring to. This will become most evident when we talk about clinical endpoints, the first crude patients being here, closest to the onset of dementia, they are beginning to manifest, but it is there and you can test for it. Contrast these patients to patients here which are early clinical stages, they are beginning to manifest cognitive impairment, it is very subtle in the beginning, most notably they have no detectable function. Just to reiterate the goals to the guidance is to provide a framework on how drugs may be studied, in early A.D. trials. So, as we get into the guidance, it covers how the early Alzheimer's disease might be made, as well as to diagnose pre-chemical or asymptomatic diseases as well. The first our working groups that are sponsored by the national Institute on aging, these groups have published criteria 2011. And then I would refer to the international working group for new research criteria for diagnosis of A.D., they were published in 2000 published in 2009, and revised in 2010. They all combine some manner of clinical diagnosis with affects on biomarkers that are thought to affect the underlying disease pathology. These are a couple of examples, amyloid pet imaging in the brain, and measures of brain volume, the position of the guidance and the agency on these criteria, we very much support the trials in early trials, the respective criteria themselves particularly as you get into the early stages of disease have yet to be evaluated. Agency is unable to endorse a specific set of criteria to make a diagnosis. The patient's been identified are very likely to go on to develop Alzheimer's dementia. How subgroups of these patients are identified are different criteria, cognitive testing, biomarkers, that would be fine, that is something we can deal with the labeling of the product. The next topic is clinical endpoints, this is so far in the guidance the dementia stage is that it could -- co-primary outcome measures, cognition, and function of global rating. -- Any effect that you see on a cognitive endpoint. As we look to early A.D. trials, it becomes primary on a couple reasons. There is no standalone for early stages, they do not have things to test for in the first place, we strongly believe the principal still holds, there needs to be some way of ensuring that there is a clinical meeting list to whatever effect we are seeing. The guidance really puts forth the pathways attempt to overcome this hurdle. This refers to the earlier slide, first I want to deal with patients that are onset over dementia, they have cognitive impairment, they have detectable function impairment, there are really no well valid skills to use in this, for that reason we put forth the idea that it would be possible to show an effect on a single primary outcome. And show it in the same scale, it internally speaks to the meaningfulness of the result. We used something used a clinical rating score, it assess different ranges of cognitive ability, this is the scale that we have given the most thought to, we are open to other skills as well that would cover these endpoints. We are aware that there are other skills under development. Going back to the earlier slide, the patients with the earlier slide of the disease, at first very subtle perhaps very -- only detectable in testing, the challenge with these patients is if you had a treatment you really believe to be disease modifying, these are the patients that would have the most to gain. They are the most earliest on. The only thing you can have is the cognitive performance, there are several such skills under development to look at cognition in early stages of patients. Incorporating elements of existing tests, regardless the effects are going to be small by virtue that these cognitive impairments will be limited. So, for that reason we put forth a possibility that we would be able to use accelerated improved pathway, listed in regulations, to approve a drug in this population. Accelerated approval is based on an effect with the I and -- that is reasonably to have an effect on my viral load in HIV. It is an effect on an intermediate clinical endpoint that is reasonably likely to predict ultimate clinical benefit. In this case and endpoint would be cognitive testing. After approval it would require that more would be done on the original studies that would ensure that there is an ultimate relationship between the intermediate clinical endpoint, and the endpoint that you care about. I want to be very clear to me, if we are going to approve the accelerated approval, we would have to identify the patients that would be exposed to the risk of treatment after approval, are very likely to go on to develop Alzheimer's dementia. We recognize that number will not be 100%. We would really have to have a good understanding of the risk before we contemplate using this pathway. For that reason the state of the science that would seek to rely on approval, for instance studies on Alzheimer's DoDs neural imaging and other studies, if that kind the evidence will weigh heavily on the use of accelerated approval. This is linking the disease with the stage with the clinical pathways, the approval could be accelerated approval based on their Mission -- based on cognition. This would be a standard approval and based on a single combined measure of function, in dementia trials, we believe they should stay as they are. A standard approval based on an effect on cognition, or function on global rating scale. In the last topic of the guidance, discusses if a drug is believed to have an effect on the pathology of Alzheimer's disease, how it can demonstrate that fact. This is a concern that leads primarily to a product and how it is labeled. We acknowledge that this is a desirable claim, if the treatment did have an effect on the progression of the disease, it would be good to have in the product labeling. One of the common ways to demonstrate is through a slopes of clinical endpoint, a separation overtime between active treatment and placebo, it is attempting approach to take, we have several concerns, I will not get into them now, it would be conceivable that a scenario will be difficult to -- it would be possible that a reset -- that would mimic the reaction. If there is a significant effective treatment that couldn't serve as the basis of approval, we do not believe that that argument in and of itself does not demonstrate. This is where biomarkers come in. We learned in the trial results, the effect on up Alzheimer disease biomarker, it is still very and clear. Where the biomarker has been altered but there is no clinical effect. The clinical outcome was the opposite of what you want to see. The bottom line is that that understanding and how it relates to the clinical outcome still needs a bit of work. We would not be willing to accept the effect on the biomarker, as a basis for a circuit -- Sarah get approval. For that to be the case, it would be a fundamental itself in the disease process. In addition to biomarkers there are other ways to show disease modification, a randomized start design, or withdrawal design. These are based on clinical endpoints. These are difficult studies to design, and conduct, and interpret. We are open to use these approaches to show modification, let me show you what I mean by randomized start design. One would be on .8, the other will be on placebo, the patients on group to will be switched over to active treatment, patients in group 2 will be caught up to group 1, they will have a systematic effect of treatment. Patients that were switched to never really caught up to the first group, can argue for an effect on the disease, this is challenging to do, but we are open to the approach. It is a devastating condition, and an epidemic make -- particularly in late stages, the field is moving to conduct trials in early stages of the illness. As I pointed out they will pose regulatory challenges. We hope that's where our guidance will come in and suggest pathways forward. Thank you. I will have Russell Katz, come up and talk for the rest of the webinar.
That is great. The first question is about systematic question, -- you have disease modifying approaches were path, and may be okay and, the first part on systematic therapy developed under the guideline, I'm not sure if the questions is asking how it is now? Or early development in Alzheimer's? As Nick just described the portion of it is small, identifying patients early, as he pointed out, the choices of the outcome measures and the states of Alzheimer's disease that it talks about, early MCI, and late MCI so-called, it is not talking about any systematic -- the point is I think it discusses ways to discuss the treatment effect, certainly we had anticipate the drugs would be systematic, and the questions of outcome members -- measures would apply to systematic therapies as well. Would be potentially disease modifying drugs. If the question is asking if it is happening now? I think although the guideline is draft, it would not become final until we have heard from anyone who would want to comment, as we read and discuss them, it does represent more or less how we currently think. We have spoken to sponsors about how applying these diagnostic criteria measures in the study, if they come to us now. So that it can be new used -- it could be used now. -- Support may be entertained, again, as Nick explained, the guidance says that we would entertain the possibility that a combination of the drugs effect on a clinical outcome with a cognitive measure and the biomarker believes to be associated with the pathology of the disease, we haven't said that we would approve a treatment based on that combination of outcomes, but we have said that we would consider the possibility, that a package of outcomes would support a disease modifying claim. Hopefully that answers that question. The next question, as the graph shows in the beginning where would purge oh no -- the patients be -- were with the patient be. I will put up the slide.
Here we go. I think that it would exist within the MCI section, it would depend on how it would be defined. Plus a biomarker, that exists in that patients that are closer to onset dementia, going back to the subgroup, I don't know that it would be cognitive normal, it depends on how you define it, it would be within that grouping somewhere.
Sometimes people use the terminology of pre-clinical, that refers to folks that are not systematic at all, to the left of the MCI patients. That Nick talked about. They have risk factors or are likely going to develop Alzheimer's disease based on other imaging or biochemical changes or even genetic predisposition. The next question I think says with regard to enrichment, what is that FDA opinion of the EMA opinion. They have accepted the use of the early diagnostic criteria, as identifying patients with early Alzheimer's disease. We are very much in favor in enriching trials, in the diagnosis, there are several and differences between them, they are minor from our point of view, we haven't formally accepted those criteria officially. As identifying patients with early Alzheimers, it is likely that either one of the criteria to identify patients. We urge them to use this criteria. There we may learn something more about quantitatively how much to increase the likelihood in patients that do have Alzheimer's disease, as opposed to other criteria, we endorse the use of these. With sponsors, we haven't believed taken the exact step of the EMA, they have formally adopted them, but we are likely to.
One thought on that as I thought the EMA qualifications are not necessarily that prescriptive, they would say patients with MCI that have changes are more likely to go on develop Alzheimer dementia.
The next question is where is the time fit into the -- is that a clinical outcome that must achieve biomarkers -- they are perfectly acceptable from our point of view, it may be at times of diagnosis of dementia, I timed for a well-defined event would be a perfectly reasonable outcome, with the basis of a treatment, it is not a design in our view, one could imagine a drug that simply has a systematic effect, and Tlingit time to a event, or the diagnosis to Alzheimer's disease. We do not believe in it of itself it establishes a treatment, as disease modifying, we think of it as a clinical outcome when combined with the appropriate biomarkers might support a disease modifying claim. The next question does a recommendation for a single to the broader population without the evidence of underlying A/D pathology. That is an interesting question. Very often patients who are enrolled in trials of MCI in the past, patients in previously done studies have not had an assessment of whether there has any underlying pathology; they have not had fluid examination, or an MRI to look at the brain. We have accepted that in the past. The concept of a single measure, Inc. patients that -- in patients that have a mild deficit, would apply to anybody that has MCI of that type. Whether they are defined by a president underlying pathology or not. We think in the studies that are being done now, it is very useful to examine patients for underlying pathology, for several reasons, for one, to enrich the study population to increase the chance that the patients will be responsive. And another which Nick talked about, if we were to approve a drug based on the effect of early patients, we would very much want to be sure that we are pretty sure they have Alzheimer's disease, some patients that are simply clinically diagnosed may not go on to have Alzheimer's disease. For ultimate approval we want to make sure that we are not exposing large numbers of patients to treatments in which there is no chance to respond, those patients will be exposed to risk. And a broader MCI population in theory, in most studies in the early patients, now days, these biomarkers are assessed, or again for no other reason it will increase the likelihood to yield a result. Again, systematic treatment covered by these guides or moving away from the approach? We are not moving away from systematic treatments, they are reasonable, they are continuing to develop treatments, there is a major shift, him potentially modifying disease potential. Between systematic disease and modifying disease, if you want to see the effect, these are the things you will have to show the effect on.
I think it would be a little challenging were accelerated approval would apply to a systematic treatment. It would suggest that the benefit you are getting would be well taking, it is more focused on in the longer term increasing benefit overtime, it is a little difficult to envision that approval mechanism will apply.
I agree. A number of commentators, -- in addition to the component of there are other measures that can be approved? I think the short answer is, we are open to looking at any measurement that someone believes, can measure executive function in the beginning, the cognitive function, or a combination of cognitive and behavioral of global changes, as the guidance talks about. It does not take a position on other outcomes. It doesn't mention the MPB, the simple answer is yes it certainly might be other measures, we do not have any particular ones in mind. It is very clear on the guidance that we would entertain other measures.
In a randomized start design would they have to be re-randomized? I don't know that it would have to be half and half, we would anticipate that there would be some randomize station involved. It has been rarely done, I'm not sure if there has ever in done successfully, I think we would want that second phase to be blinded. Will be FDA provide similar to Parkinson's? Thank you that was part of the question. We do not have any plans to do so at the moment. It is a possibility, we are thinking of writing other guidances, and in the process of doing so, we have not developed a plan for Parkinson's disease at this time.
What supports -- a disease modification? The guidance says that we want to hear from the expert community, which combination of biomarkers might be acceptable, certainly many people have their own personal favorite, potential biomarkers, Nick talked about imaging alloyed in the brain. Incher Cuyler -- all of these have been proposed and actively looked at in clinical trials, and being assessed. Any of these or perhaps others are at least potentially, useful as providing support of evidence to clinical finding.
One other addition to that, because we don't know which is the ideal biomarkers at this point, in trial design, there will not be a ordering of these markers. We would want these markers included analyzed, and that we can interpret them in the science coming get with the application, it wouldn't be necessary to order how you would handle those markers.
Which of course is a slight deviation from the plant, the science is new here, we want to be open to the possibility at some point, it may become clear which biomarker.
Can you elaborate on slopes approach, the text mentions it as a concern. The use of the interest to the development community. I think it is possible we seeing in shorter periods of study, these typical modifying diseases studies are, have it be related to a systematic effect alone. When Nick put up the slide of the randomized withdrawal design schematically, the whole point is when you take the treatment away, there is a possibility they will return back to where the placebo patients were. Which applies systematic effect. They could show the systematic treatment, and the second is to address that question. We don't understand how these drugs work area very well, it could be a systematic effect could increase over time. That is a possibility, what we are looking for in the point of view, a disease modification claim will be extraordinary major claim for a sponsor to have. One may decide a particular drug granted modifying claim, everybody would have to be on that drug. It is a big deal to grant it, we want to be sure when we conclude that a drug has a modifying effect, that it really does. That implies that we would like a study design, that can be interpreted as showing a disease modifying effect with as few assumptions as possible. And so we think a clinical design that forces the conclusion, that the effect is modifying, or the combination of the two, the randomize withdrawal that Nick has described, has those qualities if they can be done appropriately. We do not want to have to assume that it is demonstrating a disease modifying effect.
Why do asked for single endpoint well other patients are less functioning? I think we believe for all intents and purpose, I think we ask for a single combining functioning, is that as Nick pointed out they are still impaired in functioning, whether it is early patients, or late patients, we want to make sure any treatments we approve have a meaningful effect on the patient globally functioning. It is one thing the drug can improve the ability in a cognitive test to remember two words, doesn't necessarily imply that the patient what actually be benefited in their life. We want to look at functioning, as a concept, the principal of assessing whether a drug has the effect on the functioning, is what we want to preserve whenever we can. We think in patients with MCI, they are impaired, and we believe there are tests that can detect their functioning. That is really any goal for treatment for Alzheimer's disease, it is not to remember one or two more words on a list. The guidance is a draft specifically so that we can hear what people in the field think. We look forward to hearing what people say.
Could you elaborate how diagnostic criteria could be? Some of this is evaluated from the formal process, it would involve looking at them in a test result, in a large cohorts of people suspected of having Alzheimer's disease, and following them forward. I think we are particularly interested in looking in it quantitatively and how much they help, in diagnosing patients with MCI today. I think you have to follow a group of people and see how many had abnormalities, in the baseline, and how many go on to have Alzheimer's disease.
Does enrichment within a clinical trial automatically translate for patients that meet the criteria? That is an excellent question, I don't think we have a definitive answer yet. If you identified people with a trial using clinical as well as laboratory, markers, would one have to require it to be treated? You must identify your patience with the following tests. I don't think we have taken a position on that. It is not a priority given that we would echo we would have to think about two things. One how much better are we at diagnosing these patients? With the diagnosis of the test, with it alone. The other bit would be -- in other words how much do those lab tests help us. The other piece is how dangerous is the drug? We might be willing to say yes in trials, they were evaluated in diagnosing clinical plus lab tests. If you do not do that 20% of patients will have Alzheimer's disease. The drug is extraordinary benign, we may be able to live with that miss rate of diagnosis. If the criteria only help us a little, it may not help us at all. We need to take those two factors into consideration.
Another thing is patients, with Anna Lloyd imaging -- could you identify it as another measure? I don't think that is an answer we have it is another consideration.
What is the overall message they are trying to send with this guidance? I think there are a couple of big messages, it talks about potentially distinguishing -- as Nick pointed out that is a labeling question, it is not critical for approval, I don't think that is one of the big ideas, the big idea is how do we assess a clinical meaningfulness, or drug effect in patients with the very early disease, or not significantly impaired? So far it has been with patients that are significantly impaired, the big issue is how we assess outcomes in very early patients? That is the big message from my point of view. We talk about how we could do that, obviously. The other big idea is the endorsement, of the relatively new criteria to identify patients early. And to do it that are job of identifying patients early.
When using a biomarker as a marker, is it required to develop the test? If the label says you must use this test, to diagnose your patience, then that test becomes a companion diagnostic. That is my understanding, that would depend, as I said before, we may not require these tests be done if the drug is approved under these approaches. Again, it is a good idea at the beginning of a development program to come to the agency with these questions. We could bring all of these the relevant experts to weigh in.
Okay, this is the last question. I'm glad it was asked, there's been media headlines, when the draft has come out, that the FDA is loosening guidelines, do you agree with the assessment? I don't know who ask this, but thank you. A couple of things I don't believe it is loosening our guidelines. First of all, whatever approach is taken, there would be substantial evidence, whatever the population is, that is a given. The thing about loosening guidelines, further, first of all there is no standard for developing treatments for early patients, there are no standards in place. We have never approved the drug for these folks, that is what it is about. It only makes sense to utilize outcome measures, that are appropriate for the condition being treated. For patients with clearly impaired functioning, separately, we could do that. We are tailoring the outcome, it is important that we do that with every drug we deal with, that is the approach here, we think the fact that we go to a single measure which combines both, as opposed to outcomes, is just the appropriate thing to do for this population. We do not believe that we are loosening guidelines, accelerated approval for a very early patients is an appropriate standard. There still has substantial evidence to that effect, we do not believe in that is loosening guidelines either.
I would like to thank Nicholas A. Kozauer, MD and Dr. Katz for this webinar. I would like to remind the audience to submit questions.
Thank you. [Event concluded]


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