Quantitative Morphology in Kidney Research
February 13-14, 2012 Conference Videos

Quantitative Morphology to Generate Surrogate Outcomes: Morphologic Changes as Surrogate Outcomes – How Are These Defined and Validated? FDA Perspective
Aliza Thompson and Lynne Yao, U.S. Food and Drug Administration (FDA)

Video Transcript

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JEFFREY KOPP: So, the last session was about starting to think about taking these tests to the clinic and the next speaker from the FDA is going

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to help us think at least some of these studies we’re looking at potentially might be brought to the clinical practice at some point and therefore are

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going to have to pass through the FDA if they’re going to be actually used in clinical medicine as predictors to help us choose therapies and so

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forth. So, what is the road map—to use that commonly-used term—that we need to be thinking about now as we develop these various

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tests? Our speaker is Dr. Aliza Thompson, a nephrologist who is a team leader with CDER, Center for Drug Evaluation and Research, at the

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FDA and she is the perennial nephrology group go-to person when we want somebody from the FDA to come help us think through what the

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process is; in this case, biomarker and particularly, renal pathology biomarkers. So Aliza, thank you very much.

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ALIZA THOMPSON: Hi. Can everyone hear me? Maybe I’m too loud. Thanks for this invitation to speak and Happy Valentine’s Day to everyone.

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Clearly, the work that’s being discussed at this meeting has many important applications and I’m going to focus on one application, which is its

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use as a tool in drug development. If you look at drug development, certainly histology has been used in the preclinical setting in animal studies as

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a way to inform our understanding of a drug’s potential for nephrotoxicity in the clinical setting, but to a much lesser extent it’s been used,

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actually, within the context of clinical trials as a way to facilitate the development of therapies that could potentially improve the lives of people

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with kidney diseases, and so I’m very hopeful that this will be one of many discussions we will have about the use of this as a tool within the

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context of drug development. Let’s make sure I can work this. Okay. And so, the topics I’m going to touch upon in this talk are a few. One is I’m

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going to give you a general sense of what the efficacy requirement is, then I’m going to talk a little bit about how we evaluate potential

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surrogate endpoints, talk about the use of surrogates and their implications for assessing a drug’s safety profile, and then from there talk

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about morphologic changes in the kidney as a potential surrogate endpoint for the purpose of drug development, keeping in mind that, of

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course, there are a lot of ways we could use changes in kidney morphology within the context of drug development, but I’m just going to focus

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here. Of course, the disclaimer. What you want to hear is what the FDA thinks, but regrettably I can’t tell you what the FDA thinks. So, the regulatory

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framework. Before a drug can be marketed in the United States it has to be shown to be safe and effective for its intended use. This requirement

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really arose just within the last 50 years and came about in the setting of a safety crisis. Probably as many of you know, thalidomide had

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been marketed outside the United States both as a sedative and as a treatment for morning sickness in pregnant women, and unfortunately it

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was later discovered that this was a horrible [---] and led to the birth of many children with marked abnormalities, specifically in limb formation. In the

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U.S. the drug wasn’t approved and the crisis was narrowly averted but nonetheless, as a result of this crisis, it led to the passage of laws

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that dramatically expanded both the responsibility of the FDA and also its power and essentially led to what many would call the Efficacy

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Requirement. If you look at actually what the law said it really spoke more and speaks more to the quantity and the quality of data that you need in

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terms of showing that your drug works. So, what the law refers to is “substantial evidence” of efficacy and that this evidence is supposed to

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come from adequate and well-controlled trials. In practice what that’s generally been taken to mean is that you need two studies, you need P values

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less than .05 in those studies, and that those studies should be randomized studies with either an active or a placebo control. But if you ask sort

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of what endpoints you need to show your drug effects, that was something that really came about later and something that the courts really

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addressed, and what the courts concluded later on was that that endpoint that you had to affect actually had to be clinically meaningful. So again,

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drug approval can be based on clinically meaningful endpoints which the agency has come to interpret as an endpoint that reflects

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how a patient feels, functions, or survives; or we’ve also allowed the use of surrogate endpoints and from a regulatory standpoint,

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surrogates have a very specific meaning. I know when we refer to surrogates often we just mean that they’re substitutes, but from a regulatory

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standpoint a surrogate is supposed to be some…can be a laboratory measure or a physical sign, but it’s used in therapeutic trials as a substitute or

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in lieu of the actual clinical outcome that you care about. And so really, surrogate endpoints are expected to predict the clinical benefit of your

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therapy on that outcome of interest. From a regulatory perspective we view two types or we have two types of surrogates. One is an

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accepted surrogate, something like blood pressure which, if you show an effect on that endpoint, it’s a basis for outright approval. You’re

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done; we believe that your therapy is providing a benefit to patients. There’s another type of surrogate, however, and that’s a surrogate

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where there’s a little bit less certainty about what it’s predicting and those types of surrogates are used in the setting of accelerated approval for

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diseases that are serious or life-threatening, and this type of surrogate or approval using this type of pathway comes with a requirement after

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approval to actually complete studies verifying the benefit in the post-marketing setting. It’s obvious to all, I think, there is a hierarchy of

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endpoints, so showing your treatment effects and mortality is incredibly compelling evidence of a drug’s efficacy. Showing that your treatment

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affects a surrogate can provide evidence of efficacy, but it’s just less compelling. I just also want to make the point on this slide that ultimately

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when we look at drugs and we try to understand what they do we often think about them in terms of what their efficacy is and then, on the other

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hand, what their safety is, but ultimately what we need to get some understanding of is whether or not they provide net benefit. So, I just also want

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to make the point that if you’re having a mortality benefit or you’re affecting cancer, that the tolerance for risk is higher; you can have a

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chemotherapy that has nephrotoxicity. On the other hand, if your effect is just on blood pressure, your tolerance for risk is much less

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and we’re probably not going to approve an antihypertensive that has marked nephrotoxicity. So, why use surrogates? Well, I think this is

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probably obvious to all of you. The appeal of surrogates is that they can be used in clinical trials to establish effects in smaller studies and

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allow us to conduct studies of shorter duration, and in terms of at least nephrology drug development, something that often rises is that

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the endpoints that we really care about may be rare events or they may be events that occur very late in the disease course, and so to a large

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extent, surrogates are seen as a way to enable drug development where it might otherwise not be possible, in essence, for early stages of

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disease or in settings where the disease is less severe. So, how do we look at surrogate endpoints? How do we evaluate them? I’ll tell you

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about the approach in a minute but I just want to open this up by pointing out that the approach that we use in our evidentiary standard is

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probably higher than that that’s used by the medical community in everyday practice or even what’s endorsed or the approach taken in

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guidelines. I think there are two reasons for this. One is that how conservative we are in our thinking depends in part on who we are making

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the decisions for, but it’s also because it depends upon how definitive our recommendation must be, and I want to illustrate this with two examples. I’m

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told, for example, that I have cancer. I may be very willing to try a therapy where there’s not a lot of data to support it; it’s my body and I make a

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decision. However, practicing as a physician, I may put a little bit more caveats around it and may not recommend it to a patient, and certainly in

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writing a practice guideline, I may not endorse it at all. So, that’s one example. Then in terms of the definitiveness of the recommendation, I want to

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make the point that in everyday practice when you see patients—those of you who see patients and make recommendations for therapies—you

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can make statements like, “Well, it hasn’t been shown but there are some data out there that suggest it might be beneficial,” when you all or

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those of you who are involved in writing the guidelines write guidelines, you can grade them. You can say, “Well, this is not based on strong

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data but we, as experts, think it’s maybe a good idea.” Unfortunately or fortunately, we as an agency don’t get to qualify our statement that the

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drug is effective or going to provide net benefit. The assumption is once it’s approved by the agency that at least in the population that’s

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described in the label, it should work. So again, what you’re about to hear is maybe a little bit more conservative but I think there’s a reason for

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that. So, what are the types of data that we often look to when we’re evaluating surrogate endpoints? I think a key thing is whether or not

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there’s a strong reason to believe that the biomarker is actually on the causal pathway to the disease. Other types of data that we look at

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include observational data, which essentially show a relationship between the marker and the outcome of interest; and finally—and this is sort

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of the highest level of evidence—is the extent to which there are actually data from interventional trials showing that your treatment’s effect on the

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marker predicts the treatment’s effect on the clinical outcome that we’re interested in. So, the agency has over the years adopted some

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surrogates, not a lot, and I think these examples are going to show you some of the different approaches that have been used or the types of

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data to support surrogate endpoints. So, let’s take the example of blood pressure as a surrogate. Why do we buy it? Well, over the years there

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have been numerous intervention trials using drugs from distinct pharmacologic classes and that experience has told us that treatment effects

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using these drugs on blood pressure ultimately predicts treatment effects on cardiovascular outcomes, so that’s one example. However,

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there’s another realm of surrogates and I would say something like: electrolytes fall in that realm. Certainly you know there are drugs that are

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approved to lower potassium levels. We also have now a whole class of drugs that been approved to raise serum sodium levels, and I

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would argue that those drugs or the use of sodium or potassium or phosphate as a surrogate endpoint, what didn’t lie in the same type of data

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that we have for blood pressure, but it more lies in the realm of biologic plausibility. We know that when your potassium goes very high you end up

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in a cardiac arrhythmia and so there’s a lot of plausibility that potassium is causing that, and we know that when you lower it you can see the

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changes in the ECG, and similarly it would argue for something like sodium, you know, that as levels get very low you see mental status

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changes, you can see cerebral edema, herniation, and we know that bringing the sodium back up can reverse some of these things. So

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again, two ways of approaching a surrogate are validating it and I again want to stress that when there’s biological plausibility that it’s really on the

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causal pathway; in some ways it’s an easier route. I would also like to make the point that it’s through all these data and intervention trials using

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these different agents that showed that effects on blood pressure predicted outcomes. I’m going to argue that. That’s, in part, why we think high

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blood pressure actually causes strokes and heart attacks in those types of things. So, surrogate endpoints. Certainly it is not unreasonable, or in

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fact, it’s very sensible to think that a marker that could identify patients that are at risk of poor outcomes is also going to predict a treatment’s

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benefit. However, this isn’t always the case and I just want to point to some examples of where markers that have performed very well at

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predicting a patient’s risk haven’t done such a good job at predicting a treatment’s effect on clinical outcomes, and I’ll pull one from the field of

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cardiology and one familiar to perhaps all of you from the field of nephrology. So, let’s talk about something like ventricular premature

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depolarizations. They were a good risk marker for sudden and non-sudden cardiac death after MIs. Unfortunately, when some antiarrhythmics

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were used in efforts to suppress these arrhythmias, you actually saw more deaths in the arm that got these treatments. Switching over to

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the field of nephrology and hemoglobin levels, low hemoglobin levels do a good job at identifying patients in populations at greater risk for cardiac

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disease and mortality and certainly do so in the area of chronic kidney disease. However, in studies where erythropoiesis stimulating agents

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were given in efforts to improve hemoglobin levels, actually using these drugs to target higher versus lower levels led to worse outcomes. So

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again, you can be a good marker of risk but not actually predict your treatment’s benefit. So, why do surrogates fail? Well, sometimes it’s simply

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because we got the relationship wrong but a lot of people believe that what’s happening in a lot of settings is that the drug has unexpected and off-

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target effects and that these are essentially negating the benefit, or worse, actually resulting in harm to patients. I just want to point out that

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this isn’t an issue just for surrogate endpoints but anytime you use some sort of intermediate endpoint which isn’t really the ultimate endpoint

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that you care about. So, I just want to make a few quick comments about safety because I think the use of surrogate endpoints has important

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implications for assessing a drug’s safety. Compared to how we look at effectiveness, safety is certainly a less-well or less-assessed

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in clinical trials, and as a compensation for this, we view safety with a very different lens than we view efficacy. So for example, to get a drug

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approved you may want a P value less than .05. You don’t need to see that to be worried that there’s a safety signal, it can be sufficient to see

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an adverse trend, and it’s not necessary that this biomarker be fully validated as a marker or in its ability to predict a treatment effect. It can be

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enough to use a marker where there’s just some association between the marker and bad outcome to raise concern. The other point just to

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make, it’s important to consider when you look at safety, it’s not just what’s actually seen within the development program but also what risks and

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level of risks the development program can exclude and how well the studies were designed to actually capture those risks. A case in point,

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again, to look to the erythropoiesis stimulating agents, it really took studies that were designed to show that these treatments were going to help

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people in terms of CV benefits to actually demonstrate their risks. Again, you need larger studies to actually see the safety signals. So,

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how does this relate to surrogate endpoints? Why am I telling you any of this? Well, keep in mind that the goal of therapy is to provide net

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benefit and also keep in mind that the concept of safety is not, again, that a drug is “safe” but it’s safe within the context of the benefit that it’s

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providing. Again, compared to an outcome like mortality or some clinical outcome that the patient directly perceives the nature of a benefit

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provided by a surrogate endpoint is just less obvious, and the implications for that is two-fold. One is that you’re going to have less tolerance

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for risk if you’ve established your efficacy by showing effects on a surrogate, but the other implication is that the size of your development

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program—how much safety data you’re going to need—is going to be dictated, to a larger extent, by safety concerns if you employ a surrogate

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endpoint in the development program. With that I wanted to move on to talk about the topic of today’s meeting or topic related to today’s meeting

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which is morphologic changes in the kidney as a surrogate endpoint. If you look at drug development, or at least drug development in the

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kidney arena, histology has been used to a very limited extent, I would argue, to support drug approval and there are really two situations that

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I’m aware of. One is it’s been used in the setting of therapies that are being developed to treat acute organ rejection and kidney transplant, and

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here biopsy proven acute rejection has been used as an endpoint; and then the other setting is in Fabry Disease where they looked at effects on

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a molecule and its deposition in certain cell types, including cells in the kidney, as a way to establish the efficacy of a therapy. In this latter setting it

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was one of the…the first setting is the concept of a surrogate endpoint that leads to outright approval, the second setting was a surrogate

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where there was still some uncertainty, and so it came with it a requirement to do a study and the post-marketing setting verifying the treatment

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benefit. So, what are considerations in using morphologic changes as a surrogate endpoint? I think they fall into a number of categories. One, of

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course, is: what’s the clinical significance of the finding? Another issue that gets raised is, even if you decided the finding is probably clinically

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significant, you have to figure out what size and effect on the finding is likely to matter, is likely to translate into a treatment benefit, and then I think

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there’s always the question, “Will use actually enable more efficient drug development?” Then, there are finally practical and ethical

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considerations. So, what’s the clinical significance? Again, this goes back to the types of data you’d like to see supporting a potential

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surrogate. What’s the nature of the data linking to a particular finding in a specific disease to adverse renal outcomes? Again, it’s not sufficient

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to know that the marker does a good job at diagnosing disease or identifying patients at high risk of progression; what you really want to

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know or what’s very helpful to know is that reasonably the finding is actually mediating the progressive loss of renal function. Then comes

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the question of effect size and I’m almost embarrassed to bring this up in an audience filled with people who think about quantifying things,

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but here we think about effect size, too, or measurement. I want to point out, again, the clinical significance of any treatment-induced

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change on a morphologic finding rests really in its ability to translate into a treatment-induced effect on renal outcomes and one can certainly have,

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when you see small treatment effects on a marker, is that it may not translate at all or at least over the course of the patient’s lifetime into

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treatment effects on the outcome. The other issue is that, with small treatment effects on the marker, you get worried about small treatment

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effects on your outcome of interest, and again, here there is greater concern that the effect on the surrogate could be weighed by some off-

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target or adverse treatment effect. What about more efficient drug development? Why do we want to use surrogates? Well, we want to use

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them because they’re supposed to translate into smaller studies and studies of shorter duration, right? The problem is that if there’s measurement

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error it’s going to limit the ability to detect a treatment effect using the surrogate. It’s also going to make it hard to validate your surrogate

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and measurement error. I think issues both with accuracy and precision have been a major topic of this meeting. I’m just going to point out two

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obvious sources. One is, when you take a kidney and when you do a kidney biopsy, you’re getting just one sample of what’s going on in a much

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larger organ, and so if that sample’s not representative of the disease process going on in the organ, it’s not going to be helpful and I think

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this has an important application, of course, in that for the use of histology as an endpoint, it’s probably going to be better and more suited for

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using diseases where the process is more diffuse throughout the organ. And then the other issue, which has been brought up by many

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speakers and important clearly for the use of morphologic changes in any setting: you’re going to need to have, really, a common and

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standardized approach for defining and quantifying the changes that you’re seeing. So, what about practical and ethical considerations

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that are going to make it hard to use this in drug development? Well, biopsies aren’t risk-free and at least in certain disease settings it’s going to be

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difficult to obtain biopsies or justify the risk. I also want to point out that there’s a limited ability to get repeat biopsy samples because of the risks

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associated with it, so it’s another constraint or limitation with the use of histology, at least, as an endpoint. In thinking about the rule of changes or

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morphologic changes as a surrogate endpoint, I think there’s perhaps one setting that it may be the most useful or particularly well-suited and I

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think the scenario is this: you have a slowly progressive disease that, at least in the vast majority of patients, is going to progress or lead

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them to end-stage renal disease over the course of their lifetime. In that setting, using histology to demonstrate a treatment’s benefit in these

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patients at a time when their renal function is still preserved could be a very important use of this type of endpoint, but then the first issue you have

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to get at, which is the real difficult one which is validating the surrogate. So with that, I’m going to close. I just want to again highlight that many

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important rules for the work that you’re doing in drug development, I just focused on one which is as a surrogate or a basis for drug approval. I also

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want to point out that there are now two nephrologists in CDRH, which is the center that regulates devices and also diagnostics and I’m

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very happy to share their names and pass on information if you have questions related to sort of validating those types of instruments and tools

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and tests and getting them out for clinical practice. Thanks.

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ROBERT STAR: Rob Star, NIH. That was beautiful, as always. I actually want to go to the…could you go back one slide to the last thing

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you talked about which was how to, you said, validate this, probably qualify to be the surrogate?

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ALIZA THOMPSON: Yeah, it’s always a struggle what to figure to put on the slide.

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ROBERT STAR: But I just want the people in the room to understand what that actually means and how difficult that might be. So in the case of

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polycystic kidney disease, again, we’re talking about an imaging surrogate instead of a morphologic one, but I think that the same

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considerations probably apply from the way you look at it. What the FDA appears to be asking for is an observational study that shows that the

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kidney growth occurs before the renal function goes away and then two randomized controlled trials, preferably using different drugs that show

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the changes in the surrogate of total kidney volume, correlate with later changes in renal function. So it’s a huge amount of information to

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validate or to qualify the surrogate. Is that approximately correct?

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ALIZA THOMPSON: Yeah, I think that the example of polycystic kidney disease is a great example. We don’t or at this point we’re not approving

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therapies based on changes in kidney volume and one of the concerns that’s been raised…you know, there’s a lot of plausibility. You take a

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kidney and you make it huge, that you’ve caused damage, but what we’re talking about here in terms of the endpoint, if people are interested, is

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really small changes in kidney volume and trying to understand their clinical significance. The sense or how we’ve approached this is that we

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haven’t been prepared to accept small changes in kidney volume as an endpoint but would, in fact, want to see data from intervention trials. Now,

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whether or not we need two in a whole range of distinct pharmacologic interventions, I don’t know. It may be that you just get one intervention trial in

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and people start to feel better about it. It may be that you needed more than that, I don’t know. But again, that is the concept, that you do need data

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from intervention trials to support some of these. It’s a hard path.

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MALE: I was wondering if you could expand on that point. I guess my question is: at what point and what kind of data do you need to actually

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reach a tipping point in your decision-making and how many studies does it take, generally, and how many different types of interventions do you

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need to see before it reaches the level of FDA proof of concept?

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ALIZA THOMPSON: Just like there’s not a standardized approach to measuring a lot of these things you guys measure, there’s no formal

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or standardized approach to validating a surrogate. I think, again, a lot of it rests on the extent to which you can make the case that your

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marker is on the causal pathway and again, looking back to electrolytes, you know, the vaptans—conivaptan and tolvaptan—were

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approved within recent history based on a surrogate, and again, you didn’t need large intervention trials showing that effects on serum

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sodium predicted your effect on outcome. If you have a finding like scar in the kidney you show that glomeruli are sclerosed and people have

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done a pretty good job of quantifying the relationship, so telling me what some given change in the kidney is going to predict in terms

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of rate of progression to dialysis, I think that’s a setting where it’s not clear to me you’d ever need an intervention trial showing that your treatment

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effect on the surrogate predicts a treatment effect on the outcome. In other settings, some other finding, you know, a little bit of deposition

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here in the mesangium, I think there you’re going to need the intervention trials and how many, again, it’s going to be subjective and it’s going to

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be based, I think, on essentially the totality of the data from all those classes. Not helpful. You should come in. One of the goals of coming here

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today or one of the reasons I was very excited to get the opportunity to speak is this is an issue that is occasionally raised at meetings or in

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e-mails but never sort of explore it within the context of a specific disease and a specific histology or morphologic change, and I think that

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you really can’t have this conversation unless you’re exploring it within a very specific context.

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MICHAEL MAUER: Thank you for your talk, Aliza. I think I understand, at least in part, the FDA conundrum and maybe Fabry Disease is a good

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example of it. So, the indication was primarily provided on the clearance of endothelial cells with the Fabrizine meta-dose at the milligram per

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kilo every two weeks intravenously. Now, it worked beautifully for endothelial cells. There were other cells like podocytes, vascular cells,

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tubular cells that clear much more slowly. Now if we pick another drug where the dose is .4 milligrams per kilo it beautifully clears endothelial

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cells. It doesn’t clear podocytes as well as the higher dose but the endothelial cell clearance, which is very easy, is now the standard—the

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level of the playing field—and it may take years and years of long-term follow-up study to find out that the .4 milligram per kilo dose is simply

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inadequate. So, this is a real struggle and Fabry Disease, I think, is a good indication of that, of how that can go wrong.

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ALIZA THOMPSON: Right, and I just want to point out that, unfortunately Lynne Yao who’s a nephrologist—pediatric nephrologist—by training

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and works in inborn errors and metabolism, was supposed to come today and talk a little bit about Fabry Disease and the experience in Fabry

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disease. Unfortunately, she couldn’t make it, but I very much agree that that’s very challenging and raises a whole bunch of issues and I think

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highlights one important issue when you look at morphology findings is you’re going to highlight some finding and say, “Look here,” but what do

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you make of the other findings that are occurring in the kidney and what that’s going to mean in terms of your treatment providing a benefit? Very

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difficult, but clearly the work of people in this area in terms of elucidating what all these findings mean will be very important.

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MICHAEL MAUER: I have a very specific question; let me see if I can frame it as a specific question. So if we have a structural parameter—I’

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m just going to pick one that I like---mesangial fractional volume and let’s say that it explains 50% of the variability and GFR loss, which is

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pretty good for a single parameter and we haven’t got glomerular number, so there’s going to be noise and there’s noise in the measurement

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and there’s noise in the sampling, but let’s say it explains 50% of the variability in GFR loss as a very slowly progressive kidney disease. So, if

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we do a baseline and a five-year biopsy, the change is going to be quite small that you’re going to measure and in and of itself the change would

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be insufficient to affect GFR. So now let’s say you have a 50% reduction in the change of that parameter that explains 50% of GFR change in

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more advanced cases. How would that be looked at from your perspective?

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ALIZA THOMPSON: Well, I think it raises a few issues. One I just want to touch on. So for finding, like the one you’re describing in terms of

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what you’re probably going to ultimately need, is you’re probably going to need data from intervention trials unless you can find some other

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way from animal studies or something else that actually shows you that what you’re seeing is actually the cause or causing a loss of renal

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function somehow, directly leading to, you know, death of tissue. Absent that, you’re probably going to need some intervention trials. But I think it

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gets back to some of the earlier points I made about effect size, which is there’s always this concern when the effect size is small, about

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whether or not it’s going to translate into your outcome of interest, which yes, on the one hand it’s GFR decline but ultimately it’s the progression

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to dialysis because that’s what people perceive, right? People are asymptomatic from kidney diseases for a long period of time, but also with

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small treatment effects we also have a greater concern about the fact that they could be outweighed by the toxicity of the therapy. But the

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work you’re describing is important work and I think that it’s going to require us to sit down and have more careful discussions about, if it were to

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be validated, how one would approach its validation or qualification and what types of data would be important, because I think, you know

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again, going back to the scenario where I think histology or morphologic changes could provide the most benefit is certainly at very early stages

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of progressive diseases where you’re not going to really be able to show an effect on people who have well-preserved renal function, so

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using creatinine is not an endpoint. But again, the concept of the type of disease isn’t just that it’s slowly progressive, but the patients are, over the

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course of their lifetime, very likely to go onto ESRD and really perceive something from their disease. I look forward to further discussions

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with you.
MARILYN HAILPERIN: Hi. I’m Marilyn Hailperin and

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I’m from the NephCure Foundation. Our mission is to support research to find the cause, cure, and better treatments for primary nephrotic syndrome

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and particularly FSGS, so it may be a question to you and also to the larger community here. How do we facilitate engaging the right constituents to

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sit down, sort of, with the FDA and have discussions around what are the appropriate clinical pathways to validate, to investigate,

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potential surrogate indicators? Our intention, of course…surrogate endpoints..our intention, of course, is to get pharmaceutical companies to

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pay attention to our rare disease and they won’t pay attention to your rare disease unless there’s some mechanism to suggest that there will be

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FDA approval at the end of the commitment for creating those drugs. Are there case studies, examples of best practices where a constituency

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group made up of maybe patient advocacy and other physicians, clinicians, scientists, who’ve been able to do this successfully that we could

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apply to this nephrology community?
ALIZA THOMPSON: How the approach has gone

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thus far, and again I’m very appreciative to the NIH for inviting me to these types of meetings. These meetings have been an opportunity for at

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least our division to sort of present some of our approach to the validation of surrogates and then one thing that happens after these meetings and

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we’ve encouraged is for the communication. So if you send me an e-mail, we’ve been connecting with more recently the members from the ASN

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about endpoints and specifically to use proteinuria as an endpoint in some diseases associated with nephrotic syndrome. So, how a

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lot of this sort of qualification goes about or for the discussions about these endpoints goes about is by reaching out after these meetings and

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we set up calls or a path for it to try and gather more data that would address our concerns about the validity of some of these endpoints.

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Because again, you guys know the data; we, however, know what the requirements are or at least how we’ve interpreted their requirements

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and it’s really the meeting of these two things that’s going to define the path forward. So, feel free to e-mail me. I think I put my e-mail up.

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MARILYN HAILPERIN: You’re on speed dial.
ALIZA THOMPSON: Okay.

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PAUL KIMMEL: Thank you, Aliza, very nice presentation. I’m just wondering, since we have so many morphologists and pathologists around,

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you focused on, I guess, clinical trial endpoints. Is it worth talking about the PSTC and how morphometric data, histologic data, were used in

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screening and how the FDA qualified those as sort of a structure for people to understand how histologic material may be used in working with

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the FDA?
ALIZA THOMPSON: Yeah, I think that’s excellent

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and Paul, you’re going to actually stay at the microphone so you can correct or fill in any blanks. I focused my talk on surrogate endpoints

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but maybe it’s because when I saw the title I thought “surrogate endpoints” and to me surrogate endpoints mean something very

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specific. But I want to say that, you know, drug toxicity, specifically renal toxicity, is a huge issue that prevents the development of therapies and

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one of the big issues with drug toxicity and nephrotoxicity is, of course, creatinine is not really an indicator of acute kidney injury, it’s an

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indicator and a late indicator of effects on glomerular function, and so there’s been a lot of interest in finding markers that can do a good job

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of allowing or that are sensitive in allowing an earlier indication of a nephrotoxicity to the kidney. So, a group in industry working through CPATH,

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which is a nonprofit institute, came together and tried to put together data to qualify the use of several markers or biomarkers of kidney toxicity

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and data specifically in the rat showing the relationship between these biomarkers and toxicity on histology. I’m trying to think of what

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else to say. In sitting here today and hearing some of the discussion I think they would have been aided and moreover think that, even within

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the context of animal studies, we could use a lot of your expertise in interpreting some of these findings and also using it to understand the

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toxicities that therapies are having, but Paul is going to chime in and say what I didn’t touch upon that I should of.

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PAUL KIMMEL: God forbid. I mean, it was a beautiful explanation but I just think that pathologic specimens can be used in the screening process

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for drugs. They can also be used, probably, as entry criteria and if there were more refined measurements, more reproducible

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measurements, I think there are many pathways for using pathologic material in clinical trials.

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ALIZA THOMPSON: Yeah, and I just want to just further that. I can give you one example where we use histology currently as a tool in clinical

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trials, which is something like with this nephritis whereas you know a lot of therapies are directed at certain types or classes of lupus nephritis and

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it’s been used as a way to identify patients with focal or diffuse proliferative or membranous lupus nephritis who were thought to have more

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severe disease and required treatment, but I don’t think we’ve optimized our use there. People use it for the diagnosis but probably should be looking

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at a whole bunch of characteristics on histology as a way to understand what patients are more likely to benefit from a particular therapy,

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particularly given some understanding of how they think the therapy is going to actually affect with this nephritis and its disease.

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JOHN BASGEN: This talk about surrogates reminded me of another possible surrogate other than podocyte number and the theoretical

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mathematicians tell us that this problem of counting number can’t be done in a two-dimensional plane because it’s a zero-dimensional

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parameter. So, this is where the two sections, and a volume that you’re sampling, makes it work. But, aren’t we using podocyte number as a

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surrogate of how well the kidney is filtering? Is there another surrogate or measurement of filtration, glomerular filtration? Well, there is—a

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filtration surface of the glomeruli—which its surface is a two-dimensional parameter which then can be easily measured in thin sections. You

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don’t have to identify whether they’re sick podocytes or disappearing podocytes. In the sclerosed area there isn’t any filtration surface

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anymore. So I’m wondering…you need to do electron microscopy to measure this surface of the glomerular capillaries; you’d like to know the

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volume of the glomeruli, so we’re back to the problem of getting a good measurement of glomerular volume; and if you knew how many

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glomeruli there were in the kidney you could multiply those three parameters together to get this total filtration surface per kidney. Now, Mike

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Mauer did part of this study a couple of decades ago on correlating this filtration surface with a measure of kidney function and I’m just saying

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that, because it’s easy for me to do electron microscopy, it’s a lot easier for me to measure this filtration—well, the surface density of the

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filtration—than to count podocytes. So, is there a better surrogate for functions than podocyte numbers?

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ALIZA THOMPSON: There may be and that’s really…you all are the subject matter experts. Come up with what you think is going to be good.

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ASHRAF EL-MEANAWY: Ashraf El-Meanawy from Milwaukee. Can these morphometric parameter accessed by data for entry of

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selection criteria for patients, say, when we get to the point that we have glomerular volume or number and we go and pick only diabetic patients

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who have big glomeruli as a treatment group in a treatment study, would that be acceptable?

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ALIZA THOMPSON: Yeah, and I think that that is an excellent use of these types of markers, is to identify patients who are likely to have poor

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outcomes, which is considered or the concept is that you’re doing a prognostic enrichment. Currently, we do that in trials of diabetic

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nephropathy by picking people who have a lot of proteinuria or you pick people with impaired renal function, but it could turn out that your marker,

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your histology actually, does a much better job at predicting people who are going to progress. The other way we do it is something called predictive

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enrichment which is this concept that patients with certain characteristics are going to be more likely to respond to your treatment, and again, it

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could be that because your drug causes B cell depletion and based on your morphologic changes or histology are seeing that in certain

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subsets you think these cells are somehow more…it’s the same disease but it’s actually maybe a different disease in some patients and

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you think there’s a reason to believe that the B cell is playing more of a role because of some finding, you could also use that to selectively

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enroll patients. I think what you’re outlining is a wonderful use, an early use, of the changes in morphology as a way to facilitate drug

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development, and you don’t need to have them validated, at least this formal process that I’ve described or qualified. Excellent. Thank you.




Date Last Updated: 10/4/2012

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