Event id: 1638018 Event Started: 11/8/2010 7: 45: 59 am et douglas Throckmorton, md

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Eric Duffy, Ph.D.

I imagine a number of you would be coming to the campus for meetings that we often have our investigators. What outlets do today, address, as was pointed out, the quality aspects and primarily for small molecules, there'll be a presentation later, for large molecules. Some of the regulations I'm going to refer to have some of the guidance is really too small molecules and large molecules.

A going to be discussing a number of areas that relate to product quality. And with this emphasis on a discussion of the investigator brochure. My talk is relatively short. I'm going to try to move quickly and will have an opportunity for questions after the first three afternoon presentations. There's going to be a panel discussion. Trotter questions down with as they arise. We have developed a number of practices, specific FDA guidance and that is that results from international discussions and the conference on ICH I want to touch on CMC issues that relate to safety because that is paramount ina IND investigation.

Specifically, the safety concerns that arise from impurities in a drug product or drug substance. And what affects the concerns might arise due to concerns over manufacturing and quality issues. I want to discuss the stability of a product in use and investigation. And specifications. Annan will have time to get to the last item, which is an overview on patents that is in your slide packet for your reference and we don't have an opportunity to discuss it in detail.

Guidance and the names and a series of hierarchies. Is there a pointer available? How do you operate a pointer? The top? Is that showing? The angle is too much. Okay. One of the top is the food drug and cosmetic act. That is the law that codifies the way in which the drugs, cosmetics, foods, devices, regulated by the federal government. Lower down in the hierarchy are the regulations that emanate from the FD&C at any specific section that relates to drugs is a title 21. There are a whole are after the titles and a lot of people are familiar with criminal 18, criminal codes of center. Title 21 regulates drugs. And Biologics and other cosmetics and devices, center. Based upon those regulations, FDA has come over the years, created a number of guidances for industry or investigators, academia, and all who are engaged in the development of drugs in the manufacture and sale of drugs we have developed those guidances. As I said, there is also a series of guidances, that have been developed internationally and this is the last item, the international conference on harmonization." To the last verse. And to describe basically what this is all of that. This wasn't effort that little over 10 years ago by the three regions being the United States, the European Union and Japan and industry counterparts in each of the three regions. And the primary lead was Pharma. Pharma research pharmaceuticals manufacturing. In Japan, JP M.A., the counterpart to Pharma in Japan. In the European counterpart, and over the years, various additional countries have become engaged not as formal members but as observers, health Canada, TGA in Australia, and others. After out my top, you will see a number of links to sites that are going to provide you a lot more information back and conveyed during this brief talk. And I have cited the ICH website and all the guidances that have been developed can be found there of what might be a primary interest to this group might be the ease East series. Series on quality, the key series. -- Q. series. As another of the others having to safety, pharmacology, toxicology, etc. In terms of specific regulations that are specific to IND, this is a citation, 21 CFR 312. That address is primarily what we need to have an IND. There are some other related sections that relate to quality issues in the second citation is serious to 11.

That is a section on good manufacturing practices which describe what the expectations are adequately producing a product, producing a test article, in the case of an IND. And what the expectations are for record-keeping, quality, tracking, and assuring the quality is sufficient for exposure to patients. And adherence to those guidances regulations and ensure manufacturing ramps to the age of steady B. and marketing products. It is very important. The quality aspects are very important to ensure the consistency that has been conducted. Example. You want to do some preclinical studies and we will hear more about my talk. And you want to ensure you know precisely what it is they were studying. What is the drug, what is the active ingredient that is a formulation. And you need to know precisely what that is. And control that through preclinical studies phase 1 phase 2, page 3, and into commercial marketed products. And I have decided the website where all of these, it will lead you into all of these regulations. Specific, tickets the investigators pressure, there is a regulation that describes the requirements for 312 serious that I have cited before, and briefly, what is described in a set of regulations is what expectations are that would the contained within this investigators pressure. It has to do with describing what the drug is, what is the active agent. Structurally identifying it as possible. But the formulation is that is going to be administered to the subjects. To the patients. A brief description of pharmacokinetics of the drug. And what other studies may have been conducted that support the finding that the product is safe to proceed with human trials. And what kind of alert might be looked for in the course of an investigation and protocols would be included in tree and criteria exclusion criteria and what that does might be.

-- What they does might be.

Does might be.

Displays that we can find specifics -- this place that we can find specific about IND submissions. Phase 1, phase 2, page 3. How you can engage the FDA discussions. Hate can request meetings and the format and have that, best be accomplished.

This map, manuals of policies and procedures which basically lays out how the FDA functions in the context of dealing with IND. As I mentioned before, practice expectations, manufacturing expectations phase 1 exploratory setting we developed a guide of that describes the manufacturing expectations for phase 1. I think would be very useful to review. Another approach, not approaching a particular drug in a formal study sense but rather an exploratory study. Determining what the pharmacokinetics are common to see that is favorable for a particular indication our patient population. That is a very interesting guidance and expectations on protection of patient rights, subject rights, and I imagine everyone has seen that guidance. Additional ICH document that would be useful to review would be good clinical practices, conduct of trials, document D6. And as I mentioned, a whole raft of these guidances having to do with clinical trials in humans. This is a guidances I just referred to. The investigators starts out, with the need for description of what the drug substances. You might hear referred to as a pharmaceutical agreement, API.

That is the active the greedy and. Intended to exhibit the pharmacological activity and specifically in intensive is intended to do direct effect of diagnosis, medication, cure or treatment of disease in order to affect the structure or any function of the human body. Now inactive ingredients can be very simple molecules. Or rather complex and the far end of complex city will talk about proteins with Dr. Kozlowski after myself.

What needs to be in the investigators pressure is how the investors -- how the active ingredient is made. That gives reviewers at the FDA clue to what kind of concerns one might have, relative to impurities or structural identity and he'd make sure you know what it is your study. This active ingredient is rarely dosed directly. It is formulated into some kind of drug product with inactive ingredients, a capsule product in early studies, it might be very simple formulation. In fact, sometimes will see an active ingredient without carefully into capsules and dosed that way, potentially for Joe's rage finding studies or initial safety study.

Drug products can be very simple. Powder and a capsule or they can be complex. A transdermal patch. A drug that is administered through an implantable pump or the range of complexity is significant. As products become more complicated, exercise a greater control, is going to be needed. The description in the investigators brochure should describe what you're done with the active ingredient, how you are formulating it and how you are controlling the quality attributes. And to see the appropriate doses being delivered.

The focus of a phase 1 study, in particular, as I mentioned, his safety. Their manufacturing issues that relate directly to safety and I will go through, in general, a few concerns to safety, emanating from manufacturing issues. The purity stand to be of particular turn. They are of particular concern because they have may have their own from logical activity which may be adverse to pay me contributing to the frog logical activity that you are hoping to explore. Teasing that this is important thing to do for the course of development. In the phase 1 study, it may not be terribly crucial to exercise control over all the impurities but they do need to be qualified from a safety perspective and how they can be qualified in a preclinical study. The impurities that are there, with the qualified by virtue of exposure in a patient population. It is a dual manner in which impurities can be qualified from a safety perspective and as I mentioned, going to make sure your delivery the appropriate dose to the patient in a consistent manner. Dosing today, dissing tomorrow. And as you go through the course of the study, or enter patient, you want to make sure you're stating the same drug in the same does across the study. Parental products, there are particular concerns relative to safety and they're probably relative to everyone. Sterility insurance being primary. Impurities, as I mentioned, the TB control. And I described here, have the typically would be controlled and special consideration for potentially highly toxic impurities, such as genotoxic. At a brief description about why attention to impurities can be important. From a number of years ago, this -- was found to be thermally unstable and when it was warmth or heat exposed to heat, because the reaction, if people can think back to organic chemistry days. Simple of a nation to produce a toxic byproduct. Attention to these details is often important. Now, when we receive an IND for initial assessment on whether it is safe to proceed, we have an expectation that impurities are addressed. And quite often, from a manufacturing perspective, this is the most important problem that is encountered, lack of adequate control over impurities or direct knowledge of impurities.

I have described what our expectations are in some people, if they don't pay enough attention to impurities, might say -- my receipt, like this, from the FDA about why we don't think it is safe to proceed yet. Dell, from the efficacy perspective, they are typically not very many concerns relative to efficacy from a manufacturing perspective except for a few general areas. That being dose, we are not sure if it is actually capable of determining what is being delivered to the patient, uniformity of it -- uniformity of the content from dosed to does to does and is a concern it can be available in efficacy findings. Manufacturing of a drug, the way it is best control this through manufacturing and adequate controls in the manufacturing process. And I put at the top of the list, adherence to good manufacturing processes. Contributing to the other contributors to product quality, are the input materials. Do you know how well those are controlled, what is the purity of those and knowing whether the process is capable of accomplishing in a consistent manner what you intended to accomplish. Now, I'm going to end my talk at this point to leave you with the remainder of the slide package. Of course one of questions coming up later. Generally, with the remainder of the slide pack is a brief description about effort that is underway between FDA and industry which is referred to as quality by design. And that essentially, is an initiative to have the development of drugs focused on knowing exactly what your intended use is going to be and what quality attributes are going to be important. So, as I go back, just to mention, knowing the process and accomplishing the process in a consistent manner is the principal way of doing it. Controlling the specifications is not the best approach. You need to know what your process capability is what the outcome is likely to be, specifications simply confirm in a general sense, what the product quality is. This is a brief presentation you'll see on our quality by design initiative that focuses on understanding your drug in understanding the product. The slide, I will briefly mention, is intended to indicate a case study. In which a particular manufacturing process and formulation gave a bioavailability profile which is shown in a standard product is referred to. By changing one attribute of this product, particle size distribution, the particle size of the drug, you can see the dramatic impact that has on bioavailability. And, changing formulation. Also showing a very clear difference of bioavailability. This is just to illustrate the need for adequately controlling aspects of the drug in terms of quality and attributes that may have a dramatic impact on the conduct of your study. I did prepare a section on patents, which I will not go through.

There is an interesting development over the last couple of years, in terms of patents and the purpose of exclusivity which is the period of time that a product can be manufactured without competition from a genericproduct.. Their exclusivity is for drug, orphan drug development, recent development is interesting and I imagine Dr. Casale ski will touch upon it. That is, with the public health service act for biologic type products, large molecules getting a 12 year exclusivity, trick -- dramatically longer the small moderate -- molecules. It will focus attention on that area for drug development. So, with that said, I want to thank you very much I'm looking forward to any questions you may have.

Steven Kozlowski, MD

I think you mentioned me by a similar bill. I think the agency is figuring out how to interpret that that is a complex subject. Let's talk a little bit about Biologics. Basically. I'm going to discuss the content of a IND and the characterizations of specifications what was a very biologic products and manufacturing changes were biologic products and comparability. On contaminants in manufactures, common pitfalls in developing Biologics. We look at the regulations, which we heard about before, for drops -- drug substance and drug product, including its characteristics, and that is the active ingredient, all the components used in manufacture, manufacturer information. The general method of preparation and the acceptable limits of analytical methods used to assure identity strength quality. He was -- Roberto specifications and information to support the stability of the drug so that it can be used in the studies that are important for the development. I want to talk about two of these areas. Obviously, large molecules are bigger. And they have long chains of polymers, amino acids for purchase. And SI higher-order structure in three-dimensional space. Also, in addition to their primary sequence, and many post-translational modifications and they tend to be complex on a variety of levels. Civic higher-order structure, the bondage term in higher-order structure or hydrogen bonds and vendor forces and air much load -- lower energy. Which means the environment in which a protein is can change the shape much more easily than the environment can change small molecules. They are heterogeneous mixtures that most proteins are products that are now licensed or approved are really mixtures of a variety of different variants.

They are not a pure single structure that want to look at. If one looks at a Stanton in terms of size and compares that to a third of the -- anti-body and FAB fragment, you can see obviously the one is much larger than the other. There are many products, here is an example of an interferon gamma, which a variety of things fit into. With inflammatory cytokines and many of these products are the protein structure alone. They can be Peggy lady, adding polyethylene glycol to change its pharmacology and they might be labeled with radioactive components, for toxicity, to kill a tumor, or to localize things. Conjugated to things like polyethylene glycol, they might be cleaved in order to prepare the final products a lot of things happen in the design and manufacture of these products that add additional complexity. Let's take an example of a Mike Lowell antibody, of which there are a large number of I. -- licensed products. Most of monoclonal antibodies, a lot of them end in a glutamate. A glutamine, which can be circular eyes into a Pyro clues and acid. There are many sites with amino acids that have a group and they can beat GMI dated. -- B. Deanna Davis.

You can have three sites that can be deamidated the might have to sites. Glycation is the addition of sugars, not through the cellular machinery, but through a reaction that is unattended by the cellular processing and development of the product and you could have sugars stuck in all kinds of places. We have sugars intended for the Monaco -- molecules have post-transactional modification and you have different states called high mannose, glactose but I one arm, and one of the other. That aside states. You could have a Sialyic acid. Again, five more states and the C term lys on antibody can be cleaved by a proxy test for days.

If you consider those independent states, that is all most and that the states for half an antibody.

If you imagine two halves of the antibody are completely independent, that is about 10 to the eight variants on such a product. To be honest, this is case is an exaggeration. Most of these don't happen. If they happen, they happen a tiny fractions. Most of them don't matter clinically but some of them do that we don't always know which ones matter. Basedow know which ones are codependent or interactive. I think all of this uncertainty is in the back of how you think of these molecules. Some thoughts on black oscillation. -- glycolsylation If you remove glycoloations of antibody, you remove binding to FC receptors, you eliminate binding to CIQ, complement to the site caught to see. And proteases. The half-life of the molecule is not necessarily effective. It is a quick oscillation he would remove. If you remove the galactose at the end, and that is an example and it -- an example of what you would remain, it tends to form mannose binding protein a little better than glycosoloated form and again, the clinical impact of that was very hurt -- Barry. If you eliminate the fucose which is a sugar the beginning of this complex, this is starting to be looked at in the early 2000, you can affect the antibody depending cytotoxicity by huge amounts. A few of the glycolsulated anti-body will adhere the ability to advance the salsa we approved antibodies that works your antibody toxicity in on the income it didn't matter in terms of clinical performance but it shows how much one needs to know how these things change.

Antibodies that have high manose forms which is very clear unless they are made in the usual substrate, tend to have very short have lives. A variety of impacts from the chain -- from these changes maybe not there may be others and in general, the more galactose you have, the more dependent antibody toxicity but again, this is not as clear as strong of an effect as removing the fucose. We talk about the complexity and impact of the bugs you clinical performance our talk a little bit about specifications.

Again, specifications can be general, related the quantity of what you are producing, the identity, the purity, or the potency.

All of these, in terms of product attributes are important to understand and control. However, early on, they may start off with wider limits because we don't really know what matters and it is early on. As development continues, they may in fact become very narrow to assure consistency of manufacturer. On the other hand, if any of the attributes under these categories relate to safety, then from the very beginning, it becomes important to control these with narrow limits or to have these things be undetectable. Clearly, purity, and you heard about this from Dr. Debbie. And a toxin, all these things are dangerous and worrisome to patients, he would not the first patient that ever gets the product. There are issues about quantity the importance of quantity and how narrow you need to define it may very well that ends on me -- locked into a very narrow range of potency may depend on the molecule you are developing. So for purity, Francis, obviously toxic contaminants, no toxic variants, need to be tightly controlled. Early on. Posting quantity. If you are making a toxin linked proteinuria radiolabeled protein or a perky with a narrow therapeutic index, with the extremely important early on to a very narrow limits on quantity.

There are specifications which are both safety and later important for consistency in terms of knowing the immunogenicity viewer measuring as reflected in the quality of the product and will continue to be predicted like that. It toxins as an example for their levels of attacks in which are unsafe. Farmer: it's that would be a safety issue from day one. However, it may be that very tight control over lower lovers of endotoxin may be more important measure leveraging the clinical data from your pivotal trial to labor the -- label the product for things like immunogenicity and I was important to control the narrowly defined limits early on. Potency. Potency again relates to quantity is always important to some level. If you are doing a dose escalation, which is a typical phase 1 trial and you are going approval, if you don't understand the quantity of potency of your molecule two or threefold, you know how to interpret what that does escalation means.

Aside from narrowly controlling it when there is a safety concern with too much, it is really important to have that defined well enough severe trial is useful and not a futile meaningless trial.

Posted, I want to talk about it. Usually for biologic product, that is measured not by assaying the amount of something but by some biological assay, they can be in vivo assays, although that is cumbersome. And they could be ordered to shoot assays, again comes up to do. Cell culture assays are the best way to look at this May can be a cell line art population response. A cell line that is -- is easier to control than getting fresh primary cells each time but again that maybe they'll away to measure what you are doing. You can look at a late response which is the most common. Side a planned production on cell viability they also may be able to design a more sophisticated potency assay which used transduction pathways but if you do that, you would have to convince the agency that those of the right pathways to look the potency of the molecule. They can be multiple cell types like a mixed lymphocyte response, cell to cell adhesion, and biochemical assays in some cases. A catalytic role and -- antibody and if you are blocking an enzyme that might be aboard look at it by a chemical assay and conversion of substrate. There is a continuum of these assays they goes from simple ligand binding to basically a clinical study which nobody uses as a potency assay. There are advantages on both sides. The more sample your assay is, like ligand binding, the less likely this would have variability in a more convenient is to produce product. Simple, low producible, low variability and on the other hand it may have nothing to do with how I molecule works if you put the wrong cell response feature which a clinical study is the real truth about the purpose of the molecule. In picking a potency assay, it is extremely important to understand the mechanism while a Mexican slide down the scale to a more useful and reproducible assay. You have to think of it in this way -- develop a product from you may have multiple potent assays and you narrow down to the one that will eventually be used because you gain understanding as you do it.

Again come you don't need the most final potency assay when you come in phase 1 but it hasn't been that is reflective of potency in Atlanta show, in fact, it is a relevant thing to look at.

At Dr. little bit about the content of a IND, focusing on the complexity of these products and characterization of specifications for these products. I want to talk about manufacturing changes in comparability. When we evaluate these molecules, or when you evaluate them, or the sponsors you are working with evaluator, you can look at it as an iceberg. The release tasks which form your specifications, only see the tip of the iceberg. We talked about the complexity of these molecules, the assays you measure a not going to show all those variants. There is characterization, which happened early on to a limited extent -- extent that would be ongoing for product development which was much further down the iceberg and finally, there is some residual uncertainty that you use the process in some ways to control and not change the process to make sure it does not change. I would say, the analytical techniques get better and better and better. That characterization arrow is moving down further and further. That is useful but it can also give you some problems because you characterize something to well, you always find the things of variability.

I think that is a challenge, but in the end, I would say that more characterize your molecules early, the less troubled -- the less trouble you will have later. Comparability.

Would look at these products, we can see we have small-scale manufacturing and for marketing, you want to have a huge scale manufacturing. That is changing in a dynamic that is changing and development of these products and in the beginning, the small-scale manufacturing, if there is not a way of showing the product to get information from is the same. In important ways the scale of his is -- the extent of the quality is dependent the safety of animals, you're moving into the clinic, the level of comparability for that is required about the same as if you have done your pivotal trial. You are extrapolating all of the safety of this product to what would be marketing and never studied any randomized clinical study again to verify that. The amount of information you transfer to some extent, Greece the boundaries for the comparability exercise in the challenges. Again, less quality data early comparability, much more later on.

It is thus extremely important that the manufacturing changes are communicated to the clinical investigators and vice versa. Because everybody needs to know what has happened to the product in order to understand what is going on in the clinic and vice versa. That is an extremely important thing on the regulatory side and developing these products. And you often see differences. Again, if you look further enough down that iceberg, then you will see some differences and the really needs to be judgment, both on the development side and the regulatory side as to what those mean. Again, the differences may be viewed as low risk, from prior knowledge and other information.

At the impact is unknown, there may need to be additional testing, preclinical and clinical studies and the lack of the observed differences aren't an automatic pass because if you have done a poor job of characterizing, even I see something. If you see something was 2200 vision, you're not going to be as sensitive to changes of the characterization is to be good enough to be convincing when there are no differences. Again, many changes in manufacturing impacts. From a file to a syringe, for a cytokine have increased abilities and insecurities and it metal ions from a stopper activated trace proteases in the product. The proteases were smaller. The whole time but the metal ions, they were invisible.

Large-scale and -- small shift in post transitional changes in viability and there are real challenges to the spirit immunogenicity is another complexity of these products. Since they are proteins they generate immune responses. And one has a solid assay to predetermine -- produce

A needs to be used to interpret package data. In the high response might have an indogenous data. There really needed in early develop. In that phase 1 study. Again, we have changes. We had a lot of changes in the mid-90s. That decreased immunity which was great. But it was not predictive so it was worrisome. Comparability has three axises. How much you know about the mechanism of the product. In the function. And clinical Elledge. What are the baselines? The endpoints that can be affected? That should determine how much and whether not you need them. Contaminants in manufacturing. Our products are made both for Kurils and from eyes -- from human and animal materials. They'll have infectious agent risks. In you need to have testing. In the source material used to be tested.

Anytime use animal source material, one has to think about that, in addition to animal viruses. Process. It turns that not only testing -- I think you heard Dr. Duffey document design. Testing is the least liable we to ensure -- a process that is robust. It is a better way of removing the infectious risks. Filtering and not just testing force to really. -- sterility. And viruses -- that only showing they are not there but having a process remove viruses. I know we are short on time. Early development. You worry about viruses that you know are not there. If you look at a photograph, you will see defective retroviral particles. Not known to have transmitted themselves elsewhere. Certain cells -- some of them can be transmitted. It is not necessarily wrapped. At the vast variety of them have no retroviral particles. You have to clear that. Even if they are not infectious, they may recombine. And late development, you worry about and environment being reproduced.

Somehow against cross contaminated. And the process can remove them. And you evaluate unit young for -- unit operations. Here is the column you would use to purify it. You would take the scale them and you would spike it with a model virus. For these infectious units. And then you would look and watch the column. What was there? Your load was three times. You are left with only 30. That is 1 million old reduction or six lot. -- lots.

It would not necessarily add clearance. Big issue until idea of Clarence. Usually we want a significant amount for product that is going to be marketed. Even for an IND, you want to be sure that virus is not there or is there at such levels that it would take Al's and to millions of doses to find one article. There are a variety of shattered use. -- Of strategies. Modular strategies to help facilitate this. It needs to be covered either through these methods or direct studies. A variety of impurities. They can be media components. And things that we choose from columns. They can also be cell proteins or DNA.

You have to show they are not thereby testing or show that your process is robust enough that even if they are there, the process removes them. I will end with some of our experience. A number of years ago, there was one where it was put on hold. It stop them into getting into phase 1 studies. The most common cause, from 50 hold -- holds, was the lack of clearing of rich are viruses. Lack of appropriate specifications for safety issues. It was the second most common reason. And lack of product characterization. W. have characterized it at the bottom of the iceberg but you have some idea of what it is. Lack of protein gene -- protein assay. And lack of product information warm -- from the manufacture -- from the manufacturer.

There are other causes for lack of information on critical component, safety data on human or animal material and in some cases, human stability. With that, I will close. And we will take questions later. Thank you.

Haleh Saber, Ph.D.

Good afternoon. I am in the office of oncology drug products. Other examples that come to mind are anticancer agents. You already heard this morning about not clinical formation in the investigator brochure. And a lot of good examples. I will talk about pharmacology and toxicology in the investigator brochure. I will go over the pharmacology data and safety data in the pharmacology data and will give you a few examples. The investigators pressure, -- brochure, it will also contain data. I will not go over that. My talk is only 30 minutes. It will be exposure in the animals. In the distribution. Pharmacology discovers the mechanism and it will depend on the various items. If it -- this is a small drug versus the biological drug.

If it's a biological project. A lot of pharmacology studies will be conducted because the sponsor needs to pick a species that has to be relevant. In rats or dogs or monkeys and how do they compare to the binding of the same receptor in the same target and humans? And what needs to be addressed by Biologics. We will have some ecology data. -- pharmacology data. As more data becomes available, they would in more studies -- they will do more studies. An example that pops up is ….This drug was shown to be a B-raff inhibitor. It now inhibits 12 and three and PFR and RET. Indication also divides how much information is provided in the Investigator Brochure . For oncology indications, if this is a small molecule, all that is required is to show that a drug has enter -- anticancer activities. If it is not known, it is okay Avanza drug has shown to block the road of cancer cells. This can be done in vitro. If you open up your Investigator Brochure , in the pharmacology section, how much attention should you pay to the section?

If this is not the first in class, let us say this is another selective inhibitor? You know all lot about and stage and inhibitors. Here is a red flag. You may want to pay more attention to GI leading and cardiotoxicity. For biologic come a as I explained, -- for biologic , as I explained, you need to do which toxicology studies to pay closer attention to. Which one will produce a better example of the monkey or the rat study?

It can often give you a hint into toxicity. It will likely cause skin lesions. If this is an anti-inhibitor, it will likely cause hypoglycemia. Able cause reduced male fertility -- and it can cause reduced male fertility. Safe from ecology is the study both on cardiovascular implement or a system. A lot of emphasis is given to the cardiovascular system. That is because cardiovascular adverse effects are often time asymptomatic and they can be fatal. Patient have CNS effects or they have visual disturbance or they are dizzy, they will feel it and it is symptomatic and they will communicate it to their physician.

But the cardiovascular the -- ready a vascular toxicity effects could be -- but the cardiovascular toxicity affects could go unnoticed and be fatal. General toxicology studies are studies that are conducted or Specter to be contacted within two species, burdens in our burdens. -- rodents and nonrodents. Suppose they do a study with a daily IV, the study would be that the pivotal toxicology studies would be done at the same schedule -- daily IV. We have guidances that they follow. We follow ICH and M3R2. The studies are conducted to find out what is a state does to be given to a patient or healthy subjects.

We heard about this approach this morning which is for non-oncology patients. We take a different approach with patients with Cancer. Because higher doses can be given. If we get to low a dose, it becomes a therapeutic. We need to know what the effects are and monitor the effects in patients. If we see the CD effects, they will communicate that to the medical officer to make sure adequate monitoring in place -- is in place. They major it is covered and they will be monitored. Sometimes there is a need to put a cat -- cap on the dose in the clinic. If they cannot be easily monitored in the clinic, there is a need to put a cap. Obviously, we can obtain as more information from animal studies.

The species to be tested -- even though the guidance says to have a variety of species to select, oftentimes, we see the same species selected over and over. A lifetime ago, someone started and now we have the historical data and we have background information. And we know the toxicity is in the species. What about rodents, Matt and mice. In nonrodents, we have beagle dogs and monkeys and rabbits.

In the Investigator Brochure, you will often see two tox study. If you see one, don't be surprised. It is often difficult to find to pharmacologically relevant species. If there is only one found to be relevant, they will do the study only one species. The second study, it will be waged. -- waived. Here is a real example. The IND was submitted for a drug that was they ab-drug -- was an ab-drug conjugate. It was in inhibitor. They are known to cause idle suppression -- myelosuppression.

They found that the monkey was a pharmacological relevant species. [ Indiscernible -- heavy accent ] . In rat -- rats, the antibody did not find. And monkeys, we saw suppression. In rats, we saw myelosuppression. [ Indiscernible -- heavy accent ] . How much should we worry about toxicity in the clinic? If we give this drug to those patients, do you expect it to be the DLT in the clinic? How many of you say yes? Are you worried about that in the clinic? Are you worried about myelosuppression. We did put monitoring in for hepatoxicity to be saved. -- be safe.

Because the road and didn't have a target, here, there was a lot of in a body drugs -- antibody drugs. It was taken up by the liver and caused hepatoxicity. Once you saturated all of the receptors, after a certain point, you might see a better point. Let the scene after the first few doses? -- Will that be seen after the first few doses? The answer is no.

The other example is a fusion protein. This protein, the IND West Semitic in the indication was PNH. -- The IND was submitted and the indication was PNH. These are two combined to the components of the immune system. More specifically to their complement pathway. The pharmacology studies show that the drug was active in rodents and non-rodents. The blue segment and green segment have 100% sequence. But it only had 60% --.

We saw this in both rats and monkeys. I will skip this because it was toxic. [ Indiscernible -- heavy accent ] . The question here is immunogenecity. To expect to see that with the human sequences? How many would say that there would be no immunogenecity? How many say that there would be? In humans? I thought more hands for it. I would I should be worried about immunogenecity in humans. The blue and green have 100% homology. I expect to see this.

We still have the data. This was recent. How much should you worry about the starting dose? There is no human data available. First time you give those two subjects. -- to subjects. Here at the FDA, we determined that the starting dose is safe. What I suggest is that you be aware of toxicities. And understand what the nonclinical data means and how relevant it is. And how relevant are they? There are all of these differences in humans and animals. As well as absorption and distribution and excretion.

The absorption might be higher or lower in humans for changing the levels of severity of toxicities. The toxins may be different. Dogs may not assimilate because they lack yes I'm -- lack the enzyme. There are differences in the anatomy. Rats do not have a gold letter -- gall bladder. If the sponsor is developing and antifolate, rats may not be the best to predict activity – toxicity in humans..

Other limitations. There are certain toxicities they can be mutated verbally -- communicated verbally. And says animals cannot talk, they cannot -- and since an old cannot talk, they cannot -- since animals cannot talk, they cannot tell us about pain.

These are nicely predicted by animal data. They can cause in fusion reaction in monkeys and humans. This in fusion reaction are thought to be related to the direction of infusion. Signal transduction pathways are preserved in the species. An example would be the IGFR/mTOR inhibition and hyperglycemia. Here is the pathway. I don't have a pointer. Just to make it brief. Not to quiz you at the end. But this is a conserved pathway. This pathway is involved in cell survival. If you have a drug that will inhibit it may cause hyperglycemia. This path is also important.

You have less reduction of insulin that can cause hyperglycemia. The bottom line is that you understand the pharmacology. In cell biology. And you can get your understanding of toxicities. Genetic technology determines whether the drug can cause damage in the DNA. If drugs damage the DNA, that they are likely to be carcinogenic. These studies are separate type of studies. They should not be mixed with genotoxicity studies -- genotoxicity studies. Most of the time they are cemented -- amended -- submitted but the marketing studies. We don't to give patients carcinogenic agents. I should correct that, we give it, depending on the indications. It also depend on the risk evaluation. There are three types of these types.

The complete battery consists of three assays. Sometimes you see in the Investigator Brochure, only one assay or two or three or sometimes none. Why is that? One could be sufficient, that could be the mutation assay. If you are proposing to do a trial, then at least two assays are needed. Before phase 2, they have to submit it to us for review. For cancer indication, genotoxicity are not required before phase 1 but before the marketing applications. The reason is because the patient already has cancer.

Were we not worried about drug induced germ cell mutations? Because we haven't seen it yet in humans. Are you worried about the results of gene toxic studies? Remember that at the FDA, review the data and we believe it is safe to move forward with the proposed indication and proposed population. Either because the results are negative, it's clean or it's not genotoxic or it may not the toxic but the benefit was higher than the risk. For oncology indications, the patient already has cancer.

In a lot of oncology drugs, they are genotoxic. Maybe the sponsor is proposing to give a single very low dosage of the drug to subjects. We define the load dosage do not cause cancer. How many of you cause cancer in the morning -- drink coffee in the morning or the afternoon. You are exposing yourself to her carcinogenic. -- to a carcinogen. Copy has a high amount of carcinogen. Other types of toxicity studies that you might see in the Investigator Brochure are the importance to do the study. There are three types of studies. The fertility study, the embryo fetal study -- developmental study and then the third one is a pre-postnatal study. The most from a year example -- familiar example is Thalidomide. It was found to be linked to birth defects.

For small molecules, the studies are typically done in two species. The rodent is usually a rat or mice and nonrodent --. It is sometimes quite comic it isn't as we don't have the pharmacological relevant cc. -- species. Sometimes the relevant species is a monkey. But it's not as easy to do it as it is with small molecules. Animals are good predictors for toxicity seen in humans. When we give the Thalidomide to monkeys, the defects seen are similar to those that have been reported for humans. Also, hormonal agents, they are linked to loss of pregnancy. We saw that in animals and humans.

Should you enter women of childbearing potential into the trials? Yes you can. Is the result of these studies are available and there are adequate percussions in place to prevent pregnancies, then the limited number of women can be added to exposed to the drug for two for 2 to 3 months. Until the studies become available. For pregnant women, the female studies should be available. And the results of genotoxicity studies.

Males can enter phase one and two clinical trials before the conduct of male fertility studies. Since an evaluation of the male reproductive organs is performed and the repeated dose toxicity study. But before going into a larger trial, it should be completed and reviewed. Women not of childbearing potential such as post menopausal, can be included without repro studies as long as a result of the repeat dose studies are available.

Some references for you. And hopefully there is some time for questions and answers.

Thank you. Thank you to all of our early afternoon speakers for your presentation. Now, it's time for them to come back to the front. To the podium. In the table. To answer any questions from the audience that you may have. The microphones are available.

Who would like to start? There are microphones at various locations.

Fertility studies.

I have two questions. From your slide presentation, it seems like you don't have to have a full level Texas City study to start a phased -- toxicity study to start a phase 1 trial.

That is the 2 mL are identified. You may end up with one species. In the toxicology study and that this is weekly administration of the drug to be given orally, it would be weekly oral administration. At the end of an we will evaluate different parameters to see what the toxicities are associated with -- the drug.

How much has been used on humans and other countries?

The reason why we did in on clinical clock the -- toxic studies, with regard to general toxicology studies. We did not talk about the genotox studies. How much you need to do if there are human clinical trials available, first of all, it depends on the liturgy of the studies conducted -- the liturgy -- the validity of the studies conducted. Medical data will supersede been on clinical data -- clinical data will supersede been on clinical data. -- supercede the nonclinical data. And you will need to complete the toxicity as it is possible. But the IND will not be put on hold.

Thank you.

Like therapeutic formulation. In the formation. That situation, we wonder for the toxicity study how we are doing it and if we would you separate Texas City with activity -- toxicity or with separate activity.

If I answer -- understood your question, do you need the tox study with the final formulation. Or active pharmaceutical agreement -- ingredient?


Imagine it is a capsule. In the Toxicity will be done in rats and dogs -- and the toxicity will be done in rats and dogs. With larger animals we are able and it is encouraged that it be used. If there are differences which depend on how much variation there is and how much you are deviating from the clinical were relation, -- formulation, I cannot comment more listen I know what the formation is. It is not always the same.

Let me offer more. You mentioned nanotechnology?

Different formulations can use a different percentage. Is that -- let's say, reversely. The good news for you is there's going to be guidance.

He will have an opportunity to have a much more comprehensive answer that we can give today. The short answer is that they can be significantly altered by these formations.

The levels would be no more than five -- 500 mg per day. We had that depending on how many months or drugs -- or weeks of the drug you are planning a giving. I don't have that slide with me. For the marketing application, it is 1.5 mg. When it comes to cancer indications, we are more flexible than other drugs that are approved which are genotoxic. They are expected to be a carcinogenic. They can cause secondary cancer. We allow or flexible it. I don't know if I answered your question. Did I answer it?

Yes. It is helpful. I'm trying to understand how you think about it in various patient populations.

These studies are not required in oncology requirements or indications. They are required for nonlife leading -- life-threatening diseases. At this as a single dose to be given, maybe they will ask for a carcinogenic study. Remember, if gentox studies are positive, there is no need to do that carcinogenicity study because it is carcinogenic. If the study is negative, it doesn't mean that it is not carcinogenic. It could be through damage and the DNA or damage through other reasons. Like a drug that causes immunosuppression which can be carcinogenic by interacting with certain viruses. It depends on the duration of the administration.

Thank you. To comment, the idea of risk across personal choices versus regulatory risk, is a very complex question. People may take that. And worry about a three per million risk from a vaccine. It would be nice if risk was viewed on this universal scale. It is not an easy thing to do. The agency needs to think about taking risk evaluation. It is not an easy problem.

I should also add that we do not add for the studies.

That afternoon, I'm not sure who to address this to. Earlier this morning we have her presentation regarding devices. I'm not a scientist. There with me on the science and of it. The second component is if there is an intent to cure or mitigate a disease, that is when the FDA regulations would apply would like to ask what the intent needs? If it is read broadly or narrowly, either by an investigator or sponsor themselves, would it need to be explicit in the protocol? What are the logical to assume that that type of mitigation would take place? I'm wondering how you would look at that?

I'm not sure I understand the question. The definition of intent --

Suppose there is going to be a definition of then assay that will determine the application of an approved drug. My question is whether the FDA regulations would apply and we would have to identify the intent of the research? And not be applicable to human subjects later on? Although the assay itself would be obtained from say human blood, to determine whether the application of the approved drug possession taken place. And be approved.

Again, it's hard to know exactly where you are headed with this. I think that in general, the expectation within --

If you submit your question in writing, we can get you an answer.

My guess would be that the answer would be very case-by-case. Is it possible to test it in advance? What is the exact details of the protocol or product in the situation? If you are thinking about a particular situation, you would be best off asking for a pre-IND meeting. You may get an answer that there are some strategies to do this. But it may very well depend on --

We have time for two more questions.

This question isn't for any specific person in the panel but a general question.

For example, same active agreement -- ingredient. They simply need to be demonstrated to be by Oakland -- bioequivalent. PK and bioavailability trump changes. Those are categories are specifically required in the regulation to be the same formulation. Quantitatively and qualitatively.

I have a question about finding a relevant animal in a biological product developer. As you mentioned, the drugs may have effects. If you are looking at the usual or five animal models, if you need to look beyond that, do you really necessarily have available all of the information or factors a components? If they are separate -- similar or different and models? Or do you have to do experimentation beyond that? And try to figure out their composition of the pathways? And the homology of the pathways.

For what I hear from your question, if the father looked at five different issues, do they need to go beyond that to develop a relevant cc? The answer is no. We have those selected for toxicology's.

Sometimes sponsors go beyond that. They can double up on these proteins and they can be active in these species. I wanted --

Re: cell therapies. There are also tremendous new technologies. PCR is an old one. It could be that part of the change in the answers you are getting are as new technologies are available, there are better ways of doing it that do not involve delaying it for culture.

Just generally, I am a phase 1 position. -- physician. In my clinic does a fair amount of testing. My question, as a physician, I am trained in human medicine. What is generally toxicology etc. is a large mystery. I received no training on what rabbits are used for and what the species of choice are. So I received a Investigator Brochure which I have to translate in an informed consent document. There may be things of great interest in that Investigator Brochure , like the fact that five animals were found dead in cages. It is remarkable to me that there is no place for an investigator at the end you see -- that the agency to go get more information. For how that substance received a IND. When I have no ability to pass along the information in a Investigator Brochure . Largely because a do not have a species --

There might the hotel it has been in the animal. But what is the indication and that does -- dose. It is a severe toxicity they cannot be monitored in the clinic, they make sure there is a cap in the clinic. That will be in the Investigator Brochure . You will see that. If that is something that is not worrisome, it is not secondary. If there was a -- for example, and necrosis in the brain. And it caused sudden-death. And it was clear that it occurred at certain exposure, they made it clear that the judge cannot be used for certain dose or exposure. And they had to do that beyond that certain specific AUC. This was captured in the informed consent. If it's that serious, we will take care of it. Most of the time, if we do not put a cap and we expect clinical trial and toxicity's to define how high you can go -- I'm not in a position to predict that. In one out of three am a you may expand. I am familiar with oncology been out with the design and others. Then you define it anyone ago but that those in the clinic. The total toxicity in humans should define how high you can go. And there are exceptions to the rule. And there are so many cases scenarios that I cannot cover every single one of them. There are different indications or less serious indications that the more attention. If it is given for a headache, obviously, we don't want toxic events in patients. That if it's a cancer indication, a higher risk to be taken. I couldn't have more than what I just told you. And I don't have an exact answer for you.

I just want to reiterate.

Feel free to challenge the sponsor of the study. Or whoever is providing it with the investigator are sure. To better understand that. If they all did that, there would be a statement. It would be considered being a good clinical investigator.

Sarah Robertson, Pharm.D.

Good afternoon. Today, I will outline the next 45 minutes of clinical studies that are discussed in phase 1 studies. And we will describe some important design elements of the studies. And the relevance of timing of how they fit into the overall drug to build a framework. Lastly, if you have time, I will review some examples of what not to do in development. When we think about phase 1 development, we know where it falls within the overall framework our -- what we refer to as clinical PK studies, they are performed throughout the compounds like -- life of the compound.

Those might be special population studies. These pharmacological studies is to determine that were using the right drug population. How do we achieve that goal? I have listed -- a myriad of studies. As well as in vitro studies. And looking at the drug metabolism and transport specificity and protein binding in all of those in the drug assessment are very informative and guiding us to that framework. In outlining what we need to see in vivo. I also want to point out the importance of the Bio analytical methods.

Of course, everything is formed by concentrations. Whether plasma or your in or other -- urine or other bottling materials. Otherwise you cannot make an informed decision for the competition data. How do we go about doing this? When the drug is first administered, we get the accurate assessment of exposure. Defining the PK parameters. You are most are money with Cmax or AUC or Cmin or Tmax. After we have determined these important parameters, we typically have volunteers to start with. Next, we have the exposure with the response. Whether efficacy or safety.

In phase 1, we get the preliminary safety data. Dr. Reynolds will speak further to that in the next session. We are linking the efficacy with exposure. Which can be a PK or AUC. We want to identify this week both -- sweet spot. And we maximize our efficacy curve. Once we have noted what the ranges, we determined the dose that achieves that exposure. And all of our patient populations. In this example, I have outlined in the blue hash marks of the minimum efficacy that we need to see. Perhaps we have seen the prolonged -- we have a maximum Cmas -- Cmax were willing to tolerate for efficacy.

And then we see the outskirts of about curve. -- of the bell curve. It accumulates in the PK tends to overshoot. We may have genetic sensitive met Lasers. They may have a higher dose. This is really what we focus on. Determining the right dose of every proposition. -- population. You heard a lot about the human studies. I will go into a lot of detail. The starting dose is based on clinical pharmacology. These are typically randomized and help the studies. Not always. As you heard.

What we get in this first in human studies is the safety and tolerability information. We get a lot of PK information as well. Such as a limitation half-life and the variability of the drug. In a sense initially between gender differences. Men and women. Some study parameters. If they are given multiple doses. Such as accumulation. Doesn't accumulate? If so, how much? And then we can get preliminary view of the drug a limitation.

If it looks like it will be eliminated in urine, it's double to get PK urine samples. Sometimes, in the first or second studies, it is helpful to get assessment of the food affect. This is an example of a very simple first in human study. Difficult that we see. It could be five It could be 5 to 10 days of drugs. We built into this drug, a food assessment. Were an earlier dose is repeated. This is very help or permission to get early on for an oral formulation. So we can get in subsequent studies. An example of what we would term intensive PK sampling. You can see it is very intensive for the first 12 to 24 hours.

In the half-life of the drug's. So we get the full a limitation of the drug. It is how full to gain the urine PK. And it might be eliminated renally. Again, just a typical study for first in human. One of the early studies you will see described in the Investigator Brochure is the ADME study. Typically, a small group of healthy males. Basically, you're in urine --, feces has collected until all activity can be accounted for. It is very useful information. We can describe the entire a limitation of the drug. Teen metabolite or urine or feces. This is a typical example along the X axis. Where we have the radioactivity. As you can see for this drug, nearly all of the drug eliminated in the urine is typically unchanged.

It helps determine which publishes studies are needed. Moving onto the special populations. These are some of the bigger ones that we think about. Not all of these specific groups need a dedicated study. Typically, the renal groups to. Pediatrics obviously do. Even gender and obesity -- they can be assessed by using population PK methods with sparse PK data. This would be data in phase 2 and phase 3 and start to look at covariant as race and age. It is an evolving thing. As possible. So we can incorporate and come back and.

This an example from a renal impairment document. The draft was published this year. With the decision tree. One of the changes that was made in this document is that we now recommend a PK studies for all molecules. With the exception of the drug. That would not be given to proposition a renal impaired study -- position. -- population. We know recommend a reduced PK study. That means we will have the sponsors for the worst-case scenario. And stage renal -- End stage renal disease. This is based on the transport and absorption can be impacted by chronic disease. Based on the data, it seems like hemodialyss -- hemodialysis patient actually handle the renal eliminated drugs quite well.

This reduced PK study can be done under certain circumstances. If it's negative, then it rolls out a significant -- rules out a significant impairment. If the result is positive, then the sponsor would have to go out and do the pull PK -- full PK study which I have outlined here. This is the design that we would have acquired for least 20% or more renal he eliminated -- renally eliminated. In some cases, multiple doses may be given. In what we call healthy subjects. They do not have the disease of interest.

In some instances, if they had safety or toxicity issues, we wouldn't be releasing healthy subjects. If they are stratified based on their renal function for moderate and severe renal disease on dialysis, compared to a cohort with normal renal function. Basically what we described as drug clarets. -- clearance. Et al. to come up with an ideal dose for each partition. -- each population. It's nice to break up that group and give it to dialysis -- pre dialysis and post dialysis. It is very helpful information for practitioners.

This an example for Doripenem. It is primarily renally eliminated. As you can see, on the x axis, as it clears and decreases, from right to left, the AUC exposure increases. Not surprisingly. You can see some removed drug much better than the other. That is the separation. That is the pre and post dialysis group. When you compare this to groups. With end stage renal disease. This was the impact on the labeling. We described the subjects with mild and moderate and severe renal impairment had a 1.6 and 1.8 dosage requirements or recommended.

In this example, the study was not done prior to face very. -- phase three. But were incorporated at the time of labeling. Even go on to describe it happened the doses will -- were removed. Useful information for the practitioner. These studies much designed the same way. We have the full spectrum of the liver disease from mild and moderate impairment. Patients or subjects are categorized based on the score. A-C. And match through a normal control cohort. Match preferably for age BMI. Again, typically, single dose is done but a multiple dose may be done to pending on the linear time ornament tabulates that might accumulate for 50. -- for safety.

Indians is where the drug is metabolized by an enzyme such as 2c19, it's double to give the metabolic status for subjects so we can better in life the result -- analyze the result. And we want to come up with better for the subgroups. As an example -- from the development of Raltegravir for patience with moderate hepatic impairment. The label could go ahead and specified that the full dose to be given with patients with moderate and mild hepatic impairment. And those with severe have been not study -- have not been studied.

Moving onto drug interactions. I outlined our guidance documents. This one is in vitro studies. Another one is into the in vitro said of things. I also referenced the white paper put out by the international Consortium this year. We are in the process of updating this document right now. Hopefully, it will be published in the next six months or so. There will be quite more information -- quite a bit more information about interactions. This is an evolving area. And we did more than the last time the kinds we not into now six -- back in 2006. It dealt more with hepatic enzymes.

As far as in vivo enzyme studies, the in vitro study really guide us in that direction. As far as the therapeutic area. It also depends on the acute toxicity of the drug that is going to be used. This is an example from the 2006 guidance document. The decision tree for other drugs that will be metabolized or modulate for these enzymes. I want to point out on the left-hand side, it breaks down the molecular activity. On the right-hand side, it goes through the decision of whether it is in inducer or inhibitor. We have to think about our NME is not just a substrate but as a potential inhibitor. This also goes for transporters. Same thing. It can be a substrate or modulate activity.

Some design issues with respect to drug

Some design issues with respect to the drug interaction studies. The cocktail of the design study which examined her on, a substrate drug, dextrophororphen given in one shot, a cocktail term. You can roll out -- rule of modulation of some during the study. In vitro, there will not be a significant effect that would preclude the need for studies and that is a similar study. Other interaction studies include crossover, half-life, one sequence crossover study. It is important to look at the doses that have been selected and ideally, but like the therapeutic dose. The steady-state or long-term testing is generally needed for inducers and inhibitors specifically inducers.

We describe an effect of the drug on inside my transporter based on the whole change that affects. One example, but Aslan -- we would determine that a potent inhibitor. We call a moderate or mild inhibitor. That is described in the guidance document. Factors affecting absorption that need to be considered, that the course of development, each formulation shillings to the previous one and if it is very early on a should be a solution of the first capsule and one or two studies, donate to link the two with a bioequivalent study. A study would be required to link those formulations and pathology study, the same type of criteria we would expect for a generic drug.

Food effect should be reassessed at the formulation changes during development, metabolism-based drug interactions are important, drugs that can alter gastric pH. Here's an example. Antiviral drug for hepatitis B. This is a very nice food effect study, the low fat and the high-fat come not surprisingly, the American breakfast is the high fat. It is absorbed better under conditions, and the labeling should be given on an empty stomach.

A lot of time talking about studies, try to have a presentation on cardiac toxicity and we will -- this is a safety study required for all systemic -- regardless of preclinical findings are thing about this is the clinical pharmacology project because it involves PK sampling and a cardiac symbol and prolongation, which related to exposure possible to have a threshold for safety.

Outlined here the guidance documents related to that study. So some studies and assessments, as outlined in general where they have fallen in the overall development framework but it depends on the compound and what we have discovered on the way. I have highlighted in blue, physicians labeling, the PLR of label those areas impacted our clinical pharmacology studies has you conceive both sections are impacted by phase 1 PK studies.

I will render a couple of quick examples from development. This drug was administered and it is given over 30 minute infusion and by injection as well. Sign-up for this drug, there are concerns with concentrations based on preclinical studies. The single-dose crossover PK study in healthy volunteers to determine the PK following a 30 minute infusion at outlining how they did their sampling and based on the results of the study, the Google said the two infusion methods, which would be suppressed for a drive with eight pretty quick illumination half-life. You expect to see higher. This is surprising. So they looked back at the data, they did a sample post bolus. So immediately, not all the drug made it to the tube into the patient and the next sample wasn't until a few minutes later and it was a rapid elimination drive. And based on simulations, we didn't necessarily -- but we had a concentration information to better decide decision-making set design can be very important and PK studies. Drug why -- drug Y, a half-life because of an extensive binding is much longer than a plasma. At 200 our half-life versus an hour and plasma efficacy stands to wear off as they had after half-life and plasma and drugs given two or three times a day. A sponsor wants to develop and extend the release formulation to be given once a day and they compare the two, the new ER formulation versus the IRA and unfortunately, the only sample cold blood concentrations and they concluded by equivalence of the two formulations, and extended release formulation should not the bioequivalent it should extend release properties so that raises a red flag and you look the elimination of the whole blood, this is largely reflective of red blood shelves and the site of action. This was not informative arrests from PK study to guide decision-making to have a sustained release formulation should go. It is sufficient to begin on today. And the study had to be done over again.

My last example is a drug based on just and wait for a development. Early PK studies whoever revealed the correlation between body weight clearance or I am of distributions are typically, with drugs of these characteristics, it'd give a fixed flat dose. And they did a PK study how these subjects and as weight increases, the exposure of the drug increases precipitously. Again, this would point to the direction of dosing with a mixture of flat dosing and a Joseph ceiling. Have a move to phase 3 with a weight taste does. Which may not have been an issue this has been a positive QC signal. As you can see in the lower right, the higher super therapeutic dose was administered, is especially lines, the higher super therapeutic dose produced a

Is associated with a 30 and 40 ms UTC. This is a significant potentially clinically relevant signal associated with a concentration. The exposure data, the concentration is going to the cessation of the 30 to 40 ms concentration and the culmination of this data said this should be fixed flat dose or an upper limit of applied to the weight-based does the word is used in patients. And lastly, I put together a couple of slides with our guidance documents. There quite a few, just for your reference. Thank you.

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