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

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Kelly Reynolds, Pharm.D.

Second talk by Dr. Kelly Reynolds director of clinical pharmacology and the office of pharmacology will guide us into the phase 2 and three clinical development and what information we can learn from clinical development and phase 2 and three and how that informs the effective and safe dose.

Good afternoon. I love when I get to the last place I know I am between you and getting out the door. The information to be presented today follows on what Sarah presented. As you mentioned, phase 1, even though it is called phase 1, during phase 1, the information that is collected, continues to be important that the drug development process and I'm going to talk about information that is important to Germany drug interactions, phase to phase 3 drug development decisions that are affected by drug interaction and 1K struck exposure can be altered and the need to evaluate specific populations that will examine the impact of complete and incomplete clinical pharmacology packages. Just to outline how to go over this information. I will talk about one exposure response information is important. Whatever. Shtick good exposures. It pays to phase 3 case study for drug interactions and specific populations, briefly, and relevance of exposure response information. The same slide that represents during phase 2 and phase 3 and the right patient at the right does, that we went administered at the right time. We have been focusing on phase 1 today so phase 2 and phase 3. Phase 1 studies are preliminary data on the -- this is the no go decision and allows the selection of appropriate dose range for further subject to phase. Phase 3 studies are the ones that provided little information about effectiveness and safety at Lasher to the brave the risk and benefit of the drug. Advocacy -- efficacy and toxicity are importantly a look at exposure and pastry. We think that exposure response during phase 2 to select the appropriate dose for phase 3 but it is important to her vied for space. And why it is important to collect data during phase 2 sometimes unexpected innings happened during phase 3 and you can go back and ask -- collect the white -- the exposure data and the samples are completely sample to show will reiterate that. One exposure response is important. You can add to the weight of evidence support -- supporting efficacy. Good exposure response to this can't replace one of the phase 3 studies in a well lighted to explain the results based on concentration data and knowledge of exposure response and safety concerns. There may be problems of safety in a certain population as we find out later combat population had higher concentrations that concern other operations. And other subgroup differences. For example, the drug does work as well in one subgroup, we might find out later they have lower drug concentrations.

In some cases, there is a drug that is improved and they response was to come up with a new distant regiment. Three times a day to twice a day, exposure response can help every concentration time profile from immediate release to extend a release and the new route of illumination. Some of the examples arrows talking about. Going into new population. Probably the most common one to think about is going from adult population, to pediatrics and exposure response is important here. If you want to -- and subgroup so many of these cases, it is not possible to give population of the previous populations up if you're going to understand exposure response you can interpret those differences. Also, I'm pivotal bioequivalent, after they're done they pivotal trial, there may be a change in the formulation. They want to market in that case we want to -- conduct a pivotal bio -- study.

To meet the same criteria, it is no problem at all but in some cases you may have slightly lower exposure is slightly higher exposure and as we understand exposure response was to make it the formulation improves.

The food effect is understood to make the early formulation and during development and formulation changes in a different formulation is used in the trials and they allow for it to be used or not used in patients can take it however they want to.

We may find that there is a food effect we don't know how significant that is we understand exposure response we can interpret that determine whether or not they can take it with without food.

So center is a good case that exposure response information is important, I want to talk about some of the barriers to adequate exposure response information that is aside from the fact that sponsors don't want to collect information to begin with. And they agree it is important to collect information, there are still some barriers.

In some cases, the studies may be underpowered. You have enough exposure information that may not be enough doses of the doses are too too close together. 100 mg or 150 mg, which is not a very wide range and you can't evaluate exposure response if you don't have a wide range of exposure and some samples are not collected at the appropriate time you can catch it the proper exposure parameters.

They could be lost in study conduct and seen many cases where sponsors have been a wonderful job of collecting exposure information and collecting pharmacodynamic information but it turns out that we don't know when the concentrations were collected relative to the dosing times. That does not do us any good. As Sarah mentioned, analytical methods are very important. We need to make sure they're just astringent in the phase 3 studies will have a pharmacology studies. We went talk about to case studies and these are specifically for drug interaction but they can also apply to any situation where exposure changes in population in the first case is a wrapper rock, HRC CCR five inhibitor. For the example I am shy, this is a first submission for it -- this is the first submission for this drug and for patients with HIV. The dose was selected for the phase 3 studies based on phase 2A exposure response evaluation. Excellent exposure response information neglected and we were comfortable with the dose was selected, 300 mg once a day of 300 mg twice a day to study in phase 2 and three studies. Some of us have a lot of drug interaction information is drug is a three-day substrate and other drugs may increase or decrease the concentrations were however, does not change the concentrations of other drugs. And the dedicated drug interaction studies, when you give inhibitors with -- that is a wide range of there are some drugs that increase only three folders some increase it as much as 11 poultry if a industry was given with it, the concentrations decreased by 50% but there is another inducer that had little effect on the concentrations. There is a wide variability in the drug interaction information and you might have a lot of differing dosage adjustments because of that. That would be very confusing during a clinical trial and also with the drug was approved.

So because we had exposure response information, we know a range of concentrations would probably be affected and interested which concentrations had safety concerns. We were able to break it down to two to adjustments. A standard 300 mg dose of skin with an inhibitor, 150 mg one was given with an inducer, with 600 mg. So we didn't have the exposure response information, who is quite likely that would have drug dosage, hundred 75 mg, 600 mg, would be a lot more doses and that would have been very confusing.

So that is why it was very beneficial, in that case, does the drug interaction information and the phase 3 settings. In the next case I want to talk about from an example from page 3.

This is another HIV drug, and they had two identical phase 3 studies. And both of the studies, the drug trauma rain was given in combination with -- and on the safety and efficacy information was collected with the other drugs on board. Fascinated based on phase 1 drug interaction information that the administration -- with a trauma rain decreases the transferring concentrations by 30% and 50% decrease of the HIV drug is the efficacy concern. You're concerned about resistance. In this case, there was the efficacy concern because of the phase 3 study was conducted. There was a 50 -- safety concern. A pretty good chance that not all patients that received this drug would be getting -- so our concern was, if you take the dash away, and the concentrations are higher, what does that mean? Would it be a safety concern because the patients in this study did not have concentrations that high. So what we had to consider was how much higher with the concentrations be? Are they higher concentration save? A one of a specific risk benefit concerns of the population in question?

Severs you consider a specific case. Perhaps the patients would receive -- instead of lopinavir ritonavir and that increases the -- of 80%. However compared to when it is given with ritonavir lopinavir purchased on average. We did, we collected information from all patients in phase 3. This is a case where the data ended up being very beneficial. Most of the observed concentration data from phase 3. It was the higher concentration range of and for those higher concentrations, rail her to calculate what the demonstrations would have been if they would have received the lopinavir ritonavir vendors of the highest concentrations and we had to consider the population that would receive this drug for the individual's forget the lopinavir ritonavir because HIV patients have a specific position on why they decide who receives these combinations. There was a safety risk and that the higher concentrations of because they are the concentration data and understood the distribution we were comfortable with labeling the drug to be ministered with lopinavir ritonavir.

Different study designs from phase 1 studies, renal impairment, hepatic impairment. Bass is a gender studies and age that is, when pediatric and I want to go for a decision tree for pediatric studies. This is another case where exposure response information can be important. If we have exposure response information from adults and if it is reasonable to assume the diseases similar pediatrics at adults, and the exposure response is the same in adults and children, but exposure data from children along with safety data in children can often be enough to get the drug approved in pediatric populations. However, in case we to understand exposure response, they'll not impossible that has to be at dedicated efficacy study in pediatric patients.

After everything I've told you about exposure response, I want to go to some questions. This is a rhetorical question we heard before. If a tree falls in the forest and no one hears it, does it make a sound? I don't have the answer to that question. So ask another one. In the drug has exposure response relationships for efficacy and safety the concentrations are not collected in phase 2 in pastry, can we optimize therapy for all patients? This question I can answer. The answer to that question is no.

There a couple of -- other versions of the center. You don't know what you don't also just because you don't know the concentration is too high does not mean it is not too hot and ignorance is not bliss. And to further drill down into the answer, that exposure response information, we can't interpret significance of exposure changes. For both of the examples I gave you, the sponsors would have had trouble if they do not have exposure response information they collected out without adequate phase on information, I'll drug interaction a specific interactions, we've understand the magnitude of changes we need to put the two together the result is, the lack of dosing instructions for certain groups, they are deprived of therapy, sub optimal safety and efficacy.

Thank you very much. And now we have time to ask questions from the audience. -- Are here to answer any of your questions regarding pharmacology.

I guess this is a two-part question. I am not sure. It's about ethics, primarily we did have a reference to redo trials in the first presentation. And my question is, is it okay for us to be redoing trials because of sponsor negligence in study design or for whatever other reason that we don't get enough data and is it okay because we are exposing humans to investigational drugs, to me, unnecessarily. That is the first part. One of the reasons I am realizing the agency is finding this out later, is because after the first initiation of a study in the submission of a high-energy, sponsors have the option to have the agency review later studies are follow-up studies. So, I'm not very big difference. It is a good question. Ideally, we review protocols and they would not go forward if they are going to provide information if you wish to have volunteers that have exposed healthy volunteers tried to should not have taken. -- To the drug they shouldn't have taken. [

In cases where we did the study reports, and something was done incorrectly, which I is hard as we can to get the information we need to think about the fact that healthy volunteers were used in the study. If we can get the information we need, pulling it from other studies possibly, we were not asked for another study that essential information and we can't get it, a study would need to be done again.

You may want to get a contact of the sponsor to say if they had additional sample stock somewhere to get some plasma samples are concentrations from. We do try and always get the information owner of a possible without having to redo a study.

Ethicon Columbus together with experience in phase 2 for four studies that find the sponsors are coming to me asking for help in phase 1 studies have seems like they're looking to study in phase 1 targeted populations is a hybrid phase 1 to a study as to the normal volunteers ran wondering if this is a sponsor initiated move to save costs and expedite studies or the FDA has some guidance or thoughts on that as well?

You're talking about the study where they incorporate healthy volunteers struggling to patients the same city?

Ari phase 1 study in a targeted population? I said we have seen -- I certainly have seen.

Had a quick question regarding products with a major -- you want a mature approach to establishing PK and dosing when there is a table -- there is a metabolite with the efficacy and safety. Any thoughts?

It depends on what you identified metabolites which was number they do early on, figure out whether those metabolites have activity, personal ethic and will that God does not need to be at assessed with respect to efficacy from a safety perspective, the metabolite could be important. Again, that is the important thing to outline, the metabolites in print once we were safety studies as the PTC study and have a very special population studies of it is important to know how relevant metabolites are.

Any more questions?

Can you comment on the safety reporting requirements for the phase 1 study and the requirements report the prevalence or instant rate for the adverse event and how that is applicable for phase 1 study you have a small number of -- volunteers?

I know to have changed very

Clinical pharmacology, another someone speaking on that tomorrow or not.

Two-hit ethnic diversity in the United States and the ethnic diversity is increasing dramatically, with their time is that it requires an adjustment in the labeling related to any differences? --...?

We consider how the drug is metabolized would understand there are certain enzymes that there are ethnic differences of them.

Is probably more likely and why in the direction of pharmacokinetics are it is particularly linked to James owner telling down more towards that. You see a racial disparity which I don't investigate what the cost of that as we can provide more useful information beyond the race factor again, just up, there is a respected is going to some sort of genetic difference for

We require a PK study to actually evaluate and characterize the differences?

We could. Yes. That was needed for a specific drug. I would not rule that out.

We usually got the raise of a face to face for using population PK methods as well populated race study there is a particular that have

Question about the pediatric decision tree. It seems a little but like a catch. Assess, test them or assess a similar response of intervention, where would you get this data from if there is no -- or would you do offer viable evidence for that in order to really pursue have to do any follow-up dynamic studies or Tinkertoy pharmacokinetic study the second question to that, a lot of pediatric drug development, no interest in the industry because the revenues are not there. So a lot of those studies are investigator sponsored on the question comes, do we need -- for those studies could you comment on that?

Because it is easier for information about the end projection convention is expected to be the same in pediatrics and adults is based on what is known about the disease and other interventions for that is a state. For example, any invectives and searching the bacteria's bar with her treating a virus, we expect intervention to be the same.

We have specific expectations for how -- nice to have control over the studies to make sure it's contents of the questions because there is a lot of input on the protocol.

I have seen non-IND studies come in. Usually they are not in the United States.

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