Thank you Williams, okay. My name is Kourosh Parivar, I am a clinical pharamcologist. my basic training is in Pharmacy. I completed my pharmacy training in Uppsala University in Sweden, and I did a postgraduate in Kinetics at UCSF. completed my training in 1989. And since then, I've been working for 22 years in Chemical Pharmacology at different pharma companies, AstraZenica, Pharamacia, and currently at Pfizer. And in training today, I am doing in behalf of myself, I'm not representing my company. So I I was asked to give you a course in Clinical Trials with the focus in Phase II setting. So with that I would like tom and start with my lecture. Just a quick notice about trials, I believe that most of you have been exposed to clinical trials in some form or fashion. But, generally speaking it's a, it's a controlled experiment. we try to control the setting of the experiment as much as we can. In order to exclude confounding factors so that any findings observed in that setting of that study could be directly attributed to the actual product. Rather than just a from a bias or other findings. If you look at the drug development per phase, and again, some of you may have been exposed to different information about about drug development. But the, we usually break it down in different Phases. Phase I to Phase IV, yeah, each Phase, each bucket has its own primary objective. If you look at the Phase I, you could see that the, there are a few primary objectives of Phase I studies. Yeah, one of them would be to identify the maximum tolerated dose. The second one would be to characterize the Pharacokinetics and dynamics of the compound. And thirdly would be to characterize the safety profile of the prodo, of the compound. These are the primary objectives of the, of that segment of your development, it doesn't mean that you can't do more. But the, these are the primary objective. You try to identify these three objectives first. And then if there are any other objectives, secondary objectives you will add on. And when you complete your Phase I your, your process proceeds to Phase II, which will be my focus of the discussion today. And in Phase II again, the primary objective of Phase II would be to establish proof of concept, and to characterize the dose response, or exposure response. And by response, I mean either the expected response in form of efficacy or the unwanted response in the form of side effects. So we tried to establish a correlation between them. Eh, and also tried identified the doses that we are eventually going to test in the Phase III setting. So, Phase II, in my opinion, is one of the most important area of drug development. Yeah, that's an area you need to really identify if you've a viable product or not. after Phase II, comes Phase III. And if you can see them, main objective of the Phase III is to confirm the safety and efficacy of the product. And again, with the focus on confirming. Yeah, you really need to know of your product before coming to Phase III. In Phase III, you just add larger normal population it, of the target population and try to confirm what you've already seen in Phase II setting. After Phase I, II, and III is completed, you usually put together a submission package. Put the package into regulatory agencies across the world, that being FDA or MEA, or KFDA in Korea, or SFDA in China, and so forth. And apply for an approval. The process will take extra number of months, and then hopefully you will be awarded an approval to market your product in that market. after which, the Phase IV comes on board. In the context of discussion, the regulatory agencies, in many times you end up with a negotiation. After which you may yet be requested by regulatory agency to do x number of additional number of studies. And we call them post approval commitments. Yet those studies are performed after the approval is given. Product enhancement studies is the studies that the companies undertake. In the form of, for instance, if you have a drug for which you are using an immediate release product. If you are giving it two or three times a day. That's not that convenient for a patient. But you know by virtue of pharmaceutical sciences that, that you can, if this drug, so that the drug could be having an affect across the whole GI tract all the way down to the colon. So by, and then when you know that you can develop what we call a sustained release, a controlled release formulation for that one. And by help of that one, the drug can be given just once a day to the patient, instead of three times a day. So, those type product studies are product enhancement studies. And, of course, the last one, would be Drug-drug Interaction studies. We do perform a number of drug-drug interaction studies during the the actual Phase I, II, and III. Yeah, but, yeah, after a registration of product, when it comes to real market when you see, when the product being used by yeah, a large and much, much larger population of patients. You may end up getting additional requests for additional drug-drug interaction studies, and those are studies are performed in the Phase IV setting. Yeah, in the bottom part you have, tried to give you an idea about the number of patients or subjects that you see usually in a Phase I to Phase III. And in a Phase I setting, you usually see about 20 to 100 healthy volunteers or patients, the length could be several months. In Phase II, the number of subjects or patients you see is about up to several hundreds. And it could take as short as, yeah, four weeks to six weeks, or it could be as long as two years. Usually Oncology studies are the ones who are long in, in, in duration. It may take you two years to recruit all the patients you need for your study. And in Phase III setting, you could be again from 100 patients to higher, yeah, and it could be a lot, lot more patients needed for that one. Yeah, and again, in, in, in therapeutic areas where you have difficult access to patients because of the prevalence of disease is smaller, you end up with smaller Phase III studies. But, in other therapeutic ares such as CVMED in cardiovascular for instance. In order to do a, a, present a drug to the market, you may need to do studies as big as 5,000 or 6,000 patients. In order to assert in safety and efficacy of the product. So why do we conduct Phase II studies? the purpose of Phase II studies is yeah, filtering, tool. And you want to make sure the product that you are sending to Phase III has a proper yet, efficacy and safety. Yeah, it's a filter. If the filter is too porous, you're sending too, too many products to Phase III. Yeah, products which may not have the characteristics for success. And there by, and thereby, they may very well fail in Phase III. And if the filter you put in Phase II is too tight, you may be killing too many programs. Even the programs that may have had a chance to succeed in Phase III setting. So, it's a pretty difficult balance for you, where you've got to, where you put your hurdle. If your hurdle's too low, it's too easy to jump over it. If your hurdle is too high, it is difficult to pass it. Yeah, and there, and there is, comes this balance between success in Phase II, and success in Phase III. And if your hurdle's too low, you have too many programs succeeding Phase II. They go to Phase III and fail. If the hurdle is too high, again, your, your, your success in Phase III would be high because programs are few. Which passes the hurdle, go Phase III, they succeed by, by, by, by your running the chance of actually killing good products. And, and that's the tricky part of Phase II, its design. there are two stages in Phase II. Phase IIa and Phase IIb. Phase IIa is the first, first kind of a step as to Phase I, during which you just take the highest dose that you can give to the patient, the maximum safe dose, MTD. And you give a two arm study, your test study, test product at maximum dose. And then you take the standard care /g, the product which is already in America for treatment of the patients. You test them against each other. If you succeed, then you go to Phase IIb. If you don't succeed, then you don't go to Phase IIb, the product will, will die, and get terminated there. Phase IIb would be when you already know that your product works, but the dose that you tested in Phase IIa was the maximum dose given to the patient. You may not need to give the maximum dose to get efficacy. You may get, you may be able to give a lower dose, obtain efficacy, but more, more milder side effects. So that's why in the Phase IIb setting, you do a multi-arm study. You test the different doses of your product, your test product. Again, against the standard of care product, which is already in the market. So and by virtue of that you will find out which one of the tested doses of your test product is the best dose to be given to the patient. And I will come back on that a bit later on about the design of these two studies.
