My name is Joe Ma and I'm assistant professor of Clinical Pharmacy at the University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences. And also one of the co-chairs for this elective course. so today's lecture is going to talk about clinical studies start up activities. So, for our lecture objectives for today, we're going to talk about three key elements of a clinical study protocol. And I'll highlight a little bit of the innuendos and details of what needs to go into a clinical study protocol. We'll highlight some objectives of the institutional review board, of IRB. I think probably most of you have probably heard of the IRB, but we'll get a little bit more depth and detail in terms of their function and role. State 3 key elements of an informed consent form, and then state a difference between a site evaluation visit and site initiation visit. So the outline for the lecture includes the following, the basics is what I want to call, the clinical study protocol. And I think it, I think the best way to kind of look at this is lets just use a case example. So, we have a case example of an investigational agent, that's going to be looking at this gene, called myostatin and a potential investigational agent to inhibit the action of myostatin. We'll talk about the IRB, or Institutional Review Board. And we'll actually bring up, a true story of a healthy subject who was involved in a clinical study who actually died from participation in a clinical study, and she was a healthy 24-year-old. we'll talk about informed consent, and some of the important pieces in terms of content of the informed consent form. Another very large area of concern from a regulatory perspective is how data is collected from a clinical study. the FDA has come down very, I would say very hard on regulatory on pharmaceutical companies, but also institutions that conduct the study. It's been a very large area where the FDA can give what we call warning letters, and actually place the study on clinical hold. And a lot of that has unfortunately been, been driven by poor data collection. And then finally we have some information in terms of, okay. If I'm in charge of running a clinical study, I'm going to start let's say, a phase one, a phase two or phase three clinical study. What are the key questions and key things I need to, you need to know in terms of, alright how do to, maybe pick the best study? How do I make sure I meet my timelines? And, how do I make sure I stay within budget? So, we'll highlight that. [SOUND] Alright, so Clinical Study Protocol, the basics. So what is it? I, I think how I like to try to describe it is it's a cookbook. It's a set of instructions in terms of how the clinical study will be conducted. And how it really has it's role is that it really tries to describe okay, who can be enrolled or participate in the study. There are going to be instances where you are going to have what we call inclusion, exclusion criteria. I kind of look at those as a set of rules to say, alright you know person A can be enrolled in this study, because you meet all of the inclusion criteria. But Person B unfortunately can't, because maybe you've met one of the exclusion criteria. And we will get into some of the detail in terms of. How do you design that? What do you think about in terms of design what we call I/E criteria. We've talked about the protocol, include a lot of details. As specific as you can in terms of how's data going to be collected, what procedures are going to be done for the study, and what not. The other thing that's important is why do we have these protocols kind of who cares about having these protocols. Well, a lot of times is the reason it's important is you're going to have, let's say sample size maybe of 50 to a 100 subjects that you need to participate in your study. So, it's going to be very difficult to have it done at one site. So, you're going to have at least two, maybe three sites, performing the same study. So, you want to make sure that they're consistent in terms of what is being done between sites. So, the key elements of a protocol include the following. And we're going to spend, I have a couple more slides after that we'll get into a little bit more detail in terms of the what. What are some of the key aspects for each of these sub-bullet points. So, you need to include your background of the target rationale. You'd include your hypothesis. What are your objectives? What are your endpoints? Study plan and I've kind of defined or at least highlighted some key parts of a study plan. You study design, your study procedures. Some of the statistical considerations, what I mean by that is depending on the type of study you're doing. Whether it B as an example a drug, drug interaction study, you're going to do something called bio-equivalence testing. And this is quite different from a statistical test that you may do for a clinical phase three study, or even some clinical phase one studies. So, you need to kind of describe it, define it, and really have it detailed in your protocol. I alluded to this earlier regarding I/E criteria, so I, I, we'll get into a little bit more detail regarding that with our case example. What are some stopping rules for a study? So that the rationale for that is in situations where I see, you'll see this commonly. Maybe there's an interim analysis of the data, or let's say your target enrollment is a sample size of 100 subjects. But then a lot of the companies will say, well, let's look at the data after we've gotten data on 50 subjects, and we call this an interim data analysis. We'll look at safety outcomes, and if we see a signal that could be either in a positive format or in a negative format, we can say, look, we're going to stop this study. And it's one way where you can do that and it can be addressed in the protocol. And that looks much more straightforward versus trying to do something post fact, where the protocol is already developed and then you want to say well I want to have stopping rules. The FDA is going to be like, what's going on here? So, the other key element is really it's huge in terms of the phase one study perspective, is. How will subject safety be determined? For the case example, I'm going to be highlighting from a context, from a phase one study perspective. in the past generally this lecture would be just before your clinical studies, but we had to make some scheduling changes. So, but from, for purposes of this talk, and for future, it's going to be from the perspective of, we're going to start a phase one clinical study. We've gotten all of the preclinical and animal data to us, but we have very little to no human data from either phase two or phase three. So, you're at a critical junction where you don't, you have very little human data, so I need to still do a phase one study and how to go about doing that. So, giving a little more detail in terms of the key elements. So, we alluded to the background of the target rationale. So, in essence, you want to include any past literature. So like as I've alluded to in the context of starting a phase one study, you want to summarize what are your preclinical data. What, what are the data findings whether it be in your toxicology studies, in in either a rodent or a monkey or whatever species you're looking at. You may want to address if you have an idea of a potential target population if you're trying to meet and end that medical need. For your objectives, it's going to vary depending on the clinical study that you're doing, if it's phase one, two, three or four. So again, from the perspective of a phase one study, essentially the objectives are you look at safety and tolerability of a drug and you look at the, you look at the pharmacokinetics or PK profile. So, I've kind of underlined the key words here in this slide. And the reason being is that regardless of the drug, these objectives for a phase one study are going to be basically the safety tolerability and characterizing the PK of the drug. Regarding the study plan. So, it includes aspects of the study design. So I think probably some of you are probably aware of these terms. But just in case if you're not, I'm just going to give a little bit of background on what, what do we mean by some of these terms. So randomization if there is a decision to randomize subjects, meaning they get randomized either to active drug or to placebo. it's a methodology to minimize potential bias, where if there was no randomization The investigator or physician would say all right, I may, you know, knowingly or unknowingly be biased in terms of placing subjects, in a specific group. So there's always randomization to help avoid that potential conflict. Placebo control is another way to minimize, again, bias and variance in a study. Meaning they either get active drug, or they get a dummy, or, or non-active drug or placebo. Are you going to give a single dose, a multiple dose, in terms of your investigational agent? Again, are you going to do, have the study done at one site or several sites? Your I/E criteria, I've just as a little overview, you want to clearly define your study group or your study population. So, for our example we're going to be focusing on healthy subjects. But you will see phase one studies, primarily in cancer, or at least agents dealing with cancer, they will actually enroll patients in a phase one study. The rationale of using healthy subjects, in phase, phase one study is traditionally in, in a non cancer arena. Is that, since we have very little human data, we want to get our "the healthiest of subjects" and their, I hate to say this, but they're probably the most homogeneous. They don't have a huge heterogeneity in terms of having patients, because of the fact that the largest risk you have is going into patient, going into healthy is for your first time in a phase one study. So that's why they call FIH, first in human or first in man. You'll hear that terminology a lot. And so when you're at that point, of gosh this drug has never been given, given to a single human on this planet, you want to say all right, where can I minimize risk. And one way to to do that is to say, all right, I'm going to first dose a healthy subject or a healthy volunteer. in terms of their rational for the criteria, is again to minimize either confounding variables or inter-subject variability. As I alluded to picking healthy subjects versus patients.
