If you’re thinking about a career within Clinical Research, maybe you’re someone who wants to be a study coordinator, clinical research associate, CRA, CTC or CTA. Or maybe you’re a new study coordinator, maybe you’re an investigator that wants to set up your own practice, or you’re just someone who’s interested in learning more about clinical research, this is for you. This crash course is going to be I hope something that can give you a good foundation for clinical trials. And I’m going to roll out more crash courses in the future, specifically GCP training which is Good Clinical Practice and things of that nature but for now this is a great starting point. If you have any follow-up questions, email us through the contact page or post your comments on our facebook page. Let’s get right into it.
So we’re going to start this course with discussing ”what is a Clinical Trial?” Let’s assume you’re almost brand new to this field of research, which you probably are, so what exactly is a clinical trial? Check out the index to browse through the different sections of this course. I hope this material will give yo a clear view what clinical research and trials is all about. This information will be very valuable if you’re trying to get your foot in the door at a CRO or pharma company.
1. Clinical Trials
So a clinical trial is a series of tests that scientists do when they come up with new ideas for new drugs, new molecules and compounds, new medical devices or perhaps even some medical procedures (especially true when it comes to surgery). Oftentimes the surgical procedures, even surgical tools which will be known as medical devices technically, have to be FDA approved. And also all drugs have to be FDA approved. If you’re getting something prescribed to you by a doctor, it got to be FDA approved.
This shouldn’t be confused with herbal supplements which are very popular. We all actually take quite many. Those are not FDA approved. They don’t go through the clinical trial process. They can’t make medical claims so that’s why drug companies invest millions, if not billions of dollars testing out new compounds and new medical devices so that they can get FDA approval. And so that they can make medical claims that this drug treats a certain disease, this drug cures that disease, this device helps with this medical condition, and things like that.
So drug companies – that’s their job, they make drugs, they make treatments, they find cures, and all that stuff. Clinical trials is at the root of it, it’s at the heart of it all and that’s what a clinical trial is. Next we’re going to get into the different phases of clinical trails which is Phase 1, 2, 3 and 4. But before we do that, I want to mention the pre-clinical stuff.
1.1 Preclinical trials – in the lab and animal studies
So what happens when a scientist at a pharma company is looking to come out with a new drug for, let’s say, high blood pressure?
First, he or she is probably in his lab with a team of colleagues and they’re looking at the way blood pressure regulation works and the mechanisms involved. They try to brainstorm different ideas and different processes that certain molecules can maybe contribute towards slowing down the disease or just treating and curing it altogether. So they’ll come up with hypotheses in their heads and often use computer models, very fancy computer models, to do all this stuff. They create a molecular structure. Then they want to see if it’s actually possible to synthesize that real molecule. So they’ll do this in the lab and this is called ”preclinical trials”.
Once they get the molecule, they study it on animals. These are still preclinical trials. They’re called ”animal studies” and from this portion of clinical trials is where the stigma of lab rats and guinea pigs come in. It’s very different from studies in humans. Humans have rights when it comes to clinical trials and animals don’t. But regardless of the fact, whether you’re for or against animal studies, for now you should just know that animal studies are done at this stage. It’s in the preclinical phase and what they do is they want to see how their drug, their idea that they just synthesized makes an animal respond and what kind of effect does it trigger in an animal.
If they’re okay with the early observations, with the data they receive for an animal studies, they’ll move in to the Phase 1 Healthy Volunteer Studies, and we’re going to get into that in this next chapter.
1.2 Phase 1 clinical trials – first in human
So phase 1 clinical trials, also known as first in human clinical trial, healthy volunteer trial – these are studies where the drug, let’s go back to our drug against high blod pressure, these are studies where they’re first studied on humans. We mentioned the animal studies in the past, now it’s moved on to the healthy volunteers. So notice that the drug is not being tested on people with high blod pressure in phase 1 studies. It’s being tested on healthy volunteers and the reason for that is because they want to see what the toxicity level of the drug is in a human being at this point. They’re not interested in seeing whether it works. They already have an idea that it works for high blood pressure. These are smart people. They’re not just going to create random drugs and then just kind of throw out at everything. They actually have an idea, an educated hypothesis that this drug works to lower blood pressure.
So right now they’re not concerned about that. They’re concerned about toxicity levels in human beings. So healthy volunteers come in and this is where study participants, healthy, completely healthy and normal. By “normal” I mean they have no medical conditions, they’re not overweight, they’re in perfect shape, perfect age range although there’s no such thing as a perfect age range but they’re generally within there – at least 18 to 45. I really haven’t seen phase 1 studies allowing people over 45. I may be wrong here but the point is they’re looking for healthy individuals that have no medical conditions, because they want to see the toxicity levels of the drug.
When you’re in a phase 1 clinical trial, you’re in an in-patient study. You join a study and they take you in a unit where you have TV, cable, internet etc. You can interact with other people. You get food, you sleep there. They do tests on you. They draw your blood like every 2 hours, every 4 hours. They’re constantly measuring the molecules in your system and they’re introducing this study drug to you. And what they do is they keep on increasing the drug until you start producing some kind of side effect as far as your body reacting to the toxicity of the drug. So that’s their ceiling. They know not to get past that point.
Phase 1 studies usually have, I want to say about 80 to 100 study participants nationwide, at various research clinics throughout the country, throughout the world. So drug company X is doing a study. They’re doing it on 80 subjects, 80 study participants worldwide. They may be using 5 different research centers to do this, 10 different research centers each one enrolling 10 people, whatever it is. Once they get their data from all their participants, they’ll analyze it and they’ll say, “Okay, at this level, statistically significant number of participants experienced toxic levels”. And obviously that’s our limit and actually we want to be well below that just in case people take more than they should. But anyway we’re getting too far ahead of ourselves.
So in the phase 1 studies, it usually lasts anywhere from 30 to 60 days. The study participants can withdraw from the study at any time for any reason. But they’re seeing toxicity levels and these people who join these studies, these phase 1 studies get paid a good amount of money, up to several thousand dollars depending on how long they stay in the study and what the study entails.
So that’s phase 1 studies. They want to see the ceiling for the drug and they want to see if the toxic levels are really bad.
Now if the researchers are happy with the results, once they have the toxic levels at a certain range, their hypothesis is that the effective dose for the drug is much less than that range. They’re going to move on to phase 2 studies which are the first in-patient studies and we’re going to get into those right now in the next section.
1.3 Phase 2 Clinical trials – First in patients
So now we know the estimated dose range and toxicity level of the potential drug. Next we are interested in the efficacy.
In phase 2 the efficacy of the drug is studied on patients with a target medical condition
1.4 Phase 3 clinical trials – pivotal trials
So we talked about phase 2 studies, where the first tests being tested on actual study participants are carried out. Participants with the medical condition that the study drug is supposed to treat. Now we’re going to get in to the phase 3 studies and these are pivotal, they’re called pivotal trials because it’s the last study, last clinical trial that the drug company will do before they submit it to the FDA, the Food and Drug Administration, before they submit what’s called an NDA which is a New Drug Application. They’re trying to get the drug approved by the FDA so that doctors can prescribe it.
From the phase 2 studies we understand what the dose range is and if they went to phase 3 that means that the phase 2 study drug, it demonstrated that it works on people with high blood pressure. This is called efficacy – it works at that dose range and it’s safe, safe enough to proceed to phase 3. And mind you, let’s back up here. In between each phase, the drug company usually consults with the FDA. They have meetings with them. They talk about their results. They try to get the FDA’s opinion and guidance, and feedback on what they can do, how they can design the studies to make sure that the side effects are being tested accurately and that the drug is really showing to be working with the study.
So we also got to talk about placebos because if you’re in a study, if you’re in a trial and this starts from phase 2 and phase 3, you can get a placebo instead of the actual drug. That’s how the drug company, as well as the FDA will know whether the drug really works and these are double-blind placebo studies. For the most part they’re double-blind studies. That’s the FDA kind of golden standard, double-blind studies, which means that neither the researchers nor the patients know who’s getting the placebo, but someone is. But the people who analyze the data, they all know and so they want to see if the study drug can prove that it works better than placebo at a statistically significant level. We’re not going to get into those details. That’s a different topic that really gets into the complexity of it. But they want to see if the drug separates itself from placebo, whether it actually demonstrates that it’s better than placebo, which is a plain sugar pill, a non-active substance.
So now, if the trial gets to phase 3, that means that the drug is relatively good. It’s shown to have worked, reasonably well enough to move to phase 3. It worked in the phase 2 studies at a certain range and the side effects were reasonable probably, nothing unexpected. The phase 3 studies enroll many people, thousands of people, anywhere from hundreds to thousands of subjects. Study participants can be recruited worldwide at hundreds of clinical trial research centers. The phase 3 studies, needless to say, are extremely costly for the drug companies. So they won’t even do a phase 3 study unless it’s a very promising drug that they’re testing.
So the phase 3 studies are also long-term. If you remember the phase 1 studies were 30 to 60 days for the study participants and the phase 2 studies were about 2 months to 8 months. Phase 3 studies are anywhere from 8 months to 3 years. I’ve even seen some for 4 years so they’re really testing the efficacy – remember whether the drug works, and the side effects over a long period of time on a much larger patient population as opposed to the previous studies. These ones, they look for anywhere from 800 to 2,500 subjects worldwide.
The phase 3 studies are called ‘pivotal trials’ because it’s the last study that the drug company will do on that particular compound before they submit it to the FDA.
Now, let’s say they submit the NDA, the New Drug Application after phase 3 study has been completed. The FDA can either accept the drug, decline the drug or it’s called “reject” the NDA or tell the drug company to redo another phase 3 study and the “redo” part happens a lot. Maybe the FDA didn’t like one of the particular side effects of the drug and they want to do more scales on that particular side effect. They want to measure it more. They want to measure the severity of that particular adverse event which is the technical term for side effect. And we’re going to get into all these terms later on. So the FDA may ask the drug company to redo the phase 3 study.
1.5 Phase 4 clinical trials – after marketing
Finally we get to phase 4 studies. These are post-marketing studies. The drug has already been approved, but if you notice sometimes drugs that are approved have warning labels on them. Phase 4 studies are often done to try to either remove these warning labels, if they can demonstrate to the FDA that they collected enough data, the FDA may consider removing these warning labels. Or maybe the drug company wants to market and promote the drug and promote it for treating other kinds of things loosely associated with the first medical condition that it was approved for. They can then do phase 4 studies.
The FDA will say:
“Okay, we’ll approve it but you can’t promote it outside of this range. You can’t make claims that it does this. We approved it for treating high blood pressure but if you want to make claims for it treating something else, please do a phase 4 study.”
Phase 4 studies can last anywhere from 1 year to many years. They are clinical trials but they’re not really clinical trials because the drug has already been approved. They’re just looking for marketing stuff. They’re looking for other things that the drug can perhaps treat that they can promote and so this is usually marketing studies.
Anyway, it’s still very important and in my opinion phase 4 studies are really good for the study participants because they’re getting free drug and they pretty much know what the drug is. So I’ve seen many people who have done phase 4 studies just because they’re getting free drugs for many years sometimes. That’s a very interesting aspect of phase 4 studies.
In the next section we will discuss the role of the Institutional Review Boards (IRBs).