Skills Lab: Moving Through the Phases of Clinical Research

This transcript has been edited for clarity. 
Hello, everyone. Welcome to the first video in this series. As I mentioned in my introductory video, we are going to focus first on phase 3 clinical trials, and then we’ll move on to other phases of clinical trials and other types of clinical research. Just to give you some introduction, what is a phase 3 clinical trial? 
Clinical research can happen in different ways. One is observational research, where you don’t do any intervention, but you observe what is happening. These are population-based studies, registration-based studies, or case reports; things that you observe and draw inferences on. We can talk about it in detail in the future, but I want to start with phase 3 clinical trials because that is what is changing our clinical practice most often. Once we finish that, we can move on to other types. 
Just to give you an idea, there are observational types of studies and there are interventional types of studies. In interventional studies, you actually intervene, and you want to measure the effect of the intervention. That intervention is in the form of a new idea, so it could be a new product, a new innovation in terms of surgery, or a new device. If you are experimenting, then it is a clinical trial. A clinical trial is an interventional type of clinical research on human subjects. 
A clinical trial, fundamentally or classically, can run from phase 0 to 4. Phase 1 is the first phase of the clinical trial that is actually done in human beings. Then, we go to 1, 2, and 3. Phase 3 is usually randomized, so whenever we are referring to a randomized, controlled trial, it’s usually a phase 3 randomized trial. Phase 4 is postmarketing, postapproval, real-world collection of evidence. We’ll skip phase 0 and phase 4 for now. 
Phase 1 is first in human studies. To give you a brief idea — again, we’ll discuss this in detail in future videos — phase 1 is when we’re using the drug for the first time in human beings. 
What do we want to see when we are using a drug for the first time? First, we want to make sure that we are not harming people. That means we want to make sure that the drug is safe. A phase 1 clinical trial is fundamentally answering the question of whether this drug is safe and we can continue to use this drug. Phase 1 classically does not tell you whether the drug is a good drug or whether it is effective or not. 
Once we have proven that the drug is safe in phase 1, we take it to phase 2. In phase 2, we ask if this drug actually works — what that means for cancer is whether it shrinks the tumor, for example. In phase 2, we are not asking about the effectiveness of the drug in terms of what we already have. We are not comparing it with anything. 
Phase 1 and phase 2 are classically single-arm trials. We are just asking, does this drug work or not? Does it do the thing that it is intended to do? Does it shrink the tumor? Once we have proven that, yes, it does shrink the tumor, then we take it to phase 3. 
In phase 3, we ask the most important question: It shrinks the cancer, but is it better than what we already have? That’s where the randomized controlled trial comes into play. If you look at the journey of a cancer drug’s development, only 4% of the drugs that have started in phase 1 actually succeed in phase 3. The success percentage is pretty low. Out of 100 drugs that start in phase 1, only four of them become successful after the phase 3 trial. 
Most of the drugs fail in phase 1, then they fail in phase 2. I guess it’s understandable because phase 3 is a randomized trial, and we do a randomized trial when there is clinical equipoise, so almost 50% of the trials fail in phase 3. 
If we look at the cost of these clinical trials, the cost increases proportionally. Phase 1 trials cost the least amount of money, phase 2 costs even more, and phase 3 costs the highest amount of money. A drug failing at phase 3 is also a financial disaster in addition to being bad news for science and bad news for patients. 
If you look at the sample size, which is the number of patients that are enrolled into these trials, a phase 1 trial will have a very limited number of patients because we are testing a brand-new drug for the first time. We don’t know whether it is safe or not. 
After that limited sample size, in phase 2, when we are testing whether the drug works, we have a larger sample size. Then in phase 3, we have an even larger sample size. The sample size increases from phase 1 to phase 2 to phase 3. 
What I have just described is classical cancer drug development. In modern times, sometimes these things have become a little more complex to understand, and we’ll touch on those special cases after we have completed our discussion on phase 3 trials. To give you an idea, sometimes what is happening nowadays is there is a seamless trial design. That means phase 2 and phase 3 can be combined instead of doing two separate trials. The trial starts with phase 2 and if the response is good enough, then the same trial automatically moves on to phase 3. 
Sometimes there are phase 1 and phase 2 that are combined. Once you measure the safety, there is no reason not to measure the response in those patients as well. Instead of losing the efficacy data from the patients who have been enrolled in phase 1, they can also contribute to the phase 2 data. There are phase 1 to phase 2 seamless transition trials as well. 
Also, in terms of regulatory approval, classically, drugs are supposed to be approved after showing that they are better than what we already have, which is a phase 3 trial. Nowadays, as you all know, in oncology, we have seen several drugs approved on the basis of the phase 2 trial itself, which is a change from the classical paradigm. We’ll discuss this in the future. 
We also have some drugs that are approved on the basis of a phase 1 trial. These pivotal phase 1 trials that have led to approval defy some of the norms of a phase 1 trial that we just discussed. For example, they enroll a larger number of patients than what a classical phase 1 trial involves so that it is good enough for regulatory approval. 
This is just to give you a background on the different phases of clinical trials that we have. In future videos, I’ll focus mostly on phase 3 clinical trials. I’ll start by discussing how I go about reading a phase 3 clinical trial report. How do I start? Starting from the title and abstract, we’ll go all the way to conclusions, conflict of interest, and even the supplementary appendix. This is an important point to understand because important information can actually be hidden in the supplementary appendix, but will be important for us to make correct clinical inferences. 
Thank you.