Episode 88: The Skinny on Clinical Trials in PD

Dan Keller 0:08

Welcome to this episode of Substantial Matters: Life and Science of Parkinson's. I'm your host, Dan Keller. At the Parkinson's Foundation, we want all people with Parkinson's and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research—the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow.

When you take a medication, have you ever thought about what went into that pill? I'm not talking about the chemical powder, the binders that hold its shape, or the capsule, but what is behind the discovery or invention, the development, testing, approval, and manufacturing process. From discovering the biological mechanisms that a drug is supposed to alter, to finding the right chemical compound, to laboratory and animal testing, then to clinical trials in people takes several years. And the vast majority of drug candidates that enter this pipeline fail testing along the way and are never approved, costing millions of dollars in development but with no useful outcome.

For the ones that do succeed and gain US Food and Drug Administration approval, manufacturing plants have to be built or contracted for and adhere to strict standards for design, monitoring, and control for purity, cleanliness, and record keeping. All this is to say that it's not a cheap or quick process to bring out a new drug. For an explanation of what it takes to bring a drug to market, I spoke with Dr. Hubert Fernandez of the Cleveland Clinic in Ohio about the process of drug development and the value of people volunteering for clinical trials. People get involved in clinical trials, people also end up taking drugs that came from clinical trials, but do they really know what's behind them?

Dr. Hubert Fernandez 2:20

Well, actually, not so much. This is sort of a big black box to a lot of people. They don't realize that this is a long process. At least a drug would take 10 to 15 years before it's marketed in the pharmacies, and all that people know about would be how expensive the drug is, but the investment—not only monetary-wise, but time investment and the effort investment by a lot of people, not just the drug company makers—is not trivial.

Dan Keller 2:52

And not every chemical compound that enters an early trial ever makes it out the other end as a drug.

Dr. Hubert Fernandez 2:59

That is correct. In fact, we divide them into phases. So there is this preclinical phase. This is the phase where a compound is in the petri dish or is tested in animals, and once that shows that it is a reasonable compound to further develop, it goes to what we call the clinical phase. And the clinical phase is typically divided into three phases: phase one, two, and three.

Now, believe it or not, only one out of about 1,000 compounds tested in the preclinical phase would be good enough to go into phase one of the clinical trial. And on average, a drug company would spend about $400 million already testing 1,000 compounds for that one drug that can get into phase one. And the chances of that drug in phase one right now getting marketed is about 12%, so it's another 1-in-10 chance that for every 10 drugs we test in phase one, that will be available to patients. And that's the clinical phase.

In the clinical phase, we cannot test it to all Parkinson's patients, you know, from the beginning. So early on, you want to make sure that the drug is safe, and safe preferably first in non-Parkinson patients. So we test in phase one. We mostly test it to college students and patients without Parkinson's just to make sure that they tolerate the medication okay. And if that's okay, we test it in a small number of Parkinson's patients to make sure that it's safer. And if that's okay, it goes to a phase two trial.

A phase two trial is tested in a slightly larger number of Parkinson's patients, and the objective for that phase is to make sure that it's safe still, and have a hint of efficacy, that it actually works as well, but not a definitive answer, but just a hint. And if it is still found to be reasonably safe and probably with a hint of efficacy, then it goes to a phase three.

A phase three trial now is a trial that tests the compound or the drug or intervention in a larger number of Parkinson's patients, usually in the 200 or 300 patient number range, and that can take up to two or three years, usually would cost a drug company about $400 million to do. And this one, it should show that the drug continues to be safe and is clearly now efficacious. Just to make sure it is not a fluke, the FDA typically requires another study that has an identical or near-identical findings from the first study, so there has to be two separate clinical trials that show the same thing: that a drug is safe and a drug has some benefit in patients with Parkinson's disease. And then by then, it gets full New Drug Application to the FDA, and the authorities then decide whether this is good for general consumption or not.

By the end of it all, from the start to finish, it will be about 10 to 15 years and about $1.5 billion total of investment done. And so that's one reason—not the only reason, but one reason—why drug costs a bit more than its actual production by the time it's at that stage.

Dan Keller 6:50

And then there's sometimes, with some kinds of drugs, even a phase four—a post-marketing. It's made it on the market, but now you've got lots of patients taking it.

Dr. Hubert Fernandez 6:59

Yes, so phase four is an additional phase that is drug testing continuing after it is marketed and available to patients. Just because you have two pivotal or phase three trials that show the same thing doesn't really mean we know everything about the drug.

The one limitation we have in clinical trials is that we need to ensure that any good or any side effect of what we see, as much as possible, is because of the drug. The good that comes out of it, the bad that comes out of it, is because of the drug that you're testing, and therefore in clinical trials you tend to be very restrictive as to the type of patients that you enroll in a study. They can't be patients with other comorbidities—with previous cancer history, with a significant heart disease, or lung problem, or kidney problem, etc., etc. Because if something goes wrong to the patient, you want to really blame the drug and not the other comorbidities that are sitting within that patient, so it is a rather restrictive inclusion criteria in clinical trials.

So, once it's marketed, it is likely safe and it is likely efficacious, but we're not 100% sure that every single Parkinson's patient would benefit from it or not. And this is the role of the phase four trial: to continue to learn about the medication, see if there are subpopulations of Parkinson's that would benefit more or less than what was seen in clinical trials, to have continued vigilance on the medication. Just because we did not see any safety signals or red flags in clinical trials doesn't mean there will never ever be one. We always have stories of products out there in the market where you have a late-breaking side effect that occurs in some patients, which was never seen in the clinical trial. So we need that vigilance, and that's the role of phase four clinical trials.

Dan Keller 9:04

Plus, if people have other conditions and diseases, they're probably taking other medications, and you can get drug interactions, which in the phase two/three trials, you would have excluded those people from even entering the trial.

Dr. Hubert Fernandez 9:17

Yeah, absolutely, absolutely. So it is a logistical problem and an ethical problem, especially to investigators or clinical researchers like myself, because we realize that in the eyes of the patients, drug development is way too slow. They're suffering right now and they need relief right now. They can't wait 10, 15 years—I mean, they will, they have no choice—but it's really inconvenient for them. And in their eyes, justice delayed is justice denied. So this is quite a bit of an injustice to have such a slow process for something that could be really promising and could change their lives.

In our eyes, however, there are many mimickers of drugs. Drugs can look very promising, but they may not when you actually test them. We took an oath to do no harm first, above all else, and therefore we have to be sure. We want to make sure that before a drug is ingested by 1.5 million Americans that it actually would do something good for them and not cost them an arm and a leg with minimal benefits. So the fine balance of meeting unmet needs of patients and still ensuring quality and safety from the scientific rigor standpoint is always something that we need to walk a fine line every single day. And that's a challenge to us, and we are looking at different avenues to satisfy, hopefully, the best of both worlds.

So, there are certain pathways that are exempt from the normal process of the FDA. So we have orphan drug indications, we have fast track mechanisms. For example, if a drug that you're testing applies only to a small portion of Parkinson's patients, for example, then it is not so practical to do all the steps and phases that we normally would do in regular Parkinson's interventions, so they could be designated a fast track mechanism, and we can shortcut a few of these steps. It could be done quicker and it could be done cheaper, and therefore it becomes available to the general population in a sooner amount of time, but it's not for all drugs.

Dan Keller 11:47

What you've described is from the perspective of the drug developer, or even from the perspective of the chemical going through trials, but the trials require people. What can people expect when they enroll in a trial?

Dr. Hubert Fernandez 12:01

So that's a great question, and thanks for asking that. The biggest benefit in my eyes in participating in a clinical trial is that you can say that you have contributed in the advancement not only of our knowledge of Parkinson's disease, or whatever disease you're volunteering to, but in the therapeutic landscape of that disorder. So the only way we can advance treatment in Parkinson's disease is by testing medications.

I tell my patients, you know, the reason why I am able to offer you a dozen drugs to choose from right now for your Parkinson's disease is because not so long ago, 5, 10 years ago, one of your neighbors volunteered to be in a clinical trial. And the reason why, if a relative of yours developed Parkinson's disease in 5 or 10 years, I would be able to offer him or her two dozen options, it's because today you participated in a clinical trial. So your ability to contribute to therapeutic advancement, I think, is the greatest benefit in participating in clinical trials.

Of course, when you're in a clinical trial, we need to be really careful about what we do, and your safety is first and foremost. And so you have an indirect benefit of closer monitoring. We get to know you more, and you get to know yourself more through participating in a clinical trial, and therefore even after the clinical trial, we get to know you better and treat you better because we know how you react to things, and so that's kind of an indirect benefit from it.

I would say the biggest challenge we have in clinical trials is that investigators like myself and other doctors feel like we need to hype the benefit of participating in a clinical trial and the promise of the medication so that the patient would say yes and agree to participate in the clinical trial. That then sends sometimes a false sense of hope or unnecessary increase in expectations on the patient. They're vulnerable, they have a disorder, they want to get better, and so they sometimes cling on participating in a clinical trial more than they should. And what happens is we lose objectivity to the benefits and the side effects of the medication, and patients feel that they're better, even if they're not so much better, and doctors also feel like their patients are better because they want their patients to feel better, even if objectively they were just a little bit better, not a lot better.

And so to maintain objectivity from both the clinician and the patient is a challenge in clinical trials. And I think we need to keep reminding our patients, when you participate in a clinical trial, we are depending on you to tell us exactly how it is—good, bad, or ugly. You have to tell us how you're feeling, if you're having any side effects, if you're getting any benefit from it, and you just have to be as objective as possible, and we have to do the same thing. And that's the only way to get to the truth, which is why the process is so lengthy and the process is so repetitive and duplicative. It's because we have to find a way to overcome our personal biases when testing medications, so that's our biggest challenge in clinical trials.

Dan Keller 15:51

Thank you.

Dr. Hubert Fernandez 15:52

Oh, you're welcome. Thank you.

Dan Keller 16:02

For a good primer on the process and stages of drug development, and where clinical trials fit in, go to parkinson.org/clinicaltrials, where you'll also see a discussion of some things to consider about participating in a clinical trial or other form of study. There are also links to resources to find trials that may be recruiting volunteers. For more on the process of drug discovery and development, listen to podcast episodes 3, 4, 59, and 60.

Also, episode 6 discusses new levodopa delivery methods, which brings up another aspect of clinical trials. When a new formulation of a drug is invented, such as a skin patch or an extended-release tablet, they too have to undergo trials to make sure they behave as predicted. Similarly, devices such as for deep brain stimulation have to undergo rigorous testing, although under a different FDA set of standards. Even wooden tongue depressors are classified as medical devices, and if stem cell therapies come to pass, they too will have to meet strict criteria for safety and effectiveness.

One thing that can speed up bringing a drug to market is repurposing of older chemical compounds that may not have worked out for their original purpose, but that have already passed safety testing. An example of this is amantadine, which was initially developed as an antiviral medication to treat influenza in the 1960s and was later recognized as a potential treatment for PD, which was then confirmed in clinical trials.

You can learn more about how people with Parkinson's and care partners work as primary partners in research alongside scientists, industry, and government through our Parkinson's Advocates in Research program at parkinson.org/pair or by listening to episode 45, Patient Engagement in Research: The Parkinson's Advocates in Research Program.

As always, you can talk with our PD Information Specialists on our helpline, where they can answer questions and provide information in English or Spanish about today's topic, or anything else having to do with Parkinson's. You can reach them at 1-800-4PD-INFO. To receive news and updates about future events and resources, you can opt into our email list at the bottom of our website's homepage. If you have questions or want to leave feedback on this podcast or any other subject, you can do it at parkinson.org/feedback, or if you prefer, email us at podcast@parkinson.org.

If you enjoyed this podcast, be sure to subscribe and rate and review the series on Apple Podcasts, or wherever you get your podcasts. At the Parkinson's Foundation, our mission is to help every person diagnosed with Parkinson's live the best possible life today. To that end, we'll be bringing you a new episode in this podcast series every other week. Until then, for more information and resources, visit parkinson.org or call our toll-free helpline at 1-800-4PD-INFO, that's 1-800-473-4636. This episode is supported by a grant from Genentech, a member of the Roche Group. Thank you for listening.

Hubert H. Fernandez, MD, is Professor of Medicine (Neurology) at the Cleveland Clinic Lerner College of Medicine, Case Western Reserve University and the Head of Movement Disorders under the Center for Neurological Restoration at Cleveland Clinic in Cleveland, Ohio.

Dr Fernandez received both his BS in Biology and MD degree in the Philippines. He completed his internship in internal medicine at University of Pennsylvania/Pennsylvania Hospital in Philadelphia, Pennsylvania; his residency in neurology at Boston University Medical Center in Massachusetts; and his fellowship in movement disorders at Brown University in Rhode Island.

Dr. Fernandez is an internationally recognized expert in movement disorders who has been voted one of the Best Doctors in America by his peers. After completing his medical training, he joined the faculty of Brown University School of Medicine as Assistant Professor of the Department of Clinical Neurosciences and served as Associate Director of the Movement Disorders Unit and Neurological Director of its Functional Neurosurgical Program. In 2003, Dr Fernandez relocated to the University of Florida, where he eventually became Director of the Clinical Research Unit for Neurological and Psychiatric Disorders, Vice Chair of Academic Affairs, and Professor of Neurology prior to joining Cleveland Clinic. An active and productive researcher, he has initiated or participated in over 50 clinical trials and has published his findings in well over 300 articles and abstracts on Parkinson’s disease, cervical dystonia, blepharospasm, and other movement disorders. He has nearly 40 published book chapters and books to his credit, and has served on the editorial board of Movement Disorders and is currently an editorial board member of the American Journal of Clinical Neurology, European Neurological Journal, and Clinical Neuropharmacology.

Dr Fernandez is a fellow of the American Academy of Neurology, and a member of the American Neurological Association. He is currently elected as a Councilor for the AAN Movement Disorders Section, Executive Committee Member of the Parkinson Study Group and Dystonia Study Group; and is also an Executive Board Member of the World Neurology Foundation. He has served as President of the Florida Society of Neurology, and is the current Co-Medical Editor of the Movement Disorders Society Web site. Recently, he has been elected the Co-Chair of the Parkinson Study Group for a 6 year term.