When choosing a treatment option, it helps to know how it was developed. Today co-hosts Dr. Gillian Goddard and Erin Stein walk through the backbone of our healthcare: clinical trials. We walk through how a drug gets from an idea to the pharmacy shelf through preclinical lab and animal studies, pilot studies, and phases one through three, covering safety, dosing, and proof that the drug works. We explain why new drugs are usually tested on top of standard care instead of against nothing, how much it all costs, and how the patent clock adds pressure. We cover what happens after FDA approval, including phase four studies and registries like the ones that tracked women who became pregnant while taking GLP-1s. Before your doctor can prescribe a medication or procedure, it goes through this extensive process. Join us as we go behind the curtain.
If you are interested in participating in a clinical trial, visit clinicaltrials.gov or clinical.nih.gov for more information and to search trials.
We take a moment to remind you that while this is a medical discussion, it is not providing a diagnosis or treatment or any medical advice. The only way to get a diagnosis, treatment or medical advice for your particular condition is through a discussion with your doctor.
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Get your copy of The Hormone Loop by Dr. Gillian Goddard wherever books are sold.
This episode was produced and edited by Erin Stein. Music: “All We Live For (instrumental)” by Wolfclub licensed through Audiio.com. Intro and outro edited, and video created, by Ian Mayer. The Savvy Patient logo by Amanda Spielman.
TRANSCRIPT
Erin Stein: Hello everyone and welcome to The Savvy Patient.
Gillian Goddard: Hello.
Erin Stein: Today is yet another [one of] Gillian's favorite topic episodes. She is going to tell us all about clinical trials. Why? Because she loves them.
Gillian Goddard: I do. I do love them.
Erin Stein: Ha ha.
Gillian Goddard: Before I decided I wanted to go to med school, I worked in pharmaceutical public relations, and I got my first real exposure to clinical trials and how they get designed and how they get reported. I think everyone should understand them because they get reported on in the media all the time. And most people don't really understand the investigation process. It's much more structured than most people realize. And it takes a lot longer.
Erin Stein: And yet ideally it has happened before we go around telling people they should take or do things.
Gillian Goddard: Well, it's required for FDA approval. So, the structured process is the structure that the FDA expects to see when you submit a new medication. So, if you want your drug to be approved by the FDA or by the equivalent bodies in other countries, you need to follow the rules.
Erin Stein: The point is there are some rules and that is generally a good thing.
Gillian Goddard: Yes. Yes. The point is there are rules.
Erin Stein: We didn't always have rules, and some nasty things were done to people when there weren't any rules. But I thought it was interesting to look at, what is the history of clinical trials? Because there have been inquiring minds throughout history.
Gillian Goddard: Humans have always been curious and liked to do scientific experiments, sometimes on themselves or other humans.
Erin Stein: Yes. And so, we have records of curious minds studying things, testing diets and drugs in the 500s, 1000s and then 1747, if you're a fan of pirates, a Scottish surgeon was, you know, checking out some sailors and scurvy proved that feeding them some citrus was good.
Gillian Goddard: Yeah, it was the British Navy. That's why they're called limeys.
Erin Stein: And then into the 1800s, we get into some placebo-controlled trials. And then there's a little thing called World War Two.
Gillian Goddard: You know, it's interesting when you think about modern medicine. World War Two really was this watershed event and it's sort of like everything before that is like pre-modern medicine and everything after that is modern medicine basically.
Erin Stein: And not that I'm a historian or going to go into great detail, but I think it's safe to say that the Nazi doctors were doing some horrible things to human beings.
Gillian Goddard: They were.
Erin Stein: And as a result, generally speaking, humanity thought maybe we shouldn't do horrible things like that, and maybe we should have some rules about how we investigate medical questions and medications and treatments.
Gillian Goddard: Yes.
Erin Stein: And so, part of why it's such a turning point is there was this collective movement to establish these standards. To have some ethics around testing.
Gillian Goddard: Exactly. Yes, because if you want to publish your trial in a peer-reviewed journal, so in a medical journal, it has to go through an ethics review before you start enrolling participants and collecting data. Submitting for IRB approval. The IRB is the institutional review board. Required 100% of the time. And it is basically a process through which you explain how you are going to conduct the trial ethically and fairly, and how you are going to inform the participants the checks that you have put in place to make sure that the trial is done as safely and ethically as possible.
Erin Stein: Yes, I also don't mean to erase the fact that governments continued to do some shitty stuff to people, including the US government. So it's not like everything was all fixed after World War Two, but that was a big change and the rules started to be put into place and all of that history is interesting, but walk us through… what do we have now, what do we do now in the more recent times of clinical trials. “I've got a drug; I want to see if it works.” What happens?
Gillian Goddard: Yep. You first have to do preclinical studies. So preclinical studies are lab studies. It is required that you study your medication in animals before you study it in humans. Rats are the most common animal model used, and the people who conduct a lot of these preclinical trials are typically PhDs and medical doctors in academic settings. And just like with human trials, there are really strict requirements around ethical research in animals and how you are supposed to treat the animals used in medical research. But animal research is not a piece of this process that you can or should skip. It is really critical to the drug development process. So, you start with your preclinical trials that might start even before you get to animals. It might start just in cells, in cell culture, which is like cells growing in Petri dishes. And then you work your way up to animal studies.
Erin Stein: Is there a future where we don't have to test on animals? Is there an AI model that could be used or some sort of fancy Iron Man level computer version to avoid testing on the poor rats?
Gillian Goddard: I never say never, but I don't think we're going to be moving away from preclinical animal testing anytime soon. Because animals create a setting where we can see and often do see some unexpected results. And I think you would have a really difficult time from a liability point of view allowing people to test something in humans that had not first been tested in animal models. And again, rats are particularly useful because they are similar enough to people that in many, many cases it's a good model.
Erin Stein: Which is such a weird thing to say, but we're not as different from animals as you would like to think.
Gillian Goddard: No, we share a great deal of DNA with other mammals.
Erin Stein: I also think computer models are fine, but as we say in some way in every episode, every human body is unique and how things function or react within such a complex system you cannot fully predict in a computer model and so we have to eventually test it in humans. You got to start somewhere first to make sure we're not killing people.
Gillian Goddard: We've had some real catastrophic moments in clinical trials, even since World War II. So, yes, the preclinical stage is really, really important. And in fact, preclinical studies can take, five, six years on average before we even start thinking about clinical trials in a new drug.
Erin Stein: So, you've done some Petri dish, you've done some rat testing. Then what?
Gillian Goddard: So, then you enter the clinical trials. Typically, this will start with what's called a pilot study, which is just a proof of concept. You give the medication to just a handful of individuals and see what happens. Pilot studies are by definition not randomized. It's just you enroll some people and you give them the medication.
Erin Stein: How do you find these people?
Gillian Goddard: You recruit them, typically through hospitals and doctors' offices. The advantage of a pilot study is that you know you're getting the medication. The disadvantage is that, you know, this is really early drug development.
Erin Stein: Like five people could be in a pilot.
Gillian Goddard: Yeah, less than twenty typically.
Erin Stein: Less than twenty. And how long does a pilot study usually last? Like a year? Six months?
Gillian Goddard: Yeah, it depends on what you're studying, and how long it takes to see an effect, but typically one of the things you're trying to figure out in a pilot study is how long you need a clinical trial to be.
Erin Stein: Mm, mm-hmm.
Gillian Goddard: You want to prove the concept, but you also want to figure out things like what variables you want to collect, you want to figure out what tests you might do. A lot of the times you're going to do this in conjunction with the FDA. So, the FDA has different panels for different areas of medicine. And if you are doing a study on a new blood pressure medicine, they have a whole list of criteria that they're going to want you to look at as a part of your clinical trial in order to get that blood pressure medicine approved. You actually work with those criteria to design your trials. And so, the pilot is a way of sorting through some of those details, including length of the study. How long do you need it to be to show an effect?
Erin Stein: Right, okay. That makes sense.
Gillian Goddard: And then you enter the phased clinical trials. There are four phases, but there's really three pre-market phases. So, phase one is basically safety. These are all placebo-controlled trials. And phase one is to show safety and start to understand dosing. And the people in phase one are healthy. And you're assessing safety, how they tolerate it. You're studying some things about the pharmacokinetics.
Erin Stein: Pharmacokinetics? What the hell is that?
Gillian Goddard: The chemistry of what happens to the drug after you take it. How does it get absorbed? How does it get metabolized? Do you create some sort of weird unwanted metabolite? And does that have some effect? You've also looked at this in rats, but now you need to look at it in humans because we may respond differently to some of these things.
Erin Stein: You just said the clinical trial participants in a phase one are healthy.
Gillian Goddard: You're not looking for efficacy here.
Erin Stein: You're not testing people who have problems. You're testing healthy people and seeing just what it does in a human body.
Gillian Goddard: Making sure that what it does is safe.
Erin Stein: Right.
Gillian Goddard: And so, these are also pretty small, less than a hundred people, typically.
Erin Stein: Okay, so they make sure it's safe. They get a better idea of what it's doing. And that gives you a better idea of how much to give a person.
Gillian Goddard: Yes.
Erin Stein: That's something we don't always think about as part of this process, is figuring out how much medication people should be given.
Gillian Goddard: Yes. And that is the key to phase two. So, phase two trials look at dosing and efficacy. At this point, we're typically recruiting a few hundred people, and they have the target disease or condition. So now if we're testing a blood pressure medicine, we're recruiting a couple hundred, three hundred people who have high blood pressure. We're looking to see how do we dose the medicine? Typically, they'll have people randomly assigned to different dosing regimens. We're always looking for safety. But really here we're saying, okay, do you need 10 milligrams, 20 milligrams, 30 milligrams, and at what point do you only get more side effects and not more efficacy?
Erin Stein: We've talked about this before and I think it's important this idea that you can't just keep taking more of something. At some point it's causing such severe reactions it outweighs the good thing that it was doing at a lower dose.
Gillian Goddard: Benefit or you've hit the ceiling on the benefit. If I take 30 milligrams of the medicine, my blood pressure goes down the same amount as if I take 40 milligrams of the medicine. So, it doesn't make sense to take 40 milligrams of the medicine because 40 milligrams could cause more side effects and I'm not getting more blood pressure lowering for that extra 10 milligrams of medicine. So, phase two trials are looking at all of that.
Erin Stein: There is a placebo control?
Gillian Goddard: Typically, there is a placebo control and then in most of these trials there's a whole range of doses that are tested.
Erin Stein: And at this point do they have numbers they're trying to target or are they just observing people and taking measurements?
Gillian Goddard: This is still a really exploratory study, so they're not necessarily looking for specific targets, although they're often thrilled if they see that they're hitting targets that they're hoping to hit. And then we get to the phase three trial. And this is often the trials that people hear about. So, phase three trials are large. They have, depending on what you're studying, anywhere from hundreds to thousands of participants. They have participants that meet very specific criteria around the disease that the medication is for. And the goal here is to confirm efficacy and show that the drug is as effective or more effective than other medication options often. This is where you're really looking to hit specific targets oftentimes around blood pressure, blood sugar, heart rate, cholesterol levels. In many cases, you're looking to show a reduction in the number of people who have severe adverse events. So, if you're studying a blood pressure medicine, you want to not only show that it lowers blood pressure, you want to show that that blood pressure reduction results in fewer heart attacks, fewer strokes, fewer people dying in many cases.
Erin Stein: I guess it depends on what it is that you're testing because it seems like if it was a brand-new thing that we don't currently have a medication for, it would make sense to test it against a placebo. But if it's a new medication for something we do have older medications for this case might be against another medication.
Gillian Goddard: Not necessarily. So typically, the way this works is you are randomized to get the medication or a placebo. And usually what we say if it's something that we already have a treatment for, is that it's added to standard of care. Meaning, when statins were developed, there was all these things that people did in other areas that might lower cholesterol, other medications that people took for high blood pressure. The key was that you had to add the statin to usual care or standard of care. And this is really important. This is also true in cancer studies. Typically, you are adding a drug to what is considered the standard of care to show that the medicine is better than the current standard of care. So, everyone's getting standard of care and some people in the trial are getting standard of care plus placebo and some people in the trial are getting standard of care plus study drugs. And that's important it's a little bit more of a real-world situation, right? We're not going to stop all of somebody's heart medicines and put them on a statin. We're going to keep them on their other heart medicines and add the statin. So that's part of it. But the other is that it's important from an ethical point of view, because you aren't asking someone in the study to forego the things that we already know work in order to be a study participant.
Erin Stein: Right.
Gillian Goddard: And so, in many cases the patients are on other medications even for the disease at hand. And that again that is kind of how we use medicine in real life, too, but it also means it's harder to show an effect because those older medicines are already having an effect, right? We've already proven that those medicines are effective. We have to then show that the new medicine adds to that effect. And that means it can take more people and longer studies to see results.
Erin Stein: Yeah, and I think that's important because your first thought is, let's test it against nothing or let's test it against another drug. My brain went straight there, but for a medical condition that is serious, you can't tell people don't do anything else while we're testing this drug on you. That would not be ethical.
Gillian Goddard: Right. Right. Right.
Erin Stein: So, they are still getting what they would be getting anyway. They're still being treated for whatever this condition is, and we're just adding this new one to see if it helps. Okay.
Gillian Goddard: Yeah. And typically, with phase three trials, they're what are called multi center trials. So, they're enrolling in different centers all around the country or even all around the world, depending on the pharmaceutical company. Typically at academic medical centers. And it can take a long time to get them fully enrolled depending on what you're studying. Because sometimes you're looking for thousands of people. And so, this process can be pretty long and complicated. But this phase three trial is really the data that's getting submitted to the regulatory agencies like the FDA to say, we think that you should approve this drug for this indication. And this is where a lot of the details around those indications come from, is because the indications are often based on the specifics of the people who were the participants in the study. So, meaning they specifically enrolled people with blood pressures above 140 over 80 who had these other cardiovascular risk factors. And so, then when the FDA is approving the medicine, they're approving it to lower blood pressure in people who have blood pressures of one forty over eighty, you know what I'm saying? The indication is based on the study population.
Erin Stein: It can take a while, but what does that mean? Like it can take a year, it can take five years?
Gillian Goddard: It can take up to ten years for phases one through three.
Erin Stein: Okay. Another question you may or may not be able to answer.
Gillian Goddard: Do my best.
Erin Stein: How much does it cost?
Gillian Goddard: My goodness, millions of dollars. Drug development's incredibly expensive. You got to pay all the staff. Basically, the way it works is the pharmaceutical company is studying the drug and they have a budget for it and they pay the medical centers to be centers in the study, because then the medical centers have to use that money to pay the employees of the medical center who are actually doing the work of collecting the data, some of which are physicians and some of which are not. You have all kinds of other medical professionals, research technicians, who need to be paid for their time and effort.
Erin Stein: Yeah.
Gillian Goddard: And there's other things that go into this too. So, before I went to med school, I worked in a cardiopulmonary exercise lab. And we were the core lab for a clinical trial for—it wasn't a pacemaker, but it was kind of like a pacemaker. So, we were collecting all of the data from the exercise portion of the trials from all of the other participating hospitals. And one of the things that was my job was actually to travel to all these other participating centers to make sure that they were doing the exercise testing properly to make sure that we were getting good results. I was literally traveling every week, all over the country and all of those costs were part of the development costs as well.
Erin Stein: Right, to ensure the quality of the data. We're talking about medications, so usually that's a drug company funding that because they will then make money later from the drug. But there are also many research studies and clinical trials run from the academic side of things, and that is all grants and government funding.
Gillian Goddard: And sometimes also funding from pharmaceutical companies, [who] often will support those kinds of studies too. So, you as an academic physician working at a university can develop a study and go to the company that makes the drug you want to study and ask them for support. And typically they will do that. Usually, it's such a drop in the bucket in their budget that they're happy to do it, even if they just provide free medication for the study.
Erin Stein: Mm-hmm. Mm-hmm. And what happens if phase one or phase two don't go well?
Gillian Goddard: Mm. A number of different things can happen in that scenario. They can just decide to cut their losses. The pharmaceutical company can decide that okay, you know, drug XYZ was a good idea, but it's not panning out. And so, we're going to stop investing in it and put our attention elsewhere. So that happens a lot, a lot, a lot, a lot. A small percentage of the drugs that start down the process actually finish it. Drugs get repurposed. They're like, well, it didn't do what we thought it was going to do for blood pressure, but it turns out it was really good for mood. Or my favorite, it didn't work as well as we thought it would for blood pressure, but everybody reported that they were suddenly growing a lot more hair and they weren't losing hair anymore.
Erin Stein: Yeah.
Gillian Goddard: And so, they will repurpose drugs based on some of the things that they see as side effects or unintended consequences of the medication.
Erin Stein: I know we just did a whole episode about side effects, and we didn't talk about how sometimes those things are good.
Gillian Goddard: Yes, exactly. That's exactly right. Sometimes they're good. And sometimes they'll decide they don't want to invest in it anymore, but somebody else does want to invest in it. A smaller pharmaceutical company will start developing a drug. They'll decide they really don't have the money to continue to pursue it. And a bigger company will see that there's some potential there and come and buy the molecule or subsidize further development with the small company. That happens a lot. And so, all kinds of different things can happen, but the most common one is that they just pull the plug. And it's part of the reason drug development is so expensive is because you can have invested a lot of money and a lot of time on a drug, and then it cannot meet expectations. The whole drug development process from the day you get your patent to the day that you actually are able to sell the drug takes anywhere from 10 to 15 years. And the way patents work in the United States is you get the patent, and the patent ends 20 years after the day you get the patent. So, the clock is ticking, right? You get your patent. You have 20 years, you've got to do all of these clinical trials, get the drug to come to market, and make your investment.
Erin Stein: You're getting your patent at the beginning of the process.
Gillian Goddard: You get your patent before or during the preclinical process. The patent is on the molecule. So, you develop this molecule, you get the patent, and then you start studying it. So, you may only have five years at the end to make back your investment.
Erin Stein: Do people ever adjust their patent after they've tested it and changed it or not necessarily?
Gillian Goddard: Mm. There are certain things that can extend the amount of time that you have the patent. The biggest is additional indications. So, the patent will expire for one indication but will go on a couple years longer for the other indication, for example.
Erin Stein: But it's not—fun fact, Thomas Edison used to file for patents for things he hadn't actually invented yet.
Gillian Goddard: You do have to have a molecule. You have to submit a molecule.
Erin Stein: He'd be like, I'm going to make a thing and it's going to do this, and it would be very vaguely described. [laughs]
Gillian Goddard: Yeah. No, you are patenting a molecule like with a chemical structure.
Erin Stein: Okay.
Gillian Goddard: So yeah, that is part of the submission. So, the clock is ticking and if it takes ten to fifteen years to develop the drug, then there's definitely pressure to keep these steps moving along as quickly as is safely possible. And then you get your drug approved and you bring it to market, and then you have phase four clinical trials.
Erin Stein: So, you do phase three, it goes well, how long does it take to get that FDA approval?
Gillian Goddard: It takes anywhere from six months to a year from when you submit your application to the FDA. There are a couple things that the FDA has to do. They actually have subcommittees and so they assign your trial to a subcommittee based on the subject matter and the subcommittees are in theory, experts in that specific area. So, the subcommittee meets and reviews the data and issues a recommendation. And then typically the FDA follows the guidance of the subcommittee. Most of the time if the subcommittee says, yep, we should approve this drug, the full FDA panel will approve it. And if the subcommittee says, we need more data on XYZ, then that is what the full panel will recommend. It is unusual to get to the end of a successful phase three trial and have the FDA say no.
Erin Stein: I was going to ask, do they ever say no, we don't approve this.
Gillian Goddard: No, usually they'll send you back to collect some additional data or they will work with the pharmaceutical company to put language into the prescribing information that we were talking about when we were talking about side effects, to certain types of testing or cautions or some other type of language into the prescribing information that adds a little bit of caution. For example, a couple of years ago the FDA approved a non-hormonal medication for hot flushes and night sweats, Veozah. And when they approved that medicine, one of the things that they required was that when women first start taking the medicine, they have their liver enzymes tested on a couple of different occasions. And that was related to some data that was in the submission suggesting that some women did have elevations in their liver enzymes while they were taking the medicine. So, it wasn't enough women that they were like, no, this isn't safe. But it was enough that they were like, we should keep an eye on this when women first start taking this medication. And so, a lot of times there'll be caveats in the prescribing information like that, or limitations as far as the population that they will approve it for. But usually by the time you get to the end of a successful phase three trial, you've already been in conversation with the FDA, and you know what they're looking for, and you wouldn't submit if you didn't have the information that they wanted.
Erin Stein: And I guess if you had a phase three trial that wasn't successful, that would suck.
Gillian Goddard: Yes, because at that point you've already invested a ton of money. It doesn't happen very often just because usually those drugs that aren't going to be as successful as you would like, you kind of weed them out in phase one and two. And really by the end of phase two you typically have a pretty good idea of how phase three is going to go and what information you need to collect in that trial and what kinds of things you need to be looking out for. But an example of a medicine that made it all the way to phase three and then the results were still sort of underwhelming, and it did get approval a but with a big caveat, was the medication Addyi. Addyi is a medication for female hypoactive sexual desire disorder. So basically, if women are struggling with libido and arousal—and it's one of those medicines, and there's a few medicines like this—it either helps people or it doesn't. And when it helps, it can be very helpful. And when it doesn't, it just does nothing. But the big issue with Addyi is that at least initially, the FDA insert said that you could not drink at all at any time while you were taking the medication.
Erin Stein: Drink alcohol.
Gillian Goddard: Alcohol.
Erin Stein: You should drink water or other fluids. [laughs]
Gillian Goddard: Always everyone can drink water. Yes, you could not drink alcohol at any time while you were taking the medication. And there were jokes at the time that were like, well, alcohol is as likely help you with your hypoactive sexual desire disorder as Addyi is. I think that some of the postmarketing data suggests that maybe it's a little more effective than alcohol without some of the potential downsides. So, I am not suggesting that alcohol is the right treatment for hypoactive sexual desire disorder. After some postmarketing data collection, they submitted to have the label changed. And so now you're just not supposed to drink within I think it's four hours of actually taking the medication. Which means you could potentially take it in the morning and have a glass of wine with dinner in the evening.
Erin Stein: So, there is a phase four. You get FDA approval, the drug is on the market and people can take it, but…
Gillian Goddard: You still collect data. And these are programs that are set up to monitor how the medication works in real life, and kind of what other benefits there might be from taking the medication. So, like in GLP-1s, they've done all these studies looking at how taking a GLP-1 affects your cardiovascular risk, affects your risk of having liver disease. And those are all postmarketing studies or phase four studies.
Gillian Goddard: There are two things that people don't realize about drugs when they come to market. One is we don't stop collecting data on them just because they're on the market. We continue to collect safety data. We continue to collect data on side effects because if you think about it, take cholesterol medicine, for example. Cholesterol medicines might have been tested in, you know, 5,000 people before the FDA approved it. But now we have millions of people who potentially could benefit from cholesterol medicine. And so even though a trial with 5,000 people is actually quite a large clinical trial, the whole population who can benefit from a medicine is many, many, many, many more people. And so, we will sometimes see new side effects or new benefits that we didn't know existed from those initial phase three trials. And so, we keep collecting information and we keep learning about a medication.
Erin Stein: How is that information collected? That sounds great, but how are we actually collecting how it's going, if there's new side effects, all that stuff?
Gillian Goddard: There is a couple different ways that we do that. So, the first is actually we do continue to run studies in postmarketing, some of the people from the original trials they'll continue to follow. So, they might do a postmarketing extension on their phase three trial, which would be a phase four trial. They might enroll different subsets of people in a new clinical trial that's a phase four trial where they're specifically looking at other potential benefits of the medication. They've done this a lot with GLP-1s where they are looking at like the cardiovascular benefits, the liver benefits, the brain benefits, and that stems from those initial findings that they had in their phase three trials. Then there are situations that you report typically to the manufacturer; there's also registry data. For example, with GLP-1s, they were running a registry trying to collect all the information they could about women who became pregnant while taking a GLP-1. Because you can't do a clinical trial on GLP-1s in pregnancy for ethical reasons.
Erin Stein: Shouldn't be messing around with pregnancies.
Gillian Goddard: Right. But lots of women have become pregnant, perhaps unexpectedly, while taking GLP-1s. And so, we've been able to collect a lot of data showing that if you stop the GLP-1 when you find out you're pregnant, that's probably safe and you don't need to be concerned about the fact that you were taking it for some period of time while you were pregnant and didn't know.
Erin Stein: There's a difference between asking people to volunteer for something like that and collecting data from people that it's happening to naturally.
Gillian Goddard: Exactly. But that data can be super useful because we're not going to randomize you to become pregnant or not become pregnant anyway.
Erin Stein: How is the registry run? I mean, is that basically through your doctor?
Gillian Goddard: Yeah, the pharmaceutical companies will reach out to doctors and basically if I had a patient who got pregnant while taking it, I would reach out to the pharmaceutical company, and they would reach out to the patient to enroll them in a registry study. And a registry study just means they agree to be followed and see what happens. They have informed consent and all those kinds of things for a registry study the way they do for any study, but there's no intervention, right?
Erin Stein: Right.
Gillian Goddard: They were on the medicine when they found out they got pregnant; they stopped the medicine because that is still what we recommend people do. We don't recommend people take a weight loss medicine during pregnancy, at least at this point in the game. But then they give permission to have their doctor report outcomes.
Erin Stein: The GLP-1 example is there's potentially other uses for the same medication, so they're going to keep studying it for those things, and maybe there's other medications where they studied it in younger people, now they're going to study it in older people, things like that.
Gillian Goddard: Mm-hmm. Yep. Kids. Kids always are postmarketing.
Erin Stein: Right, right, that makes sense actually.
Gillian Goddard: They make sure it's safe in adults first and then they start thinking about kids.
Erin Stein: But if there's not an obvious continuation like one of those examples, how long postmarketing, post FDA approval do they keep collecting and reporting?
Gillian Goddard: Usually until the end of the patent.
Erin Stein: Okay, that also makes sense.
Gillian Goddard: Or if the FDA gave them a specific period of time based on some sort of science, sometimes they will say they want X number of years of postmarketing data.
Erin Stein: Has there ever been any huge surprises in that phase four period?
Gillian Goddard: Most of the surprises are positive, in recent history. But historically, thalidomide, I think, would fall into that category. So, thalidomide was a medication that was most heavily prescribed actually in the UK, in the post war period. It became pretty clear pretty quickly that thalidomide caused birth defects where people's limbs didn't develop in utero. Very, very devastating birth defects. And so obviously that drug was taken off the market once they discovered that, but not before there were, many people who were really affected by it. It's interesting because now in recent years thalidomide has been used again. It's actually considered to be an effective treatment for multiple myeloma. But most people with multiple myeloma are not getting pregnant because usually it affects people later in life. We have changed our thinking as a result of those studies around testing. And remember, for a long time we didn't include women in studies. And so, a lot of medications weren't well studied in women during clinical trials. That changed in the nineties. 1993 is when you had to start enrolling women in your clinical trials, if you wanted federal funding, and let's be clear, we're talking about thousands and thousands of drugs that have come on the market and since World War Two. And that's just one example. Obviously devastating. I don't want to understate how bad it was, but the fact that it's as rare as it is, highlights the fact that the system that we have, for the most part works pretty well. Other than the fact that it's expensive and takes a long time. I think most people would complain that it's too arduous and I think that that serves a purpose. But the other thing that I hear all the time, and I think that the system is set up to specifically avoid this, is people saying, well it's new. It's new. I want to wait and see what happens.
Erin Stein: Hm.
Gillian Goddard: By the time a drug hits the market, it's not new. It's typically been in research basically nonstop for ten to fifteen years and we keep following these people, ultimately by the time a drug has come to market, it has passed through several checks. We don't necessarily have data on what happens if you take it for 70 years when it comes to market.
Erin Stein: Right.
Gillian Goddard: But we do have a track record that it's safe and effective and that in many cases, maybe not for everyone, but in enough people the benefits outweigh the risks.
Erin Stein: Nothing has zero risk.
Gillian Goddard: Nothing has zero risk, including, by the way, doing nothing.
Erin Stein: Doing nothing. We should put it on a T-shirt.
Gillian Goddard: No, but think about it. Yes, your blood pressure medicine has risks, often of making people lightheaded because it lowers their blood pressure. But not treating your high blood pressure also has a risk.
Erin Stein: Yeah. A big one.
Gillian Goddard: Several, in fact: strokes, heart attacks, [and] aneurysms. And so really what we're looking at is, do the potential benefits outweigh the potential risks for enough people? And are the risks reasonable given the benefits. So, this is another place where I think there's some nuance in how the FDA and other regulatory agencies are thinking about these medicines because the risks of a blood pressure medicine versus the risks of like a chemotherapeutic agent…
Erin Stein: Mm-hmm.
Gillian Goddard: You're going to tolerate a lot more risk in a chemo drug than you are in a blood pressure drug, because the risk of the disease itself warrants that, right? You're going to tolerate a lot more risk if you're talking about, something that could potentially meaningfully extend the length of someone's life.
Erin Stein: Yes, that is another conversation for a lot of cancer patients if the treatment is going to be somewhat difficult to tolerate, if not extremely difficult to tolerate, depending on your diagnosis and where you're at. You're making a choice. You're weighing risks and benefits.
Gillian Goddard: Well yeah, absolutely. And I think that's really important to remember. It's more obvious when we're talking about treating cancer. But every time we make the decision to accept a treatment, we are talking about weighing risks versus benefits. A lot of times people don't think about their medication decisions like that. It's not, my birth control pill is going to cause a blood clot. It's, my birth control pill is going to keep me from having an unwanted pregnancy. And you know what causes more blood clots than birth control pills is pregnancy. So, you have to do an accurate assessment of the risks and benefits for you as an individual.
Erin Stein: Full assessment. Correct. Okay, so we focused on a medication going through the clinical trial process and getting approved. There's obviously tons of clinical trials for all kinds of things. Not just medications.
Gillian Goddard: They do clinical trials for devices.
Erin Stein: Mm-hmm.
Gillian Goddard: Those clinical trials are tricky because you want to have blinding. So blinding is you don't know, right, whether you're getting the treatment or the placebo. And it gets much more complicated when it comes to procedures. With certain types of devices, they don't tell the patient. If you're talking about like a pacemaker trial, they'll put a pacemaker in everybody and they'll have some people who have theirs turned off and some people who have theirs turned on, and then they'll collect a bunch of data and then they'll swap them. So, they'll have the groups switch spots. They do in some cases where it's ethical, they may do sham procedures; the person having the procedure done wouldn't know that it wasn't a real procedure. So, this gets used in like laser procedures, for example. Some of the studies that look at using laser for vaginal atrophy, half the people will have the real procedure and half of the people will have a sham procedure.
Erin Stein: Just like a red light and heat.
Gillian Goddard: Yes. But my favorite is when people become unblinded. So, this is fascinating. First of all, you either find out about a clinical trial because your doctor recommends it, or you find out about it because you're seeking it out. This happens a lot in studies for things like treatments for Type 1 diabetes because there's an ethos in the Type 1 diabetes community about participating in research that will benefit other people with Type 1 diabetes, even if it doesn't benefit you. And so those types of people tend to be really interested in seeing if they can tell whether they got the placebo or the study drug. I have friend who is enrolled in a long COVID study. And she was like, am I feeling better? I'm definitely feeling better. Is it the placebo effect or did I get the study drug? But my favorite unintentional unblinding, because they do eventually tell all the participants whether they got the placebo or the study drug when they unblind the trial, is in some of the studies of testosterone in women for hypoactive sexual desire disorder, the women who got the testosterone would become unblinded because they would grow hair. In the spot where they were applying the testosterone.
Erin Stein: That would be an indication.
Gillian Goddard: Yeah, so you have to think about your blinding and how you set that up because as we've discussed before, the placebo effect is real.
Erin Stein: It's real.
Gillian Goddard: If you are interested in participating in a clinical trial, all trials in the United States where anyone wants any hope of publishing that trial in a peer-reviewed journal are listed on a website called clinicaltrials.gov and you can go there and there you have keyword searches and all kinds of things and you can see if there are trials enrolling in your area that might be a trial you would want to participate in. And that can be anything from pilot studies observational studies, all the way up through phase three clinical trial.
Erin Stein: You are the guinea pig. We say guinea pigs. Did we test on guinea pigs?
Gillian Goddard: We must have, but not these days. The most common models are rat models and mice to some degree,
Erin Stein: Historically guinea pigs were used in scientific research and medical testing because their heart, electrophysiology, and immune systems compare well to humans.
Gillian Goddard: Mm. Mm-hmm.
Erin Stein: So, there is a reason why we say you're a guinea pig. Although it doesn't sound like we really use them so much anymore.
Gillian Goddard: No, not really.
Erin Stein: You know, they eat guinea pigs in Peru, so…
Gillian Goddard: Fascinating fact. [laughs]
Erin Stein: It's true. Thanks for listening.
Gillian Goddard: Hehehe. One of these days we'll figure out how to end this thing.
Erin Stein: I know, one of these days. Not today though.
Gillian Goddard: Not today.