Women Not Included: Drugs and clinical trials

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0:30School ready at Whole Foods Market. Ah, bike's sputtering on me. That's not what you want on a cross-country trip. Yeah, you're telling me. Looks like my journey ends here. No, mate. You ride with Geico Motorcycle Insurance and got their 24-7 emergency roadside service. They'll fix your bike right up. Where you headed, anyways? Oh, I'm going to Chromehenge. You ever been? No, I can't say I have. It's like Stonehenge, but shiny. It feels good to ride with help. It feels good to Geico. Emergency roadside service is optional coverage. When I was doing my PhD, I was researching a treatment for type 1 diabetes where I would take pancreatic cells from mice.

1:12And it always bothered me for that four-year process. I exclusively worked with male mice. Human men are more likely to have type 1 diabetes, but it does affect plenty of women. so I went and talked to more senior researchers about this and they did seem to agree with me it was odd but this was just the standard at the time diabetes is caused by an imbalance in hormones so it had largely been agreed up to this point that factoring in the kind of complicated hormone cycle of female mice would make the results too messy it would confuse things and at the time I accepted it. But now, years later, I think surely the complicated hormone cycles of women are exactly why we should be using female mice, so we can better understand how this research will be translated to human women.

2:10But that's just not how things were done. I'm Ella Hubber, and this is Women Not Included for Discovery on the BBC World Service.

2:23In this six-part series, we will be exploring the many ways the world has not been designed with women in mind. Today, we're talking about drugs, be that oral medicines, vaccines or topical treatments, and how they are made or not made with women in mind. And looking into this with me is science journalist Chavi Sachdev in Mumbai, India. Hello, Chavi. Hi, Ella. Is there anything that jumps to your mind when it comes to drugs not working for women? Well, yes, I immediately thought about migraines. Have you ever had a migraine, Ella? Sometimes I think I might have had a migraine, but I'm told that you will know when you've had a migraine.

3:02Oh, yes. So I have, and it's not a severe headache. It is a chronic neurological disease. But what gets me is how they're treated. By and large, between 1918, when a vasoconstrictor that had actually been used to narrow blood vessels and stop excess bleeding after childbirth was repurposed and prescribed for migraines, all the way from then to 1992, every single medicine migraineurs like me have ever used was developed for something else. Epilepsy, depression, heart attacks. People even get Botox injections for migraines. And all of these medicines have side effects like dizziness, brain fog, nausea, weight gain and depression.

3:48I've read that migraines are the third most common health condition in the world. They are. So you'd think given the extent of this problem, there would be a lot of work going into migraine-specific treatment. Well, at the heart of the approach of throwing stuff at a wall and seeing if it sticks is that migraines are predominantly a women's problem. You know, globally, women are more than three times likely to get migraines than men. And until the 90s, nobody was funding any drug development or drug trials. Yeah, I mean, I can't say I'm surprised here that a predominantly women's issue has been underfunded.

4:20But you also mentioned all these side effects that come with medications that are not really designed for migraines, medications that women are primarily taking. And I have to wonder if, like using only male mice to do the early testing of medical treatments, this is actually a staggering oversight by the pharmaceutical industry, by research. Yeah. I mean, women can't really trust the labels on their medication. Chavi, I think we need to go away and do a bit more research on this. I think we do. I'm also going to find some experts to talk to and I will meet you back here. So we tend to test our new medicines on healthy, young, white males.

5:05Biological sex enters the picture at every step of the way. So we score every trial, every product, every company, and then we release the rankings every year. Hi, Trevi. Welcome back. Hello. So what do you have for me, Ella? Brace yourself. One of the most damning things I came across was a study from 2020, which analysed data from several thousand medical journal articles and found that 86 commonly prescribed drugs showed differences between males and females. Oh, goodness. Okay, what kind of drugs? It covers most classes of drugs, actually. So antidepressants, anti-epileptic meds, painkillers, immunosuppressants.

5:50Oh, goodness. Yeah, the list goes on and on. Actually, Chavi, let me show you the list. Okay. Do you recognise any of these? Yeah. I mean, aspirin is on the list. A couple of my migraine medicines are on that list. And a medicine I take every day, sometimes even twice a day, fexofenadine, which is an antihistamine. Yeah. What do you mean by sex differences, though, in this case? I mean that in 96 % of cases, women had more adverse side effects than men. More dizziness, nausea, headaches, depression. As you pointed out, aspirin is on this list and that is linked to cardiovascular disease for women with type 2 diabetes and elevated fibrinogen.

6:34So your blood may be more prone to clotting. Oh, what? Ah, this is what happens when you don't properly test drugs on women. Exactly. Exactly that. And I wanted to understand how we got here. So I spoke to Jennifer Miller, co-director of the Program for Biomedical Ethics and an associate professor in the Yale School of Medicine. She started by explaining to me the normal process drugs go through before they are released to the market. We test them fairly rigorously to understand their safety and efficacy. When that research is done in humans, it's called a clinical trial. There's a few phases in clinical research.

7:12the first phase is to see if the product is safe. Then you want to understand what dose you should be using. And then you move to see how effective it is at targeting a particular condition. So the thing I'm kind of getting from my research is that this process has not necessarily worked for women. How often are women involved in clinical trials? Women are under-included. So we tend to test our new medicines and vaccines on healthy, young, white males who don't represent the patient populations who actually use a product. More often than not, we know how many women participated in a clinical trial.

7:54We can't take that for granted because, you know, several years ago, we actually didn't even know the sex of participants. So there's some good news. But the bad news is about 30 % of new drugs aren't adequately tested women. And that's women in general. If you break that down further, let's say if you want to look at it by race and ethnicity, it's almost zero drugs. And then even if there are enough women, we don't necessarily analyze the data and break it out. Oh, so we don't even necessarily know the difference between women and men, even when women are included. That's right. So we tend to test drugs on healthy young white males.

8:31And then even when women are adequately included. We don't break out the data by sex. So you're not detecting any differences, safety or efficacy differences. And it's not just that women aren't included in clinical trials. It's that the lab mice tend to be males, the cell lines that we're testing products on. It's like males all the way down. Do you have an idea of why women were even excluded from clinical trials in the first place. Historians tend to credit the thalidomide scandal as a tipping point. So in the 1950s, women were using thalidomide during pregnancy to address nausea. A good number of women who used the product ended up having children with severe birth defects.

9:18After thalidomide, there was widespread caution and hesitancy to enroll women who might become pregnant in clinical research. And if you look still today at some of the inclusion and exclusion criteria in the protocols for clinical trials, you'll often see a blanket exclusion for women who are not using contraception, who are of childbearing age. I think women were likely already underrepresented before thalidomide, but historians argue this made it worse. Is this better than it once was? I mean, it's clearly still not great, but have there been improvements? So we've been tracking representation for the last 12 years, and we have not seen improvement in representation for any group, at least in oncology.

10:10And that is likely to be pretty representative of other conditions. So no improvement, despite arguably about 40 years of policy efforts to try and improve. Right. Okay. So there has been regulation to encourage increased participation of females then? There's been a substantial number of policy efforts to improve participation of women. It hasn't had an impact yet. So in 1993, NIH passed the Revitalization Act. And in there, there was guidance suggesting that women should be better included in NIH-funded research. And then in that same year, in 1993, the Food and Drug Association also published guidelines for the study of gender differences in clinical evaluation of drugs.

10:55The challenge is that these were both guidances. So they really had no teeth. They're not monitored and enforced. And so they really haven't moved the needle. And most of the efforts focus on including women, but not, again, like I said, analyzing, making sure that the data is analyzed and broken down by sex. We'll come back to Jennifer a bit later. But what she leaves us with, Chavi, is the fact that women were not included in clinical trials for new medicines until the 1990s, potentially due to fears motivated by the thalidomide scandal. And 30 plus years on, even if women are included, their data is often not separated from males.

11:34So we don't actually see how drugs affect women differently until they're already on the market. I'm shaking my head here. It's insane because this is then compounded if you're a minority, along with being a woman. So ethnically, racially, geographically, you're not represented at all. I mean, oncology drugs, you're not going to find out if chemotherapy drugs suit you until you've started them. And I know so many women who have had horrible side effects and they can't continue them. On the geographical side of things, although Jennifer did mention regulation, which are US-based, the trends of female participation in clinical trials in the US are very much reflective of the global picture because the US often sets the standards for these things.

12:18But Chavi, now that we've heard what the situation is generally, I'm wondering if you have come across any specific examples of this in your research. I have. So one thing that jumped out at me was attention deficit hyperactivity disorder or ADHD in women. One of the first lines of treatment for ADHD is a drug called listexamphetamine, which has been around for just under 20 years. It's prescribed even today. But the drug, the dosing range and the prescription guidelines are all based on clinical trials on men. Shocker. And when women use them, they have more adverse side effects like mood dysregulation, fatigue, sleep disturbance and even loss of appetite.

13:02Several studies of efficacy across gender suggest these drugs are just less effective for women. And do we know why these drugs don't work as well for women? Well, research is ongoing, but they believe the most likely culprit is complex hormonal interactions. So women have more estrogen and they also have more fluctuating levels of estrogen, which interferes with how the brain uses dopamine. And this is the exact chemical that ADHD stimulants like lisdek's amphetamine target. I'm glad you bring up estrogen because hormone levels are a huge biological difference. that can affect drug outcomes. It's probably why I should have been using female mice in my research.

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14:56You're listening to Women Not Included for Discovery on the BBC World Service, where we explore the many ways the world is not designed for women. This time, we're talking about drugs and clinical trials. We've already heard how the studies used to test the safety and effectiveness of drugs have historically excluded women, and in many cases, still do. The result is a major gap in our understanding of how everyday medications affect women's bodies. And that's because women's bodies significantly shape the way we process these medications. So now I want to understand how. Fortunately, there's a book that explains just that, Sex Matters by emergency medicine doctor Alison McGregor.

15:40I sat down with Alison and we started at the first step. How do drugs move through all bodies? There's something called the pharmacokinetics. So the pharmacokinetics are what the body does to the drug. When you ingest a drug or if you get a shot, the journey that that drug then goes to before it gets excreted. There's a mnemonic that we use. It's called ADME. The A is the absorption. You have to absorb those ingredients into your bloodstream. D is for distribution. Once you absorb that medication, then it gets distributed throughout your body. Then your body metabolizes it. So that's the M. So the liver starts to break it down into its simplest form so then it can excrete it, which is the E.

16:33So the kidneys are the most common ways that we excrete through our urine. At what stage in this whole kind of complicated process do differences between males and females show up? Biological sex enters the picture at every step of the way. So for example, if we were to look at absorption, so if you swallow a pill. Women's stomach linings have a different pH. Our gastric emptying time is slower. So that affects how quickly we absorb a medication. So if we think about the distribution, women have higher body fat percentages. We have less body water. In fact, our body water percentages changes throughout our menstrual cycle.

17:23The fact that it can change throughout Now, our cycle is really fascinating. It is fascinating because if we think about the fluctuation of estrogen, we think about it as really just giving women periods. But we have receptors for estrogen throughout our entire body, our brain, our hearts, our livers. Our liver enzymes break down drugs. So depending on where we are in our cycle, some of our enzymes that break down drugs are either more robust or less robust. You mentioned fat distribution. This is a pretty significant difference that you see between sexes. How does this affect drug processing?

18:08One great example about fat distribution is a drug that we use for anesthesia, propofol. Women will break down propofol quickly in the blood. And so we need to know how to adjust that dosing. However, for long surgeries, because of the fact that propofol likes to hang on to fat cells, And so women have higher body fat percentages. It really can hide out in those fat cells. And so during longer surgeries, having a woman wake up is much more challenging because she has stored a lot of this medication in those fat stores. One thing that has come up in my reading around this is that women and men do have very different immune systems, different immune responses.

18:57Have we seen this affect how women respond to drugs? So we know that the sex chromosomes XX that females have, have much more genes on it that are related to a more robust immune reaction. So think of a vaccine. It's something that is designed to stimulate an immune response that could be protective. And so what we found, especially with influenza vaccine, is that when given the same dose to males and females, that the females had a much more robust immune response, but also had a more adverse drug reaction. There was this call at the time that perhaps women could receive a smaller dose of the vaccine since we don't need the larger dose.

19:49That's something where I think we really could embrace this concept of having sex-specific dosing of medications. But really, there is no mandate. Huge thank you to Alison McGregor there. So those 86 drugs that I spoke about earlier that cause greater adverse effects in women, well, this is why the pharmacokinetics. And it's not just hormone differences, Chavi, it's everything. Fat distribution, the immune system, gut clearance, water content, and we barely even scratched the surface there. One area that Alison didn't touch on, which I have read, is a particular concern are cardiac medications.

20:29Heart attacks present really differently physiologically, right? And cardiovascular medicines react differently in men and women. And both of these are just down to the fact that women are built differently. So for example, angiotensin converting enzyme or ACE inhibitors are often prescribed following a heart attack to widen blood vessels and improve blood flow. But because women's kidneys are generally less efficient at clearing waste, it can lead to a buildup of the drugs and that causes adverse effects. And these drugs do have dosage guidelines, but they're not sex specific. I mean, almost no drugs have sex specific dosage guidelines.

21:09But there is one very high profile case which made the news in the USA about 13 years ago. If you take a pill to get a good night's sleep, check with your doctor. The Food and Drug Administration says women should be taking half as much sleep medicine. The FDA says it has about 700 reports of impaired driving in people who've taken this drug. 700? Oh, goodness. Maybe these women having car accidents after to take a sleeping drug is not them. It's the drug. Yeah, this is the sleep medication Zolpidem. And it's believed that women metabolize this drug much slower than men. But dosage guidelines were written based on male bodies.

21:53Of course. Yeah, of course. And it was only after these hundreds of reports of car crashes that guidelines changed for women's dosage in the USA. Outside of the USA, mostly it hasn't changed, although some doctors may prescribe differently based on this information anyway. You know, I've taken it. My doctor has prescribed this to me for jet lag and she's really strict. I take only half the recommended dosage. This is not based on a specific guideline from any authority. This is just her trial and error with her patients. Although I should add that some research argued that there isn't enough evidence to justify the current female dosing guidelines of Zolpidem.

22:31Well, they could just do trials. Imagine that. Imagine. The thing is, there certainly is justification in many other cases, and yet there is very little sex-specific dosage advice out there. You know what? After all of our examples, it is abundantly clear that something needs to change. And the good news is something is. Let's go back to Jennifer Miller now from the Yale School of Medicine. When she saw that 40 years of regulation in the USA had not fixed how women were being ignored by clinical trials, she took matters into her own hands. We started something called the Good Pharma Scorecard, which is an index designed to rate and rank pharmaceutical companies on their bioethics performance.

23:17And one specific measure that we look at is representation in clinical trial enrollment. So we look at every new drug and biologic that the FDA approves, and we focus on the pivotal trial supporting its regulatory approval. And we look to see whether the patients enrolled in that pivotal trial, whether their demographics match the demographics of the patient population with that targeted condition. Are women adequately represented in that clinical trial? So do we have the medical evidence at the time of regulatory approval to support safety and efficacy for women? We score every trial, every product, every company on whether adequately includes women.

23:53And then we release the rankings every year. And so we show who's scoring really high. And then we, by default, you know, name the laggards. So have you actually seen positive changes using the scorecard then? Yeah. Nobody wants to look bad in the media, right? Nobody wants that New York Times headline that says X company doesn't adequately test their products on women. And so it encourages companies to improve their procedures really quickly. In 2019, when we gave companies an amendment window, we said, we'll give you 30 to 60 days to improve things. We'll publish the first score, and then we'll also publish your post-amendment window score.

24:30And half of the large companies took us up on the amendment window and improved their procedures within 30 days of getting their low good form a scorecard. And also on key measures, the scores go up year after year. Have you seen this kind of thing implemented outside of the US? Or are you actually doing that yourself? We're global. Clinical trials are global by nature. Each product is tested in a median of 16 different countries. And the sponsoring companies are global. They're not all in the US. In fact, the number of companies based in the US is dropping. And you're starting to see it become much more global.

24:59Who else? What else do you think has the power to drive change beyond the scorecard itself? I think everyone has a piece to play in this. You need every instrument to have a beautiful symphony. You know, one of the determinants of success is that they have CEO commitment. So every CEO of a pharma company should be committed to ensuring that their products are adequately tested and analyzed. It should be a priority for every CEO. And if that happens, you'll start to see the change. Then the health system, we are the sites where the clinical trials take place. Every investigator should also be making sure that women are adequately represented and that they're enrolling enough women.

25:40And then the clinicians, when they look at the medical evidence, they should be up in arms when they don't have enough evidence to prescribe a product for their patients, for women and pregnant women. 90 % of pregnant women take a prescription at some point in their pregnancy. I've had five pregnancies. I think I took a prescription for every single one of them and it was off label. That is just ridiculous. If you're breastfeeding, it's the same thing. So clinicians really need to clamor a lot more about this. And you can track whether it's going to be fixed with the Good Pharma Scorecard. You can track change over time.

26:11You can look up your products and you can look up the sponsors. Thank you to Jennifer Miller, who is leading the Good Pharma Scorecard, which really puts pressure on pharmaceutical companies to improve their inclusion and reporting of women in clinical trials. I'm so glad to hear this even exists because, you know, women have had to advocate for themselves for so long, usually with no results. So this is something tangible that we can all check. Yeah. Now, the good pharma scorecard is global, but of course, countries are changing things at a more local level too. So, Chavi, I was wondering how things are looking in India.

26:51Do you know? Yeah. In 2019, India passed a new set of rules and ethical guidelines specifically prohibiting unwarranted gender discrimination, but they stopped short of mandating a ratio of women that needed to be included. Not quite there yet with not having like a mandate. Yeah, yeah. Similar to what Jennifer was saying before about when it's guidelines and not law, then things can fall through the cracks still. But... Absolutely. And in better news, in Africa, the biopharma company Gilead had its first HIV cure trial, testing an immunotherapy-based approach, and its test subjects were all women.