Good day to everyone joining us, and welcome to today's Xtalks webinar. Today's talk is entitled "Pregnant Participants in Clinical Trials." My name is Sonya Hunt, and it's my pleasure to be your Xtalks moderator for today. Today's webinar will run for approximately 60 minutes. This presentation includes a Q&A session with our speakers. This webinar is designed to be interactive, and webinars work best when you're involved. So please feel free to submit questions and comments for our speakers throughout the presentation using the questions chat box, and we'll try to attend to your questions during the Q&A session. Now, this chat box is located in the control panel, which is found on the right-hand side of your screen. If you require any assistance, please contact me at any time by sending a message using this chat panel. At this time, all participants are in listen-only mode. Please note that this event will be recorded and made available for streaming to those who register on xtalks.com. At this point, I'd like to thank ICON, who developed the content for this presentation. ICON is a world-leading healthcare intelligence and clinical research organization. From molecule to medicine, they advance clinical research, providing a comprehensive suite of outsourced development and commercialization services to pharmaceutical, biotechnology, medical device, and government and public health organizations. They develop new innovations, drive emergent therapies forward, and improve patient lives. Their outsourcing models can be adapted to suit small local trials to large global programs, including full-service, standalone services, FSP, and full-asset development. With headquarters in Dublin, Ireland, ICON employs approximately 42,250 employees in 106 locations in 55 countries. Now, with that out of the way, it's now my pleasure to introduce our speakers for today's webinar. First, I'd like to introduce you to Heather Peterson. There she is. Hi, Heather. Pediatric Strategy Liaison, Center for Pediatric Clinical Development within the Maternal Fetal Medicine Unit at ICON. Now, Heather has a diverse background in clinical research, both as a registered nurse and in clinical operations. She applies her expertise in pediatric populations to assist in the strategic review of protocol development, ensuring critical pediatric content is thoughtfully measured and is consistent with governing bodies while incorporating patient-family- centered considerations. Next is Dr. Mark Sorrentino. He's the Vice President for Center for Pediatric Clinical Development, Co-Chair for Maternal Fetal Medicine Unit within the Drug Development Solutions at ICON, and there he is. Hi there, Mark. Mark has over 20 years of experience in the pharmaceutical and biotech industries and currently leads ICON's Global Center for Pediatric Clinical Development and Maternal Fetal Medicine Unit. Prior to joining ICON, Mark spent five years as the Global Chair and Founder of the Pediatric Practice Area at a leading CRO, overseeing all aspects of S trategy and Pediatric Clinical Development, as well as the Global Therapeutic Head of Critical Care and the Interim Head of Infectious Diseases. Next is my pleasure to introduce you to Dr. Martine Dehlinger-Kremer. There she is. Hello there. She is the Vice President for the Pediatric Clinical Development, rather, Co-Chair of Maternal Fetal Medicine Unit, Drug Development Solutions with ICON. Martine brings over 30 years of experience in the research industry, including 30 years with a particular focus on global regulatory affairs, medical affairs, and pediatric leadership. At ICON's Center for Pediatric Clinical Development, she supports pediatric developments and advances in pediatric research. Additionally, as Co-Chair of ICON's Maternal Fetal Medicine Unit, she contributes to the search for innovative solutions in maternal fetal health, and finally, Dr. Monica Lee, Medical Director, Medical Affairs, Maternal Fetal Medicine Unit. There she is with ICON. Hi there, Monica. Now, Monica is a board-certified obstetrician and gynecologist with over 16 years of clinical experience. She graduated from Stanford University with honors and went on to obtain her MD at the University of California, San Francisco. Subsequently, she finished her residency training obstetrics and gynecology, rather, at the University of California, Los Angeles. Now, before I pass the mic and the controls over to our first speaker, we do have our first poll question, and I'm going to launch that now, and there it is. Now, this is done in real time, so your participation is strongly encouraged and very much appreciated. It's a very simple question that we have for you. What do you consider the biggest barrier to recruiting pregnant women to clinical trials? We have three options below. Is it ethical concerns such as risk aversion, fetal risk, regulatory issues such as exclusionary criteria, or is it practical challenges such as study requirements? Please go ahead, everyone, and cast your votes. Oh, perfect. It looks like we have half of our audience. If I can get everyone else to join in now, that'd be greatly appreciated. Okay, perfect. That looks like it's the majority. And we have a few more people making their selection, so I'll keep it open for a few more seconds. Okay, perfect. Thank you so much, everyone, for participating in that poll question. Now, let's take a look at the results. Okay, so in our audience, 85% of our audience chose ethical concerns such as risk aversion or fetal risk, while only 5% said regulatory issues, and then 11% said practical challenges such as study requirements. So thank you very much, everyone, for participating in that poll question. And now it's my pleasure to pass the mic over to Heather. So Heather, when you're ready, you may begin. Hi, everybody. Thank you for joining today. I'd just like to take you through a quick agenda topic. So today we're going to be discussing first the perceptions and perspectives of pregnant individuals on clinical trial participation. Second, the history of pregnant women in clinical trials and understanding the evolution of policy and practice, pregnancy and clinical trials, the regulatory aspects, and pregnant population in clinical trials, diversity and safety. And then we'll also try to leave some time for questions and answers. So I'd like to go ahead and start with just a basic background. So I doubt that it's any secret that women in general are underrepresented in clinical trials, even in disease states that affect them more than their counterparts. We should also recognize women metabolize drugs different than men, and pregnant women metabolize drugs different than non-pregnant women, excuse me. Why are women underrepresented in clinical trials? One of the situations that led to excluding women stems from safety and ethical concerns for women of childbearing potential and their unborn fetuses. You may recall the extreme birth defects and infant deaths that occurred from the thalidomide use back in the 1950s and 1960s. This is a crisis that led to stricter guidelines for women of childbearing potential in clinical trials, even to the point of exclusion. The good news now is that we're moving the needle in a positive direction and have progressed as governing bodies have recognized protecting women through clinical research, not from clinical research, is the appropriate path forward. Each year, approximately 140 million births occur worldwide, with 40%-90% of pregnant individuals reportedly taking medication during pregnancy. Yet fewer than 10% of medications approved since the 1980s contain a safety profile for use during pregnancy or lactation. We can go ahead and go to the next slide. So medicine used in pregnancy is extremely common, but there are significant knowledge gaps surrounding the safety, dosage, and long-term effects of drugs used. There's minimal information on the pharmacokinetics of many existing treatments and no systematic capture of long-term outcome data to help inform choices for providers and their patients. So treatments commonly used in pregnancy are often old, untested, and used off-label, and they lack adequate safety information. This is a major public health concern, and pregnancy complications are the leading cause of mortality in children under five years old globally, and health in pregnancy is a major determinant of women's long-term health and well-being. The FDA recently released, back in 2018, I'll say, this draft guidance to support scientific and ethical issues that surround the inclusion of pregnant women in the drug development process. Next slide, please, so let's take a review of women's health, so there was a recent survey conducted in the U.S., now this is U.S. only, with a number of 1,594 women ages 18-54. These women are not pregnant with at least one existing health condition. The survey was conducted by BabyCenter to gain insight among women with health conditions and their perspectives on participating in clinical research. The study was run in 2020 and then updated again in 2023, and the findings came to show that women in this age range with at least one health condition continues to increase. Originally, the findings in 2020 stated that 66% of the 1,954 women surveyed had at least one health condition. This has increased to 87% in 2023, and of these individuals, 69% of them have two or more health conditions. This alone demonstrates the need for safe and effective treatments for women of childbearing potential. An impactful takeaway is also that 70% of these participants stated their condition has negatively impacted their quality of life. As a female, this makes me want to be proactive in supporting clinical research, and I hope you too. Sadly, the study found only 5% of participants had taken part in the clinical research study. Next slide, please. What's the awareness level of clinical trials by the differing age or differing groups of these participants? So going from only 5% participating in a study, it's really interesting to see that the awareness level of clinical research overall is very high. The survey was updated in 2023, so being post-COVID could be directly related to the awareness level. What I found interesting is the awareness is highest, not in Caucasian women, but rather Black and African-American women. The Black and American-African women voices were heard, and the most important reason they would like to partake in a study is to allow other people like them to be represented. Awareness is also highest in individuals with two or more conditions, Gen Xers that are employed with an annual income of $75,000 a year or more. Next slide, please. So of these, who is most likely to participate in clinical research and why? Taking a holistic view of the results, it's interesting, though not surprising, that women who actively manage their conditions in both daily activities or medication use and have experienced a negative impact of their quality of life due to their condition would be more likely to participate in a clinical research study. Additionally, receiving compensation, contributing to finding a cure, adding an additional provider from the research staff to review their care, and information surrounding the risks and benefits and safety profile of the study will promote interest in participation. Next slide, please. Now that we've taken a brief look from the perspectives of non-pregnant individuals, let's review insights of a pregnancy exposure registry that was conducted in 2021. First of all, just for understanding, the FDA's description of a pregnancy exposure registry is this: Research studies that collect information about the effect that prescription medicines taken or vaccines received during pregnancy or immediately before may have on you and your developing fetus. So they're looking for medications taken, vaccines given, and they want to just follow the outcome. So some pregnancy exposure registries also collect information about newborn babies for a period of time after birth. You may not be aware of this, but the FDA also posts a list of ongoing pregnancy exposure registries. So I did a quick search, and there's currently 190 ongoing studies, which is very encouraging. So the ladies in our survey found the biggest barrier to participation in pregnancy exposure registries is misconceptions associated with participating. Even among the most educated and those suffering with chronic conditions, the survey included 1,522 pregnant individuals in the U.S., and only six stated they had participated in an exposure registry. Considering 40%-90% of pregnant individuals report taking a medication during pregnancy, this number is extremely low. So where is the gap of knowledge? 70% of respondents believe these following points: One, they will be asked to take a new drug or vaccine. Two, they need their doctor to refer them for the study. Three, registries are only for individuals living with a chronic condition. And four, participants are always paid to participate. So looking at the positive side, 50% of respondents stated they would be willing to participate in research when provided adequate information. I'm sure this will be of no surprise to you, but the reason these individuals would be most interested in participating is to have more information about the safety profile of medications or treatments during pregnancy with the most importance surrounding the safety of their unborn fetus. Next slide, please. So in review, we recognize women's health is suffering with continuous increases in the number of chronic conditions suffered. Also, individuals willing to participate in clinical research studies have conditions that impact their quality of life. Motivators of participation are reimbursement, information, support in finding a cure, and lastly, individuals would prefer to hear of clinical trial opportunities from a trusted source. Next slide, please. So this is just a key takeaway slide of actionable items to support pregnant individuals with motivation to participate in clinical research. You know, it really, truly is not much different from what most individuals require and request in all of our clinical research studies. So we just need to bring all of that into support of pregnant women in clinical studies. So with that, I will go ahead and pass to Mark for insight into historical exclusions of pregnant individuals. Great. Thanks, Heather. And for everybody, I have the shortest section here because, as I think everybody in the audience knows, there hasn't been a whole lot going on with the addition of pregnant people in clinical trials. So just a little historical background. You know, when clinical research got started, both children and women and other marginalized populations were excluded, and everybody was a white male that went into a clinical trial. And then we got into the 1960s, and I think that, unfortunately, everybody remembers thalidomide as a large reason why we didn't include pregnant women in clinical trials after that. And interestingly, that was very similar to what happened in pediatrics with RSV. And there were a couple of deaths, and nobody looked at doing an RSV vaccine until very recently, where you not only see that we have an RSV vaccine, but it happens to be a maternal RSV vaccine used in pregnancy. So that's where I hope that we're going, but this is where we've been. Later on into the 1970s and after that, when IRB started taking over the ethics part of studies, it was still considered unethical to include women and children in clinical trials, especially pregnant women. And so they were essentially left out of the development profile again up until very recently, which Martine will get into in a few minutes. You can go to my next slide, [Laura]. So what were the reasonings? I think that even what you heard from a very recent poll that Heather gave you, there's still the stigma about doing clinical trials in women, and especially during pregnancy. Are you going to hurt the unborn child? What are the risks of doing that? And certainly, I think that that is top of mind with all of us that are doing clinical research. Mistrust and then gender bias. Again, I mentioned earlier, if you go back for years and years and years, almost everything that we know was done in the white male population. And certainly, if there were others, they were the vast majority. So these were what we have to overcome as we move forward. You can move to my next slide. So, you know, there has been a shift, and that's fantastic. And again, Martine's going to get into this further, but one of those has been that there's a lot of patient advocacy groups out there that are saying, "Hey, we take these medications on a chronic basis for our chronic diseases, and we end up getting pregnant. And so are these medications safe and efficacious during pregnancy and lactation? And we need to look at that. And the only way to do that is to do clinical trials." So that is where we have moved in from. In addition, we've seen that there have been, especially on the infectious disease side of things, diseases that have specifically affected fetuses and newborns and pregnant women. And again, like I show there, some of those have been in infectious diseases. So even more reason to make sure that we have medications to treat the pregnant mother so that the baby doesn't end up with the same infectious disease that could be devastating. And now we're at a place where, again, we're seeing that not only our sponsors, but also global regulators, groups like the World Health Organization and others are saying, "Yes, we need to look at these populations." Obviously, we need to do it in a way where safety is paramount, but maybe we can get data, especially out of registries like what Heather was mentioning, to ensure that we have a safety profile for all products that go through clinical trials. And with that, I'll turn it over to my last slide, which is just understanding that historical context is important. And again, I say it that this group is probably a decade behind where we were in pediatrics. It was a very similar story for not including children. And we know that now there's a mandate to include children in clinical development so that they get the same knowledge out of those drugs that we have for the typical adult population. And I think that that's where we're going for pregnancy and lactation as well. And with that, I will turn it over to Martine. Thank you very much, Mark, for this very important background, which helps us also to understand the future of research in pregnant and lactating women. The next slide. So we have today approximately 140 million babies born worldwide each year. 58%-97% of those pregnant women take at least one drug during pregnancy. And on the other hand, only 5% of the drugs that are approved have a label for use during pregnancy and lactation. There is a lack of data on safety and efficacy of the drugs for use during this condition for both the physician and the patient to weigh the risk-benefit. As a consequence, some individuals with chronic diseases just stop the necessary treatment due to concerns about their baby. Next slide, please. Pregnant individuals face challenges when considering taking medicines. Safety concerns. Many pregnant women are worried about the potential effect of medicine on their unborn child, the lack of clear guidance, conflicting information. The risk assessment, assessing the potential risk-benefit of taking a medication during pregnancy, can be a challenge. Women need to weigh the benefit of treating either their own condition against the potential of the risk for the baby. And there are limited options also because some medications are contraindicated during pregnancy due to known risks, leaving the pregnant individual with limited options for safe products. There is a fear of harms. Pregnant person fears for the harm for the baby during the pregnancy or complication during the childbirth. And then this lack of information for pregnant individuals. They have difficulties to find reliable information about the safety of specific medications for use during pregnancy. And this leads to uncertainty, anxiety. The communication with healthcare providers about medication to be used during pregnancy can sometimes also be inadequate. Pregnant individuals may feel hesitant to discuss their concerns or may not receive clear guidance from the healthcare professional. And those we already mentioned, the pregnant persons with chronic diseases face additional challenges in managing their own condition while they are pregnant, including adjusting to the usage of the medication or finding alternative treatments that are safe during pregnancy. Next slide, please. So why do we not include pregnant persons in clinical trials? There are these ethical concerns, and we saw in the response to the poll that the ethical concerns were the main reason. We can say the perceived ethical concerns. There are ethical considerations regarding the inclusion of pregnant individuals into research. Primarily, it leads to concerns about the potential risk to both the pregnant person and the developing fetus. Researchers and IRBs may be cautious about exposing pregnant individuals to experimental treatments or interventions that could harm the unborn child. Some regulatory framework also discourages the participation of pregnant individuals in clinical trials. These regulations aim more to protect the safety of the pregnant person and the unborn baby, but can inadvertently lead to the exclusion from research studies. The safety concern, researchers may be reluctant to include pregnant individuals in clinical trials due to concerns about the potential effect of the treatment on the fetus or being cautious, especially true for drugs or intervention with unknown or potential harm on the baby. We have the logistical challenges. That was the second point that was mentioned by the people attending and responding to the poll. Conducting research involving pregnant individuals can present some logistical challenges, including the need for special medical monitoring, ethical considerations regarding the informed consent, and the potential for additional follow-up visits post-pregnancy. The historical precedent, as Mark presented, in the past, pregnant individuals were not included in clinical trials, leading to a lack of data on the safety and efficacy of medication. And the historical precedent has contributed to ongoing underrepresentation in clinical trials. And the concern about liability. Researchers and sponsors may be concerned about potential legal liability if adverse outcomes occur during pregnancy when medication is taken. The next slide, please. So there has been an analysis of available human data for use during pregnancy and lactation for 31 drugs that have been approved both by the FDA and EMA. It revealed that for use during pregnancy, 90% of those drugs at the time of approval, no or limited human data were available. Only 10% of drugs had some human data. For use during lactation, only 60% of the drugs had human data. This shows that we really have a big gap of human data for medicine use during pregnancy and lactation. Next slide, please. Authorities and other s such as WHO or ICH have taken this situation very seriously and issued and initiated actions. The FDA and EMA initiated guidance documents as early as 2005 with voluntary safety surveillance pregnancy exposure guidance from the FDA and the guideline on the need for post-authorization data from the EMA. We see further guidelines. In 2008, the EMA issued the guidelines on risk assessment of medicinal products on human reproduction and lactation, a guideline that was open for consultation last year in 2024 and will be revised. In 2014, the FDA issued also the Pregnancy and Lactation Labeling Rule, which includes label requirements to list pregnancy exposure registries. NIH got involved and established in 2017 a charter for Task Force on Research Specific to Pregnant Women and Lactating Women. This task force provided suggestions, and we will come later to those suggestions. In 2018, the FDA issued the guidance on scientific and ethical considerations for inclusion of pregnant women in clinical trials, and a year later, the drug guidance on post-approval pregnancy safety. The EMA also looked at safety and is in the last step to finalize the PV guidance for pregnancy and breastfeeding women, which has been open for public consultation. In 2019, we had the initiation of the IMI ConcePTION project. This was a program to better inform the use of medicines during pregnancy and breastfeeding. The last meeting of this initiative was held in November 2024. It's closed now, but the work will go on in a different way. WHO is also supporting the inclusion of pregnant and lactating individuals in clinical trials. We have the impact guidance for AIDS, and very important is the best practice for clinical trial guidance issued in September last year, which encourages the inclusion of pregnant and lactating women in clinical trials. The issue was taken at a global level in 2023. It was issued the ICH Concept Paper on inclusion of pregnant and breastfeeding individuals in clinical trials. It is expected to have a draft available for consultation in 2025. Next slide, please. Some further authorities have become active. Health Canada finalized in 2013 the guidance on considerations on inclusion of women in clinical trials. In 2019, the U.K. MHRA announced its collaboration with the Bill & Melinda Gates Foundation to begin new research on medicine use which could impact the health of pregnant women around the world. They had also a publication. Next slide, please. As we could see, we have a lack of data, but what is the actual consequence of this lack of data? The FDA wanted to get some more clarity. They did a survey among over 1,200 pregnant women. 79% of those women took at least one medication during pregnancy. Among those 63%, made at least one change in medication use. 35% stopped the medication, 30% missed doses, 80% lowered doses. And more than 36% of those who made a change of medication use in pregnancy, they did it without consulting any healthcare professional, just on their own. The reasons were they were a bit feared about the birth defect. There were worries about miscarriage or about autism. And this illustrates the gap of information in what pregnant individuals take as decisions and also mainly on their own. Next slide, please. The wish of the FDA is to advance the inclusion of pregnant and lactating individuals in clinical trials. And the FDA tries to achieve this by issuing guidances, organizing workshops, and the next workshop is taking place on the 27th of March this year. Registrations are still open, it's a hybrid event, so please feel free to register if you are interested. The FDA is also organizing webinars as well as scientific meetings and is fostering global collaboration as this issue is a global issue. The next slide, please. The U.S. National Academy of Sciences in Nurturing and Medicines published last April a report with some interesting outcomes, namely that there is a lack of evidence of liability related to including pregnant and lactating individuals in clinical trials. The possible legal implications arising from the use of approved drugs during pregnancy and conducting clinical trials in pregnant individuals could predicate the potential liability risk. The next slide. We have also PDUFA VII, under which the FDA has committed to expand the use of the Sentinel Network and real-world evidence for assessing pregnancy safety. The FDA is developing a framework to describe how data from various types of post-marketing pregnancy safety studies might optimally be used, and they will try to set up guidance to show how, and demonstration projects to show how this data can be used later on. They have five projects that they want to use. Projects A to D will fall under regulatory purview and will be conducted in the Sentinel Network, and then Project E falls under BEST purview and will be conducted in the Biologics Effectiveness and Safety System. The FDA initiated the projects in September 2024, and the results of these demonstration projects will allow us to update guidance and provide a framework on how to use those data with a guidance, a map, and SOPs, and we will have some of this guidance by September 2027. So just be a little patient, and we will have really some more instructions from the FDA. Next slide, please. The task force on research specific to pregnant women and lactating women was established in 2017, as I showed you, in order to address the gaps in knowledge that we have for the treatment of pregnant and lactating individuals. They issued some recommendations in 2018, and 15 recommendations were reported to Congress, outlining really the proposal to include pregnant and lactating women in clinical trials. An implementation working group was set up in 2023, and they issued a report in July 2024. The recommendations include to expand and improve the quality and timelines of studies on therapeutic products used during pregnancy and lactation to adapt a forward-thinking strategy for crafting protocols, designing studies, namely to establish a structured plan to ensure the efficient collection of PK and safety data in pregnant and lactating women. They also proposed to optimize pregnancy registry to leverage and enhance existing data resources to support evidence generation and lay the groundwork for research in pregnant and lactating women, designing maybe a healthcare report system where mother and infant records are linked, and important will be also to design innovative tools for studying PK and PD. Next slide, please. The issue, as we already mentioned, is a global one and was brought at the ICH level with the aim to create an ICH guideline in order to have a globally accepted framework and best practice to enable inclusion and retention of pregnant and breastfeeding individuals in clinical trials. This harmonized guideline will address not only the inclusion of pregnant individuals in clinical studies supporting registrations, but further support the use of already approved therapeutic agents as well as preventive vaccines by pregnant individuals. The proposal will benefit pregnant and breastfeeding individuals by providing informed access to new and existing medicines that could be used then. It will provide the framework for evidence generation, risk assessment of similar drugs, drugs with the same mechanism of action, for example, for the pregnant population. And important is that there will need to be a mindset shift from excluding unless to include unless. Next slide. The ICH guidance will provide greater confidence, will also have an impact on the inclusion in pre-authorization trials, which could facilitate better generation of information on the benefit-risk in pregnancy and breastfeeding, access to medicine earlier. Nowadays, when we do pregnancy registries, they are post-marketing, and so it takes five to 10 years before we see any label for use during pregnancy and lactation. The guideline will also require expertise, especially in non-clinical as well as in clinical domains. There will be synergies and complementarities with existing ICH guidelines and also some already existing regional guidance. And it's really a growing topic. Next slide, please. Some points that the guidelines will specifically address, it's considerations regarding data collection on dosing, clinical efficacy, and safety. The guidance will provide advice on clinical development, study design, end points, outcomes to be collected, recruitment and retention strategy, ethical consideration, regulatory consideration. There will be bridgings with existing ICH guidelines. The next slide. The rapporteur for this initiative is Dr. Dorina Bischof. She is a representative of EFPIA, the European Federation of Pharmaceutical Industries and Associations, and the regulatory chair is Dr. Leyla Sahin from the FDA, and then there are representatives from all the ICH members. Next slide. This is work in progress. In Q3 this year, the draft will be released for public consultation, and then we expect to have a final guidance in 2026, so not too far away. Next slide, please, so how can we make progress? Addressing the barriers that we have spoken about requires concerted efforts from researchers, regulatory agencies, ethicists, policymakers, and patient representatives to develop guidelines and frameworks that balance the need for scientific evidence with the protection of pregnant individuals and their unborn babies. Encouraging the inclusion of pregnant individuals in research can lead to a better understanding of the effects of treatment and interventions during pregnancy and at the end, improved maternal and fetal health outcomes. Next slide. So if I can conclude, it's time for a change so that pregnant individuals and their doctors are not forced to weigh the benefit-risk of treatments in the absence of any information. A major paradigm shift is needed, moving from the systematic exclusion to the inclusion of pregnant and lactating persons in clinical trials. This is paramount to ensure the availability of essential information for making informed decisions when pregnant and breastfeeding patients require medication. The FDA intends to provide leadership in such efforts to women, healthcare professionals, industry, and public health experts. Let us hope that the FDA will experience enthusiastic engagement from partners around the world. And the health of the child begins with the health of the mother. Thank you for your attention, and I have the pleasure now to hand over to my colleague, Monica Lee. Thank you. All right. Thank you, Martine, for your overview of regulatory aspects. Now I'm going to touch on diversity and safety issues with pregnant populations for clinical trials. Next slide. Diversity and ethics in clinical trials. So in 1990, most research participants in the U.S. were still white men, as Mark touched on. By 2000, the human subject research laws and regulations were changed to encourage the participation of women, including women of childbearing potential, and efforts have been made to improve the ethnic diversity of research participants. Soon after legislation was passed to promote clinical research with pediatric populations to study medications that were used by children as well. There's still much work to be done to improve the diversity of our research populations. But as a society, we have made progress gathering and acknowledging the value of collecting evidence about how medical treatments may affect women, children, and people of different races and ethnicities. The exclusion of pregnant participants from research is not ethically justifiable. It violates the principles of autonomy, justice, and non-maleficence. While the inclusion of pregnant patients in research presents its own challenges with appropriate methodological, ethical, and clinical considerations, we may be able to narrow the knowledge gap and improve drug availability and safety for pregnant patients and their children. Next slide. FDA guidance and diversity. The FDA draft guidance on diversity action plans to improve enrollment from underrepresented populations was published last year, in June. In it, you'll find guidance on what the FDA considers underrepresented groups. Pregnant and lactating individuals are considered underrepresented populations. According to the FDA, clinical trials should be representative of the patients who will use the medical products. A sponsor developing their action plan should not only consider race, ethnicity, sex, and age group, but also whether a pregnant or lactating patient may use their medical products. For drugs, a Diversity Action Plan is required for clinical investigation of a new drug that is in phase III or as appropriate. Next slide. Exclusion can lead to significant harm in the pregnant population. Limiting what is known about toxicity and dosing specific to pregnancy can put patients who require medication at risk. Discouraging patients from accessing beneficial medication due to fear of unknown adverse effects can also lead to significant harm. A third way that we can harm pregnant patients is off-label use, exposing pregnant people and their fetuses to potentially harmful medications through off-label use without benefiting from safeguards and monitoring that is normally embedded in clinical trials. Other risks of not having pregnant women in clinical trials include the fact that some will forgo the use of medical products that will benefit their health and support the development of the fetus. Some may even decide to continue to use a medical product and report that the dose they used prior to becoming pregnant is no longer providing effective treatment. Next slide. It's really unfortunate that little progress has been made in including pregnant women in clinical trials. Recent decades have witnessed little progress in research and development to reduce the impact of pregnancy complications, for example, obstetrical syndromes. Only few drugs have been approved for obstetrical use, and the pipeline for novel pregnancy medicines looks bleak at this time. There are only 50 interventional phase II trials for pregnancy complications listed in ClinicalTrials.gov, but all trials are small academic trials testing repurposing of drugs approved for other indications. Therefore, in obstetrics, women and their infants will not benefit from effective and approved medications in the next decade. There is a real unmet need in the clinical trial space to approve drugs for obstetrical use on a large scale. Next slide. Dose and route affect teratogenicity. We have to remember that dose is a critical feature of any teratogenic exposure. Teratogenic effects occur only when the dose of an agent exceeds a certain threshold. Medications are generally considered safe during pregnancy. They can have adverse effects on the embryo or fetus if the mother takes them in doses that are so high that they cause maternal toxicity. Chronic exposure is usually of more concern than a single exposure, and if the doses are similar. The route of exposure is also really important. For example, risk is unlikely from the use of dermal agents that lack any substantial systemic absorption. The teratogenicity of an exposure is also influenced by both maternal and fetal genotypes, which can result in differences in cell sensitivity, placental transport, metabolism, receptor binding, or even drug distribution. Some medications are metabolized extensively by the mother. Their teratogenicity depends on whether a toxic form reaches the embryo or fetus in sufficient quantities to produce adverse effects. Next slide. PK and PD in pregnancy. A significant amount of pharmacological research has been conducted to improve the quality and quantity of data available for other altered physiological states, for example, kidney or liver diseases and for other patient subpopulations like pediatric patients. The need for PK/PD studies in pregnancy is no less than for these populations. Unfortunately, there are relatively few studies of drug PK during pregnancy. The dose of medicines usually prescribed during pregnancy is the same used in non-pregnant adults, but this may result in substantial under or overdosage during pregnancy. When blood or serum concentrations of medications can be measured and the most effective level is known, they should be monitored throughout pregnancy and appropriate dosage adjustments made as needed. We really need to design better and better conducted PK and PD studies of medications during pregnancy. Majority of published PK studies are anti-infective drug products during pregnancy, and they were conducted at the time of abortion and delivery. They were done to determine the transplacental passage of drugs, and in the absence of this data, the usual adult dose is typically prescribed in pregnancy. The result can be substantial underdosing or excessive overdosing. Next slide. FDA guidance on PK/PD in pregnancy. So this guidance actually states that pregnant women may be involved in PK studies if all the following conditions are met. There has to have been preclinical studies done on pregnant animals and also clinical studies conducted already on non-pregnant women before proceeding to pregnant women and fetuses. We have to remember that the risk of fetus is not greater than minimal, and the purpose of the research is to develop important knowledge that can't be obtained any other means. And the definition of minimal risk is actually very broad. The fetal risk is considered minimal when the estimated risk of the fetus is no more than from established procedures routinely used in an uncomplicated pregnancy or in a pregnancy with complications comparable to those being studied. And although PK studies in pregnancy can be considered basically three development programs depending on anticipated use in pregnancy, the results of repro tox studies, the FDA anticipates that most PK studies in pregnant women will occur in the post-marketing period and will be conducted using pregnant women who have already been prescribed drugs. So an example of minimal risk study would be one to determine PK/PD of an antihypertensive, and the pregnant woman is already taking the drug during pregnancy. The decision to use the antihypertensive medication is made by the patient and her physician and independent of her participation in the PK/PD study. This guidance also recommends that PK studies be conducted in pregnant women in the following situations. The drug has to be known to be already prescribed and are used by pregnant women, especially in the third or second and third trimesters. If it's a new drug or indication, there is anticipated or actual use of the drug in pregnancy. Use is expected to be rare, but the consequences of uninformed dosages are great. For example, narrow therapeutic range or cancer chemotherapy. Drugs of this type can be normally studied in pregnant patients. Pregnancy is likely to alter significantly the PK of the drug. The PK studies in pregnant women are not recommended if the drug is not used in pregnant women or the drug has known or highly suspected fetal risk. Some study design considerations are important when conducting a study in pregnant women to determine if the PK and/or PD are altered enough to require an adjustment from the established dose. Ideally, PK studies in pregnancy would be done pre-pregnancy for baseline comparison and then during all three trimesters, especially for chronically administered drugs. Given the constraints of study design that enrolls women prior to pregnancy, alternatively, you can determine the PK/PD in the second and third trimesters first, and the baseline assessment for comparison can be done in the postpartum period. The agency recommends that the care be taken to select the appropriate postpartum time for PK/PD determination because, remember, heart and kidney changes don't return to pre-pregnancy baseline until three months after delivery. So optimally, if you're doing a postpartum PK/PD assessment, the PK/PD in pregnancy would be done when the woman is neither pregnant nor lactating. Next slide. So strategies to promote recruitment of pregnant and breastfeeding women for clinical studies. So as Heather said in the beginning, I think it is really important to keep in mind that we should protect women through research and not from research. And then we found that some studies have provided a dedicated public engagement officer to ensure clear, open dialogue. Some studies have created community advisory boards to serve as a voice for the community and provide essential input into study design. This would actually help foster relationships and trust with the community. Some use inclusion of peer mothers as co-investigators. Some have established recruitment sites with trained staff. Many have stakeholder meetings. Many use diverse communication platforms and social media. Also, make sure to design studies with women in mind, in collaboration with women patient experts and operationalize a remote enrollment model to reduce the burden of clinical studies. And it also may be important to allow women who became pregnant during a trial to remain in the study as well. Also consider assembling a cross-functional team of experts within the organization to systematically assess the women's unmet needs. Next slide. I thank you again for your attention today. If you have further questions, I'm going to leave this contact information here for you. Now I'm going to turn it back to Sonya for a Q&A session. Thank you, Sonya. Thank you very much, Monica, Martine, Mark, and Heather for that great presentation. Now I'd like to invite all our speakers back on camera so we can begin the Q&A portion with the time that we have left. Please, audience members, if you like, you can still send in your questions using the questions window, and we'll try to attend to your questions during the time we have together. If we run out of time, which looks like it's creeping up on us, rest assured the team at ICON will follow up with you. Okay, let's start with this first question here. This question is for you, Martine. This audience member is asking, "Do you advocate for a maternal investigation plan similar to the PIP for pediatrics in the EU, thus compelling drug developers to include pregnant women by default unless scientifically justified?" What are your thoughts on that? That's a great question. Thank you very much for this great question, and thank you, Sonya. Indeed, it would be important to have a plan like we have, a plan for pregnancy that would help first the drug developer to be able to plan and also to think about, is this drug used during pregnancy and lactation? Does it make sense? If the drug is used during this period, if it's a drug use, then it would be important to have such kind of plans and to develop the drug for use or to have to test it for use during pregnancy and lactation. Nowadays, and you have seen this, of course, all the presentations that pregnant and lactating women are using drugs not approved for them and do not have access to innovative products. So to have such a plan would be important. It's something that needs a lot of thought, how to implement such a plan, but it would make sense to have such a plan, and not only for the EU, such a plan should be harmonized globally because the issue is a global one and not just to one region. Okay, thank you very much, Martine. Let's jump to the next question. This looks like it's for you, Mark. "Within that timeframe, do you expect global regulators to start requiring the inclusion of pregnant people in clinical trials?" S o I think that that just dovetails on what Martine said. I mean, I think that that's where we see things moving for sure. I also think that obviously many waivers will be granted. Nobody's going to put a chemotherapeutic agent into a pregnant woman knowing that there's obviously damage can be done to the fetus, so again, I think that a lot of waivers will be granted. But yes, I think that we do hope that we move into the direction where people that are pregnant are included just like we include the children. Okay, thank you. Let me jump to another question. I think we have time for maybe two more. Do you think there will be incentives similar to those offered with orphan drugs and pediatric populations to sponsors to do work in pregnant individuals?" I would like to take that question. Martin, you want to take that? I don't know if there will be incentives because this has not yet been really discussed, but I hope that there will be incentives similar to what we have seen for pediatrics that will encourage people to do so. And I think that companies who will perform those kinds of studies also need to be rewarded. So I think it would be important to have some incentives like we have for pediatrics now. Okay, thank you. Anyone else would like to add to that? Nope? Okay, let me jump to the next question here. I think this will be our last question. And it looks like it's for Monica. In your experience, how do pregnant women react to being recruited for clinical trials?" You know, that's a great question and I have to say that most pregnant women are pretty hesitant. A lot of them have the health of their fetus in mind and most important, so we do have to align with them and make sure that they understand that we have the best interests of their fetus and their health in mind and we're going to provide the minimal risk to the fetus establishing a baseline pre or post-pregnancy and during second and third trimesters after the teratogenic period, so great question. Anybody else? Other view on this? Heather, Mark? Okay, all right then, well, then that will be our last question, well, thank you very much for answering those questions. We have reached the end of the Q&A portion of the webinar, and there are a number of questions out there that we have not addressed. So please be rest assured that the team at ICON will follow up with you after this presentation. Thank you, everyone, for participating in today's webinar. You will be receiving a follow-up email from Xtalks with access to the recorded archive for this event, and a survey window will be popping up on your screen. Your participation is appreciated as it will help us to improve on our further webinars, and additionally, give me a few seconds. I'm going to share with you a link for today's recording event in the chat box, which you can also share with your colleagues once they register for the recording here as well. So let me just go ahead and put that in the chat box for everyone to utilize. And you should see it now. Okay. Now, please join us in thanking our speakers for their time here today. So thank you very much, Monica, Martine, Mark, and Heather. We hope you found this webinar informative. It has been my pleasure to be your webinar moderator. On behalf of the team here at Xtalks, we thank you for joining us. Until next time, please take care and bye for now. I'm Sonya Hunt. Bye, everyone. Bye.