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Now, under the basic protections or subpart (a), if a product or a study represents minimal risk for the patients or the participants, you would be able to get an expedited review through the IRB. However, when you're doing studies in pregnant women, they are considered vulnerable subjects, and so all studies involving pregnant women have to comply with all of the full IRB approval requirements.
In addition to complying with all of the requirements under subpart (a), when you're doing studies in pregnant women, you also have to comply with subpart (b). Now the regulations under subpart (b) changed about a year ago, December of last year. We have a new regulation under subpart (b). Let me just briefly talk about the new regulation. I'm not going to go into the changes for this group.
First of all, if you are a pregnant woman, you can give informed consent and engage in research if the research that is being conducted has already been conducted on animals or nonpregnant women. So that we have information about the safety of the product in animals or nonpregnant women.
DR. DAVIS: Those are pregnant animals?
DR. MILLER: It does not say pregnant animals. It says appropriate studies. So there's some flexibility about what is the appropriate study in animals, but it has to be appropriate studies in animals. One would assume they'd be reproductive type of studies.
If the research is designed to meet the health needs of the mother, so we're doing the study to meet the health needs of the mother, and the risk to the fetus is minimal or the minimum that can be achieved under the studies, then the woman's consent alone is sufficient.
Also, if the research is designed to meet the health needs of the mother, the mother and the infant or provide general knowledge that would help us in treating other pregnant women in the future, then the consent of the mother is sufficient for her to participate in the study.
If, however, the research is solely for the benefit of the fetus, you're enrolling pregnant women, but you're really not worried about the woman at all, you're looking at the benefit to the fetus, then to enroll those women in the study, you need to have informed consent by both the mother and the father before the woman can participate in the trial.
Now, as we've mentioned a couple of times, pregnancy, for those of us that did it kind of remember this, it's a time of dramatic changes. You end up having these changes I think for the next 25 years, but I'm still recovering.
DR. MILLER: You have this huge fluid volume issue. Your heart rate goes way up. Your urine output just goes through the roof, and then there's all these metabolic changes in the liver that help you do this remarkable event.
And all of these changes or some of these changes or maybe these changes, these dramatic physiological changes, have an effect on how a drug is distributed and metabolized in the woman during pregnancy, but as we've mentioned already in this talk, really we have very little information on what the pharmacokinetic and pharmacodynamic changes are because for most drugs that has not been established. And so clinicians are relying on information from nonpregnant women, we hope, but in many cases it may be healthy male subjects that those studies were done in.
So some of my partners in crime over in Drugs thought that perhaps we could make a dent in this problem if we were to conduct some studies on pregnant women and work through the protocols of how you would go about doing these studies if they were to be done, and so we put out a solicitation with the Department's Centers of Excellence on Women's Health. These are 14 academic institutions that are one-stop shopping in women's health. They have research, clinical services, education, both of professionals and outreach component.
And we wrote for them a statement of work and asked them if they could do a PK/PD measurements on pregnant women that were currently receiving prescription medication to treat a chronic condition that they had during the pregnancy. The idea was that we would take these women that were currently undergoing therapy for some chronic condition, and at discrete periods during that gestation, collect PK and PD information from them.
We thought that this would serve as a prototype for how we could collect needed dosing information in both an ethical and hopefully economical way. It is our intention, as Kathleen told you, we have a place in the label where you could put this type of information in the proposed new labeling. So this would be the type of information that could be incorporated into the pregnancy label.
So, as a result of that solicitation, we funded, in fiscal year '01, two studies. The first is kind of a traditional PK study, in which we have a cohort of about 20 women that have hypertension, and they're receiving Atenolol to treat their hypertension, and we have recruited them into the study during the second trimester.
During a window during the second trimester, they undergo intense blood sampling, so that we can determine the PK characteristics during that period. They do a similar thing during the third trimester and then in the postpartum period.
The second study is what's known as a population PK design, and what this does is this gathers up a lot of--Cook is laughing because this is so different from you're used to. You take a whole population of pregnant women that are receiving Labetalol for control of hypertension and you do spar sampling. What you do is you use this large number of people to draw your population pharmacokinetic variables. So they don't have to be during a certain window, they don't have to be off of concomitant medications. They could be lactating/nonlactating, because you're drawing the kinetics over the whole population of pregnancy during the whole time.
So we have one of each of these different designs that we're funding in the hopes that then we can see how these would, if we were to write guidance, how do you work through issues? Have we thought of all of the different issues that need to be thought of in designing these studies because now we've lived through it.
So this year what happened, and probably you've already had a briefing on bioterrorism, but with the anthrax scare, it became very clear that we did not have dosing and safety information for many, many of the products that were going to be used to treat infections that could occur as a result of bioterrorism in special populations.
Most of the studies that are done on those medications were done in the military, and the military does not intend to have a high percentage of pregnant and lactating women or elderly. So our database of information on those populations was severely lacking.
And so to address this issue, we once again thought that we could do some studies in the pregnant and lactating women, and we set out two different solicitations. The first was to try and collect some safety information to assess both maternal effects and infant outcomes in pregnant women that were exposed to medication during pregnancy, and these were medications that we might want to use to treat women exposed to a bioterrorist agent.
And it's our thinking, at the Office of Women's Health, that if there's a fetal safety concern, if you're worried that this drug might harm the fetus, the likelihood that you're going to give that medication to a pregnant woman is probably diminished. So it's not going to be a case where you're sure she's had an exposure to anthrax; it's going to be the case where we're not sure, and we're going to want to prophylax, and it's going to really influence your decision of whether or not to provide prophylactics to a woman during pregnancy.
So we were interested to see if we could use these large automated databases and the diagnostic codes to try and get some information on infant outcomes.
And the second solicitation was very much like what we had already done with the antihypertensives, where we would ask for PK/PD studies to be conducted in special populations.
So the study that we funded under the safety studies, although we asked for both fetal safety and maternal effects, the databases that were available and the solicitations that came in only were available to address fetal safety. So we are only looking at infant outcomes.
The study that we've contracted to do is with Vanderbilt University. It's going to look at infant outcomes and Ciprofloxacin, Doxycycline, Amoxicillin and Azithromycin. And you can see the number of pregnant women that were exposed to those medications in their database there.
In addition, we've asked them to do a control group, and this is pregnant women that were exposed to an ACE inhibitor during their pregnancy, and we wanted to include this group because we wanted to make sure that if women were exposed to a product that we know causes birth defects or adverse infant outcomes, that the databases that we use will be able to pick that up. Because, remember, these were prescription databases and treatment databases. They weren't databases designed to look at safety. So we have included pregnant women exposed to ACE inhibitors as a validation group or a positive control group.
We also have a group of women that were pregnant and exposed to no antibiotics, and the study includes a group of women that were exposed to Erythromycin. These investigators have already investigated Erythromycin in their database and shown that there is no increase in adverse infant outcomes. Women are exposed to that drug during pregnancy.
We are looking at infant outcomes at birth, three months and a year to see whether you pick up more teratogenic effects if you go longer, and the patient population that's in this database, it's the Tennessee Medicaid database.
The projects that we're doing with the Centers of Excellence, the dosing projects are very similar to the ones that we did in '01. We asked for PK/PD studies in pregnant and lactating women, and we also asked that they collect information on infant outcomes if they're doing the study in pregnant women, and we asked for the elderly.
Now we've funded four projects under that, but I'm just going to talk about the two that are having to do with pregnancy. The first is a PK study on Amoxicillin in pregnant women. This drug is excreted renally, and so we think that dosage adjustment may be needed in pregnancy.
The second contract is actually quite interesting because the University of Wisconsin is going to conform a consortium of five different Centers of Excellence in Women's Health, and they needed to form this consortium because in order to get enough women exposed to these drugs while they're pregnant, we couldn't just go to one site. They're not being used because of fetal safety concerns.
So we have a consortium of five different COEs that are going to try and address Ciprofloxacin, Azithromycin, and GENT.
Just one last point, the CDER has recently put a guidance on how to conduct a pregnancy registry. That is on CDER's website, and one of the things that we learned, as we were talking to the women's health community is, while CDER has issued guidances, actually, required pregnancy registries for a number of products, that the women's health community was not aware of this activity.
And just to let you know that a pregnancy registry is a very effective wy of collecting safety information on marketed products, and you enroll pregnant women after they've been exposed to a drug, but before the birth outcome is known so that we can see what is the effect of the drug on fetal outcomes by enrolling women in the registry.
So what our office did is we came up with a pregnancy registry website, and the point of this website is to tell women about registries, explain to them what they are in as simple terms as we could come up with, and then tell them how to participate in registries. And we have provided on the website a list of all of the registries that are currently enrolling women that comport with CDER's guidance. So, if someone is conducting a registry, but it's not conducted the way CDER would like a registry to conduct it, we're not including it on this website.
So that is all I have, so I'll turn it back to Susan.
DR. WOOD: To round all of this up, I think, in talking about the labeling issues, which all of these steps are sort of in process, the labeling changes are still very much in process and will require a lot further input from not only the rest of the Agency and the Department, but also then obviously, you know, input from the practice community and the women's health community about whether the proposed changes are what ultimately will become the rule from FDA.
The research projects, again, are just taken on to sort of break, you know, break through the barriers, the beginning barriers on doing this kind of work. We are very aware that the Agency and the Office of Women's Health or any other parts of the agency are not going to be funding drug-by-drug, study-by-study to collect the information on products both currently on the market, but products coming onto the market, but rather we want to be able to develop a model system, work through what the issues are and what the problems are, and then develop a guidance on how to carry out this research by others, others who have a vested interest in this.
I think there's a real question that if we have products that are out there on the market that we know are being used by pregnant women, and we know that we don't have the information on how to properly dose and treat women with either chronic or acute conditions with medications, there is sort of an ethical question, you know, is it ethical to not do the research.
We have a number of issues that we have to make sure we handle doing studies on pregnant women very carefully, and with the highest scrutiny, and to make sure we're doing it in the safest way possible, but at the same time, we know there are women out there taking drugs every day, and they're pregnant, and they need to be taking them, but we don't have the data to support appropriate clinical care, and if a woman requires an antibiotic, but is underdosed and then needs to take a different product, another course, or a second course of the same product, we're not minimizing risk here, we're actually mistreating both the women and potentially the offspring. So that's sort of our motivation with trying to start this, but it leaves us with remaining questions.
Peggy also talked about the outreach to women themselves, and I think using the web page and by talking about these activities, we're starting that process, but there's a long way to go with a lot of this information. I don't think we want to be telling women too loudly that we really don't have the information on how to treat them, but we do--but I think it does behoove us to start collecting the information and making that information available in a label as soon as we can.
So here are our discussion issues. Did we want to hand out?
DR. MILLER: I did.
DR. WOOD: Okay. Did you hand out the little flyer too? We also have just a summary sheet, which is not exactly up-to-date. The counterterrorism studies are still listed as future activities, but sort of summarizes as a take-home of some of the activities that both we and CDER are doing in the area of pregnancy.
But these are our discussion issues for the Board, which is given the complexity of this problem, how should we prioritize this effort, in terms of either identifying products to study, focusing in different methodologies and so on.
How should we encourage others to take up this research on pregnant women to help, again, break down those barriers and the very natural hesitancy to take on this work?
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