Content last updated on July 15, 2020
Drugs can impact women differently than men; these differences become even more evident when a woman is pregnant and can significantly impact women’s health. Most clinical studies involving pharmacokinetic (PK) assessments exclude pregnant women to protect the mother and fetus from unknown effects of an investigational drug. It is very common to see warnings in pharmaceutical company advertisements and drug product labels advising pregnant women or women who may become pregnant against taking many drugs.
The reasons for these exclusions are not based on evidence but rather lack thereof. Historically, when it comes to taking medications during pregnancy or nursing there has been an extremely cautious approach. The origin of this caution stems from the disastrous effects of thalidomide leading to tens of thousands of birth defects in the 1950s through the early 1960s causing women to be routinely excluded from clinical trials.
Furthermore, if a study participant becomes pregnant during a clinical trial, the common practice is to immediately halt administration of study drug and discontinue her from the study, with ongoing monitoring of safety outcomes and developmental complications through the end of pregnancy.
The Importance of Pregnant Women in Clinical Studies
Considering that, in the U.S., there are 64 million women of child-bearing age (15-44) and close to 4 million births per year, some pregnant women must take drugs to manage or treat their medical conditions. Research from the Centers for Disease Control (CDC) shows that taking medicines is common during pregnancy and that the frequency of taking medications is increased over time with maternal age. About 9 in 10 women take at least one over the counter medication during pregnancy, and about 7 in 10 women take at least one prescription medication during pregnancy. Based on a self-reported survey published in 2013, mothers during their first trimester reported taking 31 different types of prescription drugs and 23 different types of over-the-counter drugs. Among these 54 medications, only two had good data available to assess risks related to birth defects in humans.
Historically, information on drug use during pregnancy is only collected in the post-marketing phase and never during clinical development prior to approval except for drugs developed to treat pregnancy related conditions (e.g. oxytocin). However, this approach can be problematic once these products are on the market. Recommended dosing is almost always based upon PK studies in nonpregnant individuals, and the risks posed to pregnant women who may take the drug are not well-established.
Labeling information in pregnant populations is often based on nonclinical data with limited or no safety data in pregnant women, causing reluctance for many health care providers to treat diseases in this population. In some cases, the result of not treating the disease may bring more harm to the woman and fetus by not taking the medication they need. In some cases, pregnant women have no option other than to use the required medication without clear scientific rationale on risk vs. benefit to themself or to their fetus.
The draft guidance issued by FDA, “Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials,” provides a frame-work to encourage clinical studies in pregnant women when appropriate and in certain settings. Including pregnant women in clinical research is described as scientifically complex because maternal and fetal risks are deeply linked. There are numerous pregnancy-related physiological changes that are known to impact drug exposure due to alterations in drug absorption, distribution, metabolism and excretion (ADME) processes. Other physiological changes that occur during pregnancy that can impact drug exposure include:
- Decreased gastrointestinal motility, altered gastric emptying, and increased gastric pH
- Increased body water, plasma volume, glomerular filtration rate, and blood flow to organs (e.g. kidney, uterus)
- Decreased concentration of drug-binding proteins in the blood
- Changes in drug metabolizing enzyme activity in the liver
PK Assessments in Pregnant Women
The goal of a PK assessment in pregnant women should be to determine if drug doses need to be adjusted during pregnancy and to make recommendations for those adjustments based on gestation or trimester. Any dose adjustments (or lack thereof) should be reflected in the product label (i.e., the package insert).
The FDA guidance for Industry, “Pharmacokinetics in Pregnancy – Study Design, Data Analysis, and Impact on Dosing and Labeling,” recommends that PK studies be conducted if the drug is prescribed (or is expected to be prescribed) during pregnancy, especially during the second or third trimester. PK studies should also be conducted if changes in the dose can have a substantial impact on the patient, and if the PK characteristics of the drug are likely to be significantly changed.
Examples of drugs that are of particular concern include those with narrow therapeutic ranges (such as many oncology drugs) or those that are predominately renally excreted. This recommendation applies whether the drugs are intended for acute symptom relief or for chronic use. However, careful consideration must be given to the potential safety implications of drug administration in pregnant women. The key is to minimize risk. By statute (45 CFR Subpart B 46.204), pregnant women may be involved in PK studies if:
- There are already sufficient data from preclinical studies and clinical studies (including nonpregnant women) to assess potential risk to pregnant women and fetuses
- If the potential risk is minimal and the purpose of the research is to gather important information that cannot be otherwise obtained
Study Design Recommendations
An IND is required if a dedicated study in pregnant women is planned for any approved product if there is a concern for increasing risk, change in route of administration, or dose level. If clinical studies are performed, the FDA recommends one of the following study designs:
- Longitudinal Design. A longitudinal design would be the most applicable for a chronically administered drug, such as an HIV medication. The FDA recommends that each woman serve as her own control for PK parameters and that samples be taken at specified time points (“windows”) in each trimester.
- Population PK Design. A population PK (popPK) approach with nonlinear mixed effects modeling can be used to assess the impact of various covariates on PK, such as age, race, trimester, etc. This approach allows sparse PK sampling that reduces the number of blood draws required from the pregnant women.
In addition to the two recommended study designs, a number of other aspects of the study design should be considered, including: participants, pre-pregnancy and post-partum assessments, sample size, drug administration, sample collection / analysis, and pharmacodynamic (PD) assessments.
Participants should be representative of the typical patient population. Consideration should be given to intrinsic and extrinsic factors that may impact the PK of the drug (e.g., race, ethnicity, stage of pregnancy, genetic polymorphisms in drug metabolizing enzymes, weight, diet and renal function). The study protocol should include specified metrics for dating the pregnancy as well as uniform diagnostic measures.
Pre-pregnancy and Post-partum Assessments
Depending upon the intended use of a drug, an individual subject may act as her own control. If a drug is to be given chronically, a pre-pregnancy PK/PD assessment can serve as an appropriate comparator to the pregnant state. For drugs that are administered both during and after pregnancy, post-partum PK/PD assessments can serve as the control. Consider longitudinal sampling to capture potential PK impacts of a woman’s changing physiology after childbirth (which can include very rapid changes and changes that take much longer).
For certain pregnancy-related medical conditions that resolve rapidly following childbirth, a single-dose PK assessment in the post-partum period may be most appropriate. Safety precautions should be taken to avoid adverse effects on the infant from transfer of drug into the breast milk. If warranted, a lactation study in parallel with post-partum PK sampling might be an appropriate addition to the study design.
The appropriate sample size will depend upon a number of factors, including: study objective, PK/PD variability, study design (e.g., dosing regimen, sampling schedule), and stage of pregnancy. It is prudent to include excess subjects to account for drop-outs.
The amount of drug administered will depend upon the characteristics of the drug, its intended use, the findings of previous PK studies in non-pregnant individuals, and the expected risk to the pregnant woman and fetus. Lower doses may be appropriate in volunteer studies, whereas dose adjustments (higher or lower) may be required when a pregnant woman needs the drug to achieve a particular health outcome. Alternative designs for drug administration may also be appropriate.
Sample Collection and Analysis
Samples should include plasma or whole blood and urine for assessing the concentration of the parent drug and active metabolites. Since plasma protein binding is often reduced during pregnancy, consider calculating unbound drug and metabolites, especially if the extent of plasma protein binding of the drug is high (>80%).
PD endpoints, including relevant biomarkers and potentially even fetal PD endpoints, can be important. Informative study design considerations should be discussed with the FDA prior to study initiation.
When to Conduct Studies in Pregnant Women
PK studies can be considered in Phase 3, prior to submission of a marketing application (i.e., NDA, BLA). Typically, however, most information regarding the use of a drug during pregnancy is gathered during the post-marketing period. This information may be obtained from clinical studies or from real world experiences with the drug (positive and negative). Most often, post-marketing clinical studies in pregnant women will enroll women who have already been prescribed the drug by their own physicians as part of their clinical care.
Information regarding product use during pregnancy should be reported as part of the sponsor’s Periodic Safety Update Report. This report, along with other sources of safety/efficacy information in published literature, can be useful for determining the need for a dedicated PK study in pregnant individuals.
Pregnancy Exposure Registries and Reporting
It is rare to see the product label outline risks for product use during pregnancy go beyond the data available at the time of initial marketing. Historically, the risks of drug use in pregnancy was gathered from spontaneous adverse event reports and have many limitations of controls in data collections.
A prospective observational study that actively collects information on medical product exposure during pregnancy and pregnancy related outcomes, under a Pregnancy Exposure Registry, is a valuable tool to support labeling changes. This type of study should be seriously considered when inadvertent exposure and use of the product during pregnancy is expected. The requirement of this type of study increases when potential risks are indicated by animal reproductive toxicity data, structure activity relationships/pharmacological class, or human case reports.
Women who are pregnant often take prescription and/or over-the-counter medications. However, dosing recommendations almost always rely on PK parameters obtained from non-pregnant individuals, and the impact of pregnancy on drug PK is often unknown. This can pose a significant risk to the mother and fetus, especially given the large number of physiological changes that occur during pregnancy that can impact the PK behavior of a drug. For drugs that are likely to be prescribed or otherwise used during pregnancy, studies in pregnant women may be warranted to inform dosing recommendations and ensure safe use.