Preclinical research
Please refer to the nonclinical research section of pregnancy and lactation research toolkit for an overview of nonclinical testing of novel compounds, including both nonclinical and developmental and reproductive toxicity (DART) studies that together aim to generate data on a drug’s pharmacological activity, pharmacokinetic and pharmacodynamic properties, and potential safety concerns.
Further, during the WHO TB and pregnancy consensus process, the preclinical working group proposed that DART studies be initiated as soon as the range of human exposures is available from phase 1 or early phase 2 trials, to support the early and optimal inclusion of pregnant and lactating women in pre-licensure TB treatment and vaccine clinical trials.
The group acknowledged that there is a need for:
- a risk tolerance framework addressing all stages of pregnancy and lactation that defines what constitutes a concerning or alarming safety signal in the context of a life-threatening disease such as TB;
- and effective tools that communicate DART findings and clinical mitigation strategies to key interest holders to facilitate this process.
Nonclinical considerations
A number of nonclinical considerations can support the enrolment of pregnant and lactating women in TB treatment and prevention trials; these include:
- For existing drugs, publicly available data regarding nonclinical DART findings included on drug labels can be reviewed on the links provided below:
- DailyMed – Download All Drug Labels from the US National Library of Medicine: DailyMed - Download All Drug Labels
- Drugs@FDA – FDA-Approved Drugs: Drugs@FDA: FDA-Approved Drugs
- European Medicines Agency – Summary of Product Characteristics (SmPC) for healthcare professionals; Patient Information Leaflet (PIL) for patients: How to find product information on EMA website - MyMedPharm.Info
- For investigational products, researchers should consider early discussion with the product developer and trial sponsor(s) regarding the desire to include pregnant and/or lactating women in clinical trials and to request early completion of DART studies.
- Identify a framework to review nonclinical DART findings and any available clinical data to consider relevance to human pregnancy, establish risk versus benefit assessment for trial participation, and ensure that participation of pregnant and/or lactating women is performed with the highest ethical standards and community input.
Many existing and investigational medications used to treat TB during pregnancy have complex developmental and reproductive toxicology profiles with DART toxicities reported (1). The impact of TB treatment drugs and regimens on maternal, pregnancy and infant outcomes has not been systematically studied in clinical trials or surveillance studies. Multi-stakeholder engagement will be needed to evaluate nonclinical DART findings and available clinical data in non-pregnant women to determine whether enrolment of pregnant and/or lactating women, and reconsent of women who become pregnant during trials should be recommended. - Additional key considerations
- Assess the risks and benefits of including pregnant and lactating women separately. Each group has their own unique circumstances and lumping them together may unfairly restrict their participation in TB drug and vaccine trials.
- For inclusion of lactating women, consider if the lactating mother will be breastfeeding their infant(s) and, if so, also consider the risk versus benefit profile from the pre- and postnatal development studies and juvenile animal toxicology studies.
- Consider timeframe of pregnancy: enrolment of pregnant women in the 2nd or 3rd trimester directly into a study versus allowing women who become pregnant to reconsent to remain on a study both have unique risk considerations.
- Consider risk-benefit balance in relation to trial objectives – for example, this balance may differ for treatment versus prevention trials.
These data should be reviewed in light of the approved indication and associated duration of treatment for that drug compared against the intended use and duration for TB treatment or prevention.
Below, we present the case study of ASTERoiD / TB Trials Consortium (TBTC) Study 37 as an example of a TB‑specific trial that successfully obtained an Investigational New Drug (IND) authorization from the U.S. Food and Drug Administration (FDA) to include pregnant women in the trial, despite concerning preclinical data for rifapentine.
CASE STUDY: ASTERoiD / TBTC Study 37
Example: Staged approach to enrolment of pregnant women in a phase 3 trial
Status (as of January 2026): Primary study enrolling; sub-study not yet enrolling.
Overview
ASTERoiD / TBTC Study 37 is an open-label, multicentre, phase 3 randomized controlled non-inferiority trial comparing the safety and effectiveness of a 6-week regimen of daily rifapentine (6wP) against the current standard of 12–16 weeks of rifamycin-based treatment for TB infection (i.e. 4R, 3HP, 3HR).
Through a staged approach to inclusion, the study team aims to ensure that, if proven safe and effective, 6wP will be accessible to all—including children, pregnant women, and people living with HIV who are taking dolutegravir. A preliminary pharmacokinetic (PK) sub-study will be conducted at designated sites to confirm rifapentine dosing in children under 12 years, pregnant women, and people living with HIV. If PK and early safety data are acceptable, the main study will open enrolment to pregnant women and children under 12 years, enabling generation of full safety and efficacy data. If successful, this trial could transform TB prevention for pregnant women worldwide.
It feels terrible not to know what to offer a pregnant woman who urgently needs protection from TB. We wanted to help change that.
Study Design
Eligibility: Inclusion will be restricted to women in their second and third trimesters. The study team felt that this approach optimizes the risk–benefit balance for mother and fetus, given the lack of safety data on rifapentine exposure in the first trimester and the higher risk of TB later in pregnancy and in the postpartum period. Breastfeeding women will not be enrolled due to resource limitations, though this may be reconsidered in future.
Enrolment target: The sub-study will continue until 20 pregnant women and 30 children under 12 years have been enrolled in the 6wP arm. Following review of initial PK and safety data by the study team and the Data and Safety Monitoring Board, Study 37 will open to pregnant women and children under 12 years at activated sites.
Contraception and incident pregnancies: Contraception will be required for (non-pregnant) women who enrol in the primary study. Women who become pregnant during the study will not be permitted to remain enrolled due to concerns about first-trimester exposure to rifapentine.
Consent: Pregnancy-specific consent forms have been developed and will be administered.
Follow-up: Pregnant women will be followed for at least 3 months postpartum, and infant growth and development will be monitored for at least 1 year. Outcomes will be collected via medical records, facility delivery records, or direct participant report.
Study Development
Funder and regulator support: The primary study is funded by the Centers for Disease Control and Prevention (CDC), and the PK sub-study by the National Institutes of Health of the United States of America (NIH). After CDC approval, the team requested a Type D meeting with the FDA to discuss the rationale for the staged approach and broadened inclusion criteria, including pregnant women in their second and third trimesters. Type D meetings are a specific type of FDA meeting that investigators can request to have with the FDA, which allow for relatively quick agency feedback on specialized topics. Following this meeting, the FDA requested several changes. After additional discussion, some requests were implemented (e.g. updating consent forms to include more detail on fetal risk and potential for maternal haemorrhage), while others were not (e.g. requiring coagulation laboratory tests for mothers and infants).
Regulators value it when you seek and incorporate their input. Type D meetings are especially useful—they give investigative teams the chance to ask questions and guide the discussion.
Community engagement: The Community Research Advisory Group (CRAG) of the TBTC championed inclusion of pregnant women and provided a letter of support to NIH to secure sub-study funding. Members of CRAG TB also serve on the sub-study protocol team.
Ethics approval: No issues arose at the CDC level; site-level reviews are ongoing.
Insurance: The team anticipates a modest increase in trial insurance costs, which has not been a barrier.
Site readiness and recruitment: The team met with each site individually to discuss the PK sub-study and the imperative for inclusion of pregnant women. Initial reticence—due to limited experience with recruiting these populations into studies —was addressed by ensuring compensation commensurate with the work that will be required and simplifying PK sampling protocols. Sites responded positively to the family-centred approach, which allows all family members to enrol on the same TB preventive treatment regimen.
Results
Results from ASTERoiD are anticipated in 2029.
Lessons Learned
Staged inclusion is a creative solution when safety and PK data are limited or lacking: A phased approach reassured regulators, funders, and sites, and prioritized the safety of pregnant participants and their fetuses at the same time.
Early engagement with regulators matters: Proactive dialogue with the FDA clarified safety expectations and streamlined protocol development.
Site readiness requires practical solutions: Adequate compensation and simplified PK protocols helped overcome initial hesitancy and logistical challenges with regards to the recruitment of pregnant women into the study.
Resources
ClinicalTrials.gov – online database of clinical research studies and results: https://clinicaltrials.gov/study/NCT03474029
Nonclinical research resources to support enrolment of pregnant and/or lactating women in TB drug and vaccine trials
Reference
- Management of drug-resistant tuberculosis in special sub-populations including those with HIV co-infection, pregnancy, diabetes, organ-specific dysfunction, and in the critically ill. J Thorac Dis. 2018;10(5):3102–18. Esmail A, Sabur NF, Okpechi I, Dheda K.