Protocol development

The inclusion of pregnant and lactating women should be integrated into drug development plans from the earliest stages. It is imperative that clinical trials of any new investigational product include pregnant and lactating women simultaneously to the broader population. Physiologically based PK modelling may be employed to inform dose selection. Pregnant and lactating women should be included in clinical studies only after preclinical data have been evaluated. The assessment should indicate no evidence of unacceptable risks and provide reasonable assurances of safety at clinically relevant exposures to both the woman and her fetus or infant. This requirement applies to both new medicines and to marketed medicines for which pregnancy-specific indication is sought.

Pregnant women must be included in a study at the appropriate time in their gestation, as the timing of drug exposure, particularly by trimester, is crucial for interpreting outcomes. Careful study design is therefore necessary to balance maximizing the potential efficacy with minimizing the risks to both mother and fetus.

For new medicines likely to be used during pregnancy and the breastfeeding period, safety and efficacy data in pregnant and lactating populations are critical for first-time regulatory approval, with trial sample sizes large enough to reliably detect treatment effects in these populations. However, exceptions exist, such as for life-threatening scenarios in which no alternative medication is available.

When developing a clinical trial protocol for a medicine likely to be used during pregnancy and the breastfeeding period, the following steps should be followed:

• A benefit–risk assessment using a weight-of-evidence approach should proactively be undertaken for all studies to determine whether the risks of conducting trials in pregnancy and during the breastfeeding period are reasonable in light of the anticipated benefits. If the cumulative potential benefit is deemed to outweigh the risk, the trial should proceed.
• Even if potential risks to the woman and/or her fetus or infant are identified, studies may:
  • initially exclude this population and reconsider when further safety data is available;
  • still include the population if the impact of the disease is severe (e.g., malaria) compared to the deemed risk and/or if alternative treatments are riskier.
• If pregnant and lactating women are excluded, a detailed scientific rationale for excluding them should be provided based on the benefit–risk assessment.
• If available, data on the safety and effectiveness of the medicine in the wider population, including women of reproductive age, should be detailed in the background of the protocol.
• Multi-stakeholder expertise should be sought, including from subject matter experts, ethicists, clinicians, regulators, sponsors/marketing authorization holders and pregnant women, mothers, and patient advocates.
• Templated protocols may increase efficiency and encourage proactive inclusion of pregnant and lactating women. Such templates, however, do not yet exist but would be invaluable to ensure efficiencies in this process.