Inclusion of key populations in clinical trials of new antituberculosis treatments: Current barriers and recommendations for pregnant and lactating women, children, and HIV-infected persons
Citation: Gupta A, Hughes MD, Garcia-Prats AJ, McIntire K, Hesseling AC. Inclusion of key populations in clinical trials of new antituberculosis treatments: Current barriers and recommendations for pregnant and lactating women, children, and HIV-infected persons. PLoS Med. 2019 Aug 15;16(8): e1002882. https://doi.org/10.1371/journal.pmed.1002882. PMID: 31415563 PMCID: PMC6695091.
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- Pregnant women, children < 15 years old and, HIV-infected persons contribute approximately 20% of the global tuberculosis (TB) burden, with an estimated 216,000, 1,000,000, and 1,040,000 cases each year, respectively, yet these populations are currently largely excluded from TB clinical trials, leading to suboptimal treatment and poor access to new therapeutics.
- Special considerations in these populations include specific TB disease spectrum and severity, lower sensitivity of commonly used TB diagnostic tests, potential differential drug dosing and treatment responses, drug–drug interactions, and challenges in acquiring high-quality data through clinical trials.
- To counter the automatic exclusion of pregnant and lactating women that currently pervades the TB trial landscape, early discussions among trialists, pharmaceutical companies, maternal–child clinical experts, ethicists, and regulatory bodies are needed to address risks, benefits, and compelling rationale for inclusion. Reconsenting women when pregnancy occurs on a trial to allow continuation of study drug by informed choice is a practical and valuable approach to expand the currently limited evidence base.
- Children tend to have less severe, often paucibacillary TB disease and may respond better to treatment than adults. Consequently, trials of shorter, less intense TB treatment regimens in children are needed; pharmacokinetic and safety studies should be initiated earlier and involve age groups in parallel rather than in an age-de-escalation approach. More rapid development of child-friendly drug formulations is needed.
- All HIV-infected populations, including those with advanced disease, who are likely to be the intended population of the TB therapy, should be involved in Phase IIb and/or Phase III trials, as appropriate, to maximize knowledge of treatment, toxicities, drug–drug interactions, and outcomes.