Regulatory and HTA Considerations for Development of Real-World Data Derived External Controls.

Regulators and Health Technology Assessment (HTA) bodies are increasingly familiar with, and publishing guidance on, external controls derived from real-world data (RWD) to generate real-world evidence (RWE). We recently conducted a systematic literature review (SLR) evaluating publicly available information on the use of RWD-derived external controls to contextualize outcomes from uncontrolled trials submitted to the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and/or select HTA bodies. The review identified several key operational and methodological aspects for which more detailed guidance and alignment within and between regulatory agencies and HTA bodies is necessary. This paper builds on the SLR findings by delineating a set of key takeaways for the responsible generation of fit-for-purpose RWE. Practical methodological and operational guidelines for designing, conducting, and reporting RWD-derived external control studies are explored and discussed. These considerations include: (i) early engagement with regulators and HTA bodies during the study planning phase; (ii) consideration of the appropriateness and comparability of external controls across multiple dimensions, including eligibility criteria, temporality, population representation, and clinical evaluation; (iii) ensuring adequate sample sizes, including hypothesis testing considerations; (iv) implementation of a clear and transparent strategy for assessing and addressing data quality, including data missingness across trials and RWD; (v) selection of comparable and meaningful endpoints that are operationalized and analyzed using appropriate analytic methods; and (vi) conduct of sensitivity analyses to assess the robustness of findings in the context of uncertainty and sources of potential bias.

Effectively Leveraging RWD for External Controls: A Systematic Literature Review of Regulatory and HTA Decisions.

Real-world data (RWD)-derived external controls can be used to contextualize efficacy findings for investigational therapies evaluated in uncontrolled trials. As the number of submissions to regulatory and health technology assessment (HTA) bodies using external controls rises, and in light of recent regulatory and HTA guidance on the appropriate use of RWD, there is a need to address the operational and methodological challenges impeding the quality of real-world evidence (RWE) generation and the consistency in evaluation of RWE across agencies. This systematic review summarizes publicly available information on the use of external controls to contextualize outcomes from uncontrolled trials for all indications from January 1, 2015, through August 20, 2021, that were submitted to the European Medicines Agency, the US Food and Drug Administration, and/or select major HTA bodies (National Institute for Health and Care Excellence (NICE), Haute Autorité de Santé (HAS), Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), and Gemeinsamer Bundesausschuss (G-BA)). By systematically reviewing submissions to regulatory and HTA bodies in the context of recent guidance, this study provides quantitative and qualitative insights into how external control design and analytic choices may be viewed by different agencies in practice. The primary operational and methodological aspects identified for discussion include, but are not limited to, engagement of regulators and HTA bodies, approaches to handling missing data (a component of data quality), and selection of real-world endpoints. Continued collaboration and guidance to address these and other aspects will inform and assist stakeholders attempting to generate evidence using external controls.

Reduced risk of infections with the intravenous immunoglobulin, IgPro10, in patients at risk of secondary immunodeficiency-related infections.

Aim: Patients with secondary immunodeficiency (SID) are at increased risk of infections and may be treated with immunoglobulin replacement therapy (IgRT). Despite growing efficacy evidence for IgRT in infection prevention in SID, treatment guidelines are not aligned. Materials & methods: A retrospective database analysis was conducted to assess treatment patterns and infection rates in patients at risk of SID-related infections, with or without IgRT (IgPro10) exposure, to evaluate real-world effectiveness of IgRT in infection prevention. Results: Of 11,448 patients included, 222 received IgPro10. B-cell malignancies and solid organ transplants were the predominant underlying conditions. Despite being sicker at baseline, the IgPro10 cohort demonstrated fewer infections post-index than the non-IgRT cohort. Conclusion: IgPro10 may be an effective option for infection prevention in SID.

Secondary immunodeficiency (SID) occurs when the immune system is weakened by external factors, including certain medical treatments. It can leave a person with an increased risk of potentially serious or even fatal infections, as they no longer have adequate defenses against bacteria. Some patients with this condition require treatment to boost their immune system, including supplementation of their antibodies, known as immunoglobulin replacement therapy (IgRT). In this study, we explored whether: (1) patients with conditions that are at risk of SID and associated infections received IgRT; and (2) whether receiving the IgRT reduced the incidence of infections. We found that patients who had IgRT were much less likely to experience infections than those who did not receive IgRT, suggesting that IgRT may be an effective treatment option for preventing infections in patients with compromised immune systems caused by SID.

Identifying the link between chemical exposures and breast cancer in African American women via integrated in vitro and exposure biomarker data.

Among women, breast cancer is the most prevalent form of cancer worldwide and has the second highest mortality rate of any cancer in the United States. The breast cancer related death rate is 40 % higher in non-Hispanic Black women compared to non-Hispanic White women. The incidence of triple negative breast cancer (TNBC), an aggressive subtype of breast cancer for which there is no targeted therapy, is also approximately three times higher for Black, relative to, White women. The drivers of these differences are poorly understood. Here, we aimed to identify chemical exposures which play a role in breast cancer disparities. Using chemical biomonitoring data from the National Health and Nutrition Examination Survey (NHANES) and biological activity data from the EPA's ToxCast program, we assessed the toxicological profiles of chemicals to which US Black women are disproportionately exposed. We conducted a literature search to identify breast cancer targets in ToxCast to analyze the response of chemicals with exposure disparities in these assays. Forty-three chemical biomarkers are significantly higher in Black women. Investigation of these chemicals in ToxCast resulted in 32,683 assays for analysis, 5172 of which contained nonzero values for the concentration at which the dose-response fitted model reaches the cutoff considered "active". Of these chemicals BPA, PFOS, and thiram are most comprehensively assayed. 2,5-dichlorophenol, 1,4-dichlorobenzene, and methyl and propyl parabens had higher biomarker concentrations in Black women and moderate testing and activity in ToxCast. The distribution of active concentrations for these chemicals in ToxCast assays are comparable to biomarker concentrations in Black women NHANES participants. Through this integrated analysis, we identify that multiple chemicals, including thiram, propylparaben, and p,p' DDE, have disproportionate exposures in Black women and have breast cancer associated biological activity at human exposure relevant doses.

A comprehensive analysis of racial disparities in chemical biomarker concentrations in United States women, 1999-2014.

BACKGROUND: Stark racial disparities in disease incidence among American women remain a persistent public health challenge. These disparities likely result from complex interactions between genetic, social, lifestyle, and environmental risk factors. The influence of environmental risk factors, such as chemical exposure, however, may be substantial and is poorly understood. OBJECTIVES: We quantitatively evaluated chemical-exposure disparities by race/ethnicity, life stage, and time in United States (US) women (n = 38,080) by using biomarker data for 143 chemicals from the National Health and Nutrition Examination Survey (NHANES) 1999-2014. METHODS: We applied a series of survey-weighted, generalized linear models using data from the entire NHANES women population along with cycle and age-group stratified subpopulations. The outcome was chemical biomarker concentration, and the main predictor was race/ethnicity with adjustment for age, socioeconomic status, smoking habits, and NHANES cycle. RESULTS: Compared to non-Hispanic White women, the highest disparities were observed for non-Hispanic Black, Mexican American, Other Hispanic, and Other Race/Multi-Racial women with higher levels of pesticides and their metabolites, including 2,5-dichlorophenol, o,p'-DDE, beta-hexachlorocyclohexane, and 2,4-dichlorophenol, along with personal care and consumer product compounds, including parabens and monoethyl phthalate, as well as several metals, such as mercury and arsenic. Moreover, for Mexican American, Other Hispanic, and non-Hispanic black women, there were several exposure disparities that persisted across age groups, such as higher 2,4- and 2,5-dichlorophenol concentrations. Exposure levels for methyl and propyl parabens, however, were the highest in non-Hispanic black compared to non-Hispanic white children with average differences exceeding 4-fold. Exposure disparities for methyl and propyl parabens are increasing over time in Other Race/Multi-Racial women while fluctuating for non-Hispanic Black, Mexican American, and Other Hispanic. Cotinine levels are among the highest in Non-Hispanic White women compared to Mexican American and Other Hispanic women with disparities plateauing and increasing, respectively. DISCUSSION: We systematically evaluated differences in chemical exposures across women of various race/ethnic groups and across age groups and time. Our findings could help inform chemical prioritization in designing epidemiological and toxicological studies. In addition, they could help guide public health interventions to reduce environmental and health disparities across populations.