Center for Drug Evaluation and Research

Claims-based analyses can suffer from residual and unmeasured confounding due to factors that are poorly captured in claims. Some of these factors may be measured in other data sources, such as in structured fields of electronic health records (EHR), for example, laboratory test results, or in free-text physician notes. We conducted a proof-of-principle study to demonstrate a process for evaluating the potential risk of confounding-factors poorly captured in claims data but measurable in the EHR as part of drug safety surveillance activities. In future practical applications, this approach could be used along with other sensitivity analyses to evaluate potential residual confounding (e.g., E-values, negative controls). We used claims-EHR linked data from the Mass General Brigham site of the US Food and Drug Administration's (FDA) Sentinel Real World Evidence Data Enterprise. We extracted a cohort that was previously used in a prototypical Sentinel claims-based query that compared initiators of sacubitril-valsartan vs. angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on the risk of angioedema. In this cohort, we used EHR data to characterize angioedema risk factors poorly captured in claims and observed that claims-based proxies balanced most risk factors that were measurable only in EHR data. While quantitative bias analysis methods can be used to adjust for residual confounding using external information on magnitude and direction of bias, this was deemed unnecessary for this example due to the observed balance achieved on risk factors for angioedema measured in the EHR. A robust linked EHR-claims data infrastructure is crucial for routine application of these methods to evaluate and mitigate residual confounding in drug safety surveillance studies.

Challenges to medication administration arise in children when pediatric-friendly (PF) formulations are lacking. This study examines the extent to which PF formulations were developed for use in pediatric trials of drugs awarded 6-months of patent extension under a written request (WR). Publicly accessible and proprietary data were aggregated to characterize the formulations used in studies submitted to the U.S. FDA in support of pediatric labeling for WRs issued through September 2025. From 1998-2025, exclusivity was awarded to 321 unique sponsor:drug pairs satisfying the requirements of a WR. A majority, (235/321), received a new or updated pediatric indication and nearly all (310/321) resulted in pediatric labeling. Drugs intended for oral administration (n = 213) were supported by 304 studies. The majority (173/304) exclusively studied adult solid dosage forms (SDF), a minority (129/304) used at least one PF dosage form, and 2 accomplished labeling without the conduct of clinical trials. SDF were exclusively used in 26.3%, 44.9%, 85.1%, and 94.1% of studies in children < 2yr, 2-5yr, 6-12yr and > 12yr, respectively. Of trials employing an oral PF formulation, 85% were associated with a marketed PF product at labeling. Marketed oral PF formulations were also associated with 8% of cases where studies relied exclusively on a s SDF. Nearly all non-enteral drug studies were supported by existing commercial formulations with only investigational inhalation formulations making their way to market. Legislative provisions enacted to incentivize pediatric drug development incompletely extend to pediatric reformulation efforts despite the associated financial gains.

The constituents of tobacco smoke that specifically contribute to lung cancer risk have yet to be fully identified. We evaluated associations between biomarkers of potentially harmful constituents-polycyclic aromatic hydrocarbons (PAHs), tobacco-specific nitrosamines (TSNAs), nicotine, and volatile organic compounds (VOCs)-and lung cancer incidence among US women. In a case-cohort study nested within the Sister Study (women aged 35 to 74 years at baseline, enrolled 2003 to 2009), data were obtained for a random subcohort and all remaining incident lung cancers through September 2017 (median follow-up 9.6 years), stratified by race and ethnicity (Hispanic, non-Hispanic Black, non-Hispanic White, others) and smoking status (current, former, never). The analytic sample included 356 cases and 433 non-cases. We quantified 30 biomarkers in baseline urine samples and calculated hazard ratios (HRs) for associations between one-unit increase in biomarker concentrations (log-scale) and lung cancer incidence using weighted Cox regression models adjusted for urinary creatinine and demographic, health, and lifestyle factors. Among women who were currently smoking at enrolment, positive associations were observed for biomarkers of PAHs (naphthalene, phenanthrene, pyrene, fluorene; HRs 1.4 to 5.3), TSNAs (particularly 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); HRs : 1.3-2.2), and VOCs (xylene, acrylamide, acrylonitrile, 1,2-dibromoethane/vinyl-chloride/ethylene-oxide/acrylonitrile, acrolein, styrene/ethylbenzene, benzene, dimethylformamide/methylisocyanate, 1,3-butadiene, crotonaldehyde, isoprene; HRs : 1.6-4.4). Associations with biomarkers of most PAHs, NNK, xylene, and dimethylformamide/methylisocyanate remained after additional adjustment for smoking frequency, duration, and nicotine metabolites. In women who did not smoke, positive associations were observed for styrene/ethylbenzene and dimethylformamide/methylisocyanate biomarkers. Exposure to PAHs, TSNAs and several VOCs through tobacco smoking were associated with increased lung cancer risk among women.

Liquid chromatography-mass spectrometry (LC-MS) is the standard instrumental procedure for quantitating nitrosamine drug substance-related impurities (NDSRIs) due to its superior specificity and sensitivity. Electrospray (ESI) is the most used ionization source in LC-MS. However, analytes can undergo fragmentation directly within the ESI source before reaching the collision cell. This phenomenon is known as in source fragmentation (ISF). To our knowledge, the impact of ISF on analytical procedure performance for NDSRI measurements has not been explored. Thus, here, we present a case study on an NDSRI (nitroso-bumetanide) to illustrate how efforts can be taken during analytical procedure development to minimize ISF while still achieving the analytical target profile (ATP) measurement goals. In addition, we share some thoughts about incorporating risk assessment and leveraging prior knowledge for analytical procedure development for NDSRI LC-MS technology-based testing purposes.

Information from electronic health records (EHRs) may be incorporated into computable phenotype algorithms in efforts to overcome inaccuracies of algorithms based on administrative claims data alone. However, such efforts can be resource-intensive and unsuccessful. Assessing the feasibility of computable phenotyping for a health outcome of interest (HOI) before proceeding is therefore recommended. We developed a systematic fitness-for-purpose (FFP) assessment process to implement concepts outlined in a previously described general framework for computable phenotyping incorporating EHR data. Our process includes verifying the HOI is well-defined, reviewing clinical information about the HOI, identifying existing algorithms and their performance, evaluating HOI clinical and data complexity, and determining an overall FFP conclusion and recommendation. We applied this process to 10 HOIs lacking high-performing claims-based algorithms, selecting HOIs of public health importance that varied in clinical and data complexity, including neutropenia, pericardial effusion, and drug-induced liver injury. HOIs assessed as having moderate (vs. easy) overall difficulty had characteristics such as the need for natural language processing, integration of multiple laboratory test results, or longitudinal EHR data. HOIs assessed as having high difficulty required using data from multiple EHR sources, ruling out many other potential causes, or relying on low-sensitivity diagnostic tests. Input from experts in EHR data and clinical care was crucial. EHR data have the potential to enhance the accuracy of defining certain HOIs for research and surveillance compared to administrative claims data. The process and tools we created will support others in assessing FFP of HOIs for computable phenotyping.

Effective drug delivery through the female reproductive tract (FRT) presents unique challenges due to the lack of robust predictive models for drug exposure via this route. Addressing this gap, we developed and evaluated a comprehensive whole-body physiologically based pharmacokinetic (PBPK) model that incorporates anatomical and physiological information of the FRT. This model was calibrated using both published and experimental data for the drug levonorgestrel (LNG), administered via oral, vaginal, and intrauterine routes. The PBPK model simulates drug absorption, distribution, and elimination, providing predictions of local tissue concentrations and systemic exposure. The majority of observations can be contained within or overlaid with the simulated profiles. Noteworthy is the model's capability to predict the pharmacokinetics of LNG with reasonable precision across different administration routes, thereby demonstrating its potential utility in supporting drug development and regulatory decisions. The application of this model allows for exploration of drug formulations and dosing regimens, reducing the reliance on extensive clinical trials. Furthermore, the model may potentially be used to facilitate generic drug development, and thus promote generic competition, for drug products that are important in women's health. By bridging critical knowledge gaps, this model facilitates in silico evaluation of drugs administered through the FRT, potentially fostering advancements in therapeutic strategies and patient care.

Abstract Background Anti–tumor necrosis factor (anti-TNF), particularly infliximab, have transformed inflammatory bowel disease (IBD) management, but their high cost imposes a significant economic burden. Infliximab biosimilars were introduced to reduce the unmet needs. Despite the approval of infliximab biosimilars, real-world evidence of cardiovascular safety and effectiveness of infliximab biosimilars is lacking among patients with IBD. In this trial emulation, we compared the effectiveness and cardiovascular safety between patients who initiated infliximab reference product (IFX-RP) and biosimilars (IFX-BP). Methods Using the Merative Marketscan Research database (2011–2023), we conducted a retrospective cohort study to emulate the target trial where biologic-naïve adults were randomly assigned to initiate IFX-RP or IFX-BP. Primary outcomes included healthcare resource utilization (HRU), and incidence of major adverse cardiovascular events (MACE) over one year. Propensity score matching was applied to mimic the randomization. Both intention-to-treat and per-protocol effects were estimated. Results After matching, 850 patients (425 per group) were included. HRU was comparable between IFX-RP and IFX-BP groups across outpatient visits, hospitalizations, surgeries, and emergency visit. During follow-up, MACE events were more frequent in the IFX-BP group (9 vs. 3), with an incidence rate ratio (IRR) of 3.04 (95% CI: 0.82–11.23). Although the difference was not statistically significant, consistent directional trends were observed across analyses. Sensitivity analyses supported primary results. Conclusion Our study found comparable effectiveness between IFX-RP and IFX-BP in routine clinical care. While cardiovascular events were infrequent, the potential signal suggesting increased MACE risk associated with infliximab biosimilars warrants further investigation. Continued pharmacovigilance is essential to ensure the cardiovascular safety of biosimilars. Summary Infliximab biosimilars, introduced to reduce the economic burden of anti-TNF therapy in IBD, demonstrated comparable real-world effectiveness to the infliximab reference product in a target trial emulation using Merative MarketScan data, while a potential signal of increased cardiovascular risk underscores the need for ongoing pharmacovigilance and further investigation. Key Messages What is known? Infliximab biosimilars demonstrate comparable efficacy and safety to the reference product in IBD, but cardiovascular outcomes remain underexplored. What is new here? This U.S. real-world study emulating a target trial found similar effectiveness between infliximab reference and biosimilar products, with a possible trend toward increased cardiovascular risk in biosimilar users. How can this study help patient care? Findings highlight the need for continued pharmacovigilance and cardiovascular monitoring when prescribing infliximab biosimilars to optimize safety in IBD management.

Cutaneous lupus erythematosus (CLE) is an autoimmune skin condition associated with a considerable treatment burden and diminished quality of life. The absence of a consensus outcome measure to evaluate therapeutic response has posed a challenge to CLE drug development. The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) was developed in response to this need, incorporating morphological components including erythema, scale, dyspigmentation and scarring, to reflect disease activity and damage. Numerous studies have demonstrated the utility of CLASI in capturing relevant aspects of disease from clinician- and patient-based perspectives; however, no regulatory precedent for use of clinical trial data employing CLASI to evaluate treatment response in CLE exists. Thus, the Lupus Accelerating Breakthroughs Consortium commissioned a working group of members from industry, academia, the US Food and Drug Administration (FDA) and CLE patient advocates to address the potential knowledge gaps with CLASI through evidence-based research. Upon reviewing and submitting these data to the FDA, the working group reached alignment that CLASI is a suitable outcome measure for CLE clinical trials, enabling a clearer regulatory path for clinical drug development. The group recognizes the need for additional information to assess what degree of change in CLASI captures clinically meaningful improvement.