Supporting US Food Research Articles

Extrapolation of the Efficacy and Pharmacokinetics of Belimumab to Support its Use in Children with Lupus Nephritis.

Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus, has greater severity in children versus adults. Belimumab is approved for systemic lupus erythematosus treatment in patients aged ≥ 5 years, and for active LN in adults in the European Union, China, Japan and Latin America, and patients aged ≥ 5 years in the USA. Low prevalence of paediatric active LN makes conducting a clinical study within a reasonable period unfeasible. We describe a model-based extrapolation of belimumab efficacy and pharmacokinetics from adults to children with LN to support US Food and Drug Administration approval of intravenous belimumab 10 mg/kg (administered every 4 weeks after the loading dose) in children (aged 5-17 years) with active LN. This concept assumed that disease progression, response to belimumab, exposure-response, and the target belimumab exposure for efficacy are similar across adult and paediatric systemic lupus erythematosus and LN, evaluated against the published literature for paediatric LN and belimumab systemic lupus erythematosus and LN clinical trial data in adults and children. A two-compartmental population pharmacokinetic model, previously developed for adults with LN, was used to extrapolate belimumab pharmacokinetics to children with LN. The model captured the dependence of time-varying proteinuria on belimumab clearance, and therefore exposure. Sufficient target exposures for efficacy were achieved in children with active LN. A small proportion of children aged 5-11 years are predicted to have exposures below adult levels but no impact to efficacy is expected. Our model demonstrated that intravenous belimumab 10 mg/kg every 4 weeks is appropriate for children aged 5-17 years with active LN.

Abstract PO1-11-02: Reporting of Post-protocol Therapies in Metastatic Breast Cancer Registration Clinical Trials: A Systematic Review

Abstract BACKGROUND As the treatment for metastatic breast cancer (MBC) often includes sequential lines of therapy, data on post-protocol treatment in clinical trials are valuable in the assessment of long-term outcome. The objective of this study was to assess the reported data on post-protocol therapy in clinical trials supporting US Food and Drug Administration (FDA) approval of drugs for MBC. METHODS We identified all initial and subsequent published trials supporting FDA approved indications for MBC between 1/2000-2/2023. Collected data included study design, patient characteristics and whether reporting on post-protocol therapy was available. Differences in study design and population between studies with and without data on post-protocol therapy were evaluated. FINDINGS A total of 41 indications for MBC were identified. Supporting studies comprised 20,152 patients. Data were evaluated from 241 publications or abstracts. Reporting of post progression therapy was available for 21 (51%) indications. Of these, post-progression therapy data were often partial and the appropriateness of the therapy could not be evaluated. At the time of FDA approval, data on overall survival (OS) were reported only in 17 (41%) studies. Of these, in 8 studies OS was significantly improved, in 7 studies OS was not improved and 2 studies were single arm. Differences between studies with and without data on post progression therapy are presented in the Table. Studies with OS as their primary endpoints were associated with significantly higher reporting of post-protocol therapy, while studies with both OS and progression free survival (PFS) as their primary endpoint had low reporting rate. There were no other statistically significant differences. Reporting post-protocol therapy has not changed over time with reported data in 50% and 52% studies between 2000-2010 and 2011-2023, respectively. CONCLUSIONS Data on post progression therapy in trials supporting FDA approval of drugs for MBC are available in fewer than half of indications. Reported data are often partial and may not include sequential therapies consistent with standard of care. As subsequent lines of therapy may have a crucial role in patients' outcome, post protocol reporting should be included in the regulatory submission and be made available publicly. Differences between studies with and without data on post progression therapy Citation Format: Shlomit Shachar, Yasmin Korzets, Daniel Shepshelovich, Noa Zlotchover, Eitan Amir, Ariadna Tibau, Hadar Goldvaser. Reporting of Post-protocol Therapies in Metastatic Breast Cancer Registration Clinical Trials: A Systematic Review [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-11-02.

Heterogeneity and Utility of Pharmaceutical Company Sharing of Individual-Participant Data Packages

The pharmaceutical industry has made substantial investments in developing processes for sharing individual-participant data (IPD) from clinical trials. However, the utility and completeness of shared IPD and supporting documents must be evaluated to ensure the potential for scientific advancements from the data sharing ecosystem can be realized. To assess the utility and completeness of IPD and supporting documents provided from industry-sponsored clinical trials. From February 9, 2022, to February 9, 2023, 91 of 203 clinical trials supporting US Food and Drug Administration registrations of anticancer medicines for the treatment of solid tumors from the past decade were confirmed as eligible for IPD request. This quality improvement study performed a retrospective audit of the utility and completeness of the IPD and supporting documents provided from the 91 clinical trials for a planned meta-analysis. Request for IPD from 91 clinical oncology trials indicated as eligible for the request. The utility and completeness of the IPD and supporting documents provided. The IPD packages were obtained from 70 of 91 requested clinical trials (77%). The median time to data provision was 123 (range, 117-352) days. Redactions were observed in 18 of the acquired IPD packages (26%) for outcome data, 11 (16%) for assessment variables, and 19 (27%) for adjustment data. Additionally, 20 IPD packages (29%) lacked a clinical study report, 4 (6%) had incomplete or missing data dictionaries, and 20 (29%) were missing anonymization or redaction description files. Access to IPD from 21 eligible trials (23%) was not granted. In this quality improvement study, there was substantial variability within the provided IPD packages regarding the completeness of key data variables and supporting documents. To improve the data sharing ecosystem, key areas for enhancement include (1) ensuring that clinical trials are eligible for IPD sharing, (2) making eligible IPD transparently accessible, and (3) ensuring that IPD packages meet a standard of utility and completeness.

Meta-analysis of sex and racial subgroup participation rates and differential treatment effects for trials in solid tumor malignancies leading to US Food and Drug Administration registration between 2010 and 2021.

The lack of sociodemographic diversity in clinical trials limits the generalizability of results. The authors examined participation rates and effect modification by sex and race in oncology trials. The authors extracted outcome data stratified by sex and race for registration trials supporting US Food and Drug Administration (FDA) approval (2010-2021). Effect modification by race and sex was examined using quantitative and qualitative methods. A random-effects meta-analysis and pairwise comparison of progression-free survival (PFS) and overall survival (OS) outcomes was conducted by sex and race. Ninety-five trials with 123 end points and 54,365 patients provided information on sex. Trial patients were more often male (n=35,482; 65% vs. 56% male patients in US Surveillance, Epidemiology, and End Results [SEER] data), although the proportion of male patients was similar after adjusting by tumor type (60% in FDA data vs. 58% in SEER data). There was no difference in pooled outcomes among male versus female patients (PFS: hazard ratio, 0.99; 95% confidence interval, 0.92-1.07; p=.89; OS: hazard ratio, 0.99; 95% confidence interval, 0.93-1.07; p=.90). In total, 111 trials including 74,217 patients provided information on race, and 68% of patients identified as White, compared with 72.3% in US SEER incidence data. Black patients were under-represented compared with US SEER incidence data, although ethnicity was poorly reported throughout the data set. In the authors' network meta-analysis by race, there were no statistically significant differences in PFS or OS outcomes. No significant differences in PFS or OS outcomes were identified when the analyses were stratified by sex or race. Certain racial minorities remain under-represented, and clearer reporting of race and ethnicity is needed. Representation of female patients in FDA trials is similar to that in SEER data after adjusting for tumor type.

Differential treatment effect between younger and older adults for new cancer therapies in solid tumors supporting US Food and Drug Administration approval between 2010 and 2021.

Over one half of cancer diagnoses occur in patients aged 65 and older. The authors quantified how treatment effects differ between older and younger patients in oncology registration trials. The authors performed a retrospective cohort study of registration trials supporting US Food and Drug Administration approval of cancer drugs (from January 2010 to December 2021). The primary outcome was differential treatment effect by age (younger than 65 years vs. 65 years or older) for progression-free survival and overall survival. Random effects meta-analysis and a pairwise comparison of outcomes by age group also were performed. Among 263 trials that met the inclusion criteria, 120 trials with 153 end points and 83,152 patients presented age-specific outcome data. Among the included randomized patients, 38% were aged 65 years and older compared with an incidence proportion of 55% in data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Studies evaluating prostate cancer had the highest representation of patients aged 65 years or older (73%), whereas breast cancer studies had the lowest (20%). There were no changes in the proportion of patients aged 65 years or older over time (p = .86). Only 7% of end points showed a statistically significant interaction between outcome and age group. In a pooled analysis, there was an association between treatment effect and age for progression-free survival that approached but did not meet significance (hazard ratio, 0.95; p = .06), and there was no difference for overall survival (hazard ratio, 0.97; p = .79). Older adults remain under-represented in oncology registration trials. Significant differences in outcomes by age group were uncommon in individual trials and pooled analyses. However, clinical trial participants differ from real-world patients older than 65 years, and increased enrollment and ongoing research into differential treatment effects by age are needed.

Imbalance in treatment discontinuation without progression between experimental and control arms among randomized trials in advanced breast cancer.

1110 Background: In Randomized Controlled Trials (RCT), treatment discontinuation (TD) can result in censoring. Imbalanced frequency of TD between arms could impact interpretation of results. Here, we quantify TD between the experimental and control arms among RCT supporting registration of drugs for advanced breast cancer. Methods: We identified RCT supporting US Food and Drug Administration's approval of drugs for advanced breast cancer between 2013 and 2023. We extracted data for the number of participants with TD for reasons other than disease progression (PD), death, or completion of treatment. Odds ratio (OR) for TD comparing experimental to control arms were determined for each trial. To assess progression-free survival (PFS) translation into an overall survival (OS) benefit, we calculated hazard ratio (HR) for PFS/OS. Then we assessed whether there was quantitative association between the OR for TD and the ratio of HR for PFS/OS. Quantitative significance was defined according to the criteria of Burnand. Results: Analysis included 22 RCT comprising 13853 participants and supporting approval for 18 distinct drugs. TD was reported in 2212 (16.0%) participants. Among these participants, the leading causes of TD were withdrawal of consent (27.8%), site termination (20.7%), adverse events (17.2%), and loss of follow-up (10.9%). There was a statistically significant imbalance in the experimental arm in 4 RCT (18%) (Table), which was observed for everolimus, ribociclib (with fulvestrant), alpelisib, and neratinib. The OR for TD showed quantitative, but not statistically significant negative association with the ratio of the HR for PFS/OS (Beta -0.393; p=0.18). Conclusions: TD without PD, death, or completion of treatment occurs in a substantial proportion of participants of several RCT supporting approval of drugs for advanced breast cancer. all the statistically significant imbalanced TD in the RCT were in experimental arms. Quantitative association between imbalanced TD and the ratio of HR for PFS/OS suggests imbalanced TD may impact ability to translate improvements in PFS to OS. Results of RCT with imbalance in TD should be interpreted cautiously. [Table: see text]

Evaluation of Representation of Women As Authors in Pivotal Trials Supporting US Food and Drug Administration Approval of Novel Hematological Drugs

Introduction Pivotal trials evaluating the efficacy and safety of novel drugs provide the basis for their US Food and Drug Administration (FDA) approvals. Reportedly, women were underrepresented as authors in pivotal trials supporting approval of novel cardiometabolic drugs . However, gender inequity in authorship across pivotal trials of FDA-approved novel hematological drugs remains unknown. Therefore, in the present study, we sought to investigate whether gender disparity exists in the representation of women as authors of pivotal trials supporting approval of novel hematological drugs. Methods Drugs@FDA portal was searched for novel hematological drugs approved between 2008 and 2022. Drug approval labels were searched to identify all pivotal trials listed in Section 14 under "Clinical Studies.” Only pivotal trials with corresponding trial publications were included in this study. The gender of trial authors was captured as binary (women and men) and was identified by using the Genderize software (Demografix ApS) or by verifying personal pronouns on authors’ institutional profiles or other sources. Study-level estimates for the proportion of women authors were pooled using the DerSimonian and Laird random-effects meta-analysis of proportions model. Analyses were conducted with OpenMeta [Analyst] software version 10.12. Results From 2008 to 2022, the FDA approved a total of 45 novel hematological drugs, corresponding to 60 trials. Of these, 57 trial publications (21,527 participants) were included in this study (Table 1). Three publications included the results of two trials each. A total of 1203 authors were screened, and 15 were excluded because of the inability to assign author gender. Genderize was used to identify the gender of 1137 authors, which was further confirmed by checking personal pronouns listed in institutional profiles or other sources. Of the 66 authors with a prediction probability estimate less than 90.0% on Genderize, author gender was identified for 51 by using personal pronouns listed in institutional profiles or other sources. The median number of men and women authors of trial publications was 12 (IQR, 9-20) and 6 (IQR, 4-8), respectively. The overall proportion of women authors was 28.6% (95% CI, 25.3%-31.9%). The proportion of women as first and senior authors was the same, estimating about 22.8% (95% CI, 11.9%-33.7%). Conclusion Our study demonstrates gender inequity in authorship of pivotal efficacy trials supporting approval of novel Hematological drugs by the FDA. Institutions should devise targeted policies addressing unique challenges faced by women in medicine and develop a workplace environment conducive to women's academic success. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

What drives cancer clinical trial accrual? An empirical analysis of studies leading to FDA authorisation (2015–2020)

ObjectiveTo examine factors associated with accrual rate in industry sponsored clinical trials supporting US Food and Drug Administration (FDA) cancer drug approvals from 2015 to 2020.Design, setting and participantsRetrospective cross-sectional...

Advancing a managed care pharmacy research agenda: Generating real-world evidence to support US Food and Drug Administration Accelerated Approvals and improving benefit design to address health inequities.

To advance their research agenda, the Academy of Managed Care Pharmacy (AMCP) and the AMCP Foundation (AMCPF) invited a sample of AMCP membership to participate in focus groups and tasked them with developing tangible research aims for each of the top 2 previously identified AMCP/AMCPF research priorities: generating real-world evidence (RWE) to support US Food and Drug Administration (FDA) Accelerated Approvals and improving benefit design to address health inequities. The resulting research aims, which were further refined per feedback from additional stakeholders, will serve to guide requests for proposals for funding of specific research projects to address these top managed care priorities. Research aims identified by focus group participants related to generating RWE for FDA Accelerated Approvals include (1) creating a data survey tool for managed care to make RWE more readily available, (2) linking surrogate endpoints to meaningful clinical outcomes for drug development, and (3) improving patient outcomes by determining the optimal sequence of clinical pathways. Research aims identified by focus group participants related to improving benefit design to address health inequities include (1) identifying how the ability to navigate managed care benefit designs may impact inequities, (2) understanding the connection between health inequities and medication adherence, and (3) evaluating the impact of social determinants of health on medication affordability. DISCLOSURES: These proceedings were supported by Bridget Flavin, PharmD, Founder, Connected Content, Ltd. Connected Content, Ltd. received payment from AMCP for the preparation of this manuscript. Flavin is also an adjunct associate professor at the University of Florida College of Pharmacy. Diana Brixner received AMCP Foundation support of sabbatical to conduct this work, support of a medical writer to assist in putting the manuscript together, consulting fees from Millcreek Outcomes Group, Elevar, Sage, Haymarket, and AMCP funding of one trip to Alexandria, VA. This research and the development of this manuscript were funded by AMCP and the AMCP Foundation.

Enrollment of Black Participants in Pivotal Clinical Trials Supporting US Food and Drug Administration Approval of Chimeric Antigen Receptor–T Cell Therapy for Hematological Malignant Neoplasms

Disparities that affect Black persons with various hematological malignant neoplasms are substantial, yet little is known about disparities related to the use of US Food and Drug Administration (FDA)-approved chimeric antigen receptor-T cell (CAR-T) therapy. To examine the enrollment of Black participants in clinical trials that resulted in a subsequent FDA approval of CAR-T products in hematological malignant neoplasms. A cross-sectional study was performed using publicly available data on drug products and demographic subgroups from Drugs@fda in the period of August 2017 to May 2021. Data analysis included patients with large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, acute lymphoblastic leukemia, and multiple myeloma who were enrolled into 7 clinical trials that investigated various CAR-T products. The study was conducted from July 1, 2021, to November 30, 2021. Frequencies of participation of Black participants were calculated with adjustment for disease prevalence. Of the 1057 enrolled patients included in the study, CAR-T products were given to 746 patients (71%), and efficacy was reported for 729 enrolled patients (69%) across all the approved CAR-T products and indications. Most patients (1015 patients [96%]) were enrolled in the US. Black participants were included in the racial category other in the study that supported tisagenlecleucel approval in acute lymphoblastic leukemia; otherwise, their enrollment was specified either in the study publication and/or the demographic subgroup information available under the FDA product labeling information. The number of Black participants who received the CAR-T product and had reported efficacy varied between studies (range, 1-12 participants [2%-5%]). Adjusted prevalence measures showed the lowest participation to prevalence ratio of 0.2 for multiple myeloma and 0.6 for large B cell lymphoma. The findings of this study suggest that there are substantial disparities affecting Black patients across all approved CAR-T products used to treat hematological malignant neoplasms with otherwise limited effective treatment options. The study findings might aid policy discussions regarding the immediate need of regulations that enforce certain thresholds of Black patients' enrollment before granting FDA approval.

Evaluation of Representation of Women as Authors in Pivotal Trials Supporting US Food and Drug Administration Approval of Novel Cardiovascular Drugs

Evaluation of Representation of Women as Authors in Pivotal Trials Supporting US Food and Drug Administration Approval of Novel Cardiovascular Drugs

Evaluation of Drug Trials in High-, Middle-, and Low-Income Countries and Local Commercial Availability of Newly Approved Drugs

Clinical research supporting US Food and Drug Administration (FDA) drug approvals is largely conducted outside the US. To characterize where drugs were tested for FDA approval and to determine how commonly and quickly these drugs received marketing approval in the countries where they were tested, both overall and by country income level and geographical region. This cross-sectional analysis of trials supporting FDA approval of novel drugs in 2012 and 2014, sponsored by large drug companies, did not involve human participants. The settings were the countries hosting trials supporting US drug approval. Data sources included Drugs@FDA, ClinicalTrials.gov, PubMed, Google Scholar, EMBASE, and drug regulatory agency websites. Data analysis was completed March through September 2020. The primary outcomes were the proportion of drugs approved for marketing in the countries where they were tested for FDA approval within 1, 2, 3, 4, and 5 years of FDA approval and the proportion of countries contributing participants to trials supporting FDA approvals receiving market access to the drugs they helped test within 1, 2, 3, 4, and 5 years of FDA approval. In 2012 and 2014, the FDA approved 34 novel drugs sponsored by large companies, on the basis of a total of 898 trials, 563 of which had location information available. Each drug was tested in a median (interquartile range [IQR]) of 25 (18-37) unique countries, including a median (IQR) of 20 (13-25) high-income countries, 6 (4-11) upper-middle-income countries, and 1 (0-2) low-middle-income country. One drug was approved for marketing in all testing countries within 1 year of FDA approval and 15% (5 of 34 drugs) were approved in all testing countries within 5 years of FDA approval. Of the 70 countries contributing research participants for FDA drug approvals, 7% (5 countries) received market access to drugs they helped test within 1 year of FDA approval and 31% (22 countries) did so within 5 years. Access within 1 year occurred in 13% (5 of 39) of high-income countries, 0 of 22 upper-middle-income countries (0%), and 0 of 9 lower-middle-income countries (0%), whereas at 5 years access rates were 46% (18 of 39 countries), 9% (2 of 22 countries), and 22% (2 of 9 countries), respectively. Approvals were faster in high-income countries (median [IQR], 8 [0-11] months) than in upper-middle-income countries (median [IQR], 11 [5-29] months) or lower-middle-income countries (median [IQR], 17 [11-27] months) after FDA approval. Access was lowest in African countries. These findings suggest that substantial gaps exist between where FDA-approved drugs are tested and where they ultimately become available to patients, raising concerns about the equitable distribution of research benefits at the population level.

Clinical Trial Evidence Supporting US Food and Drug Administration Approval of Novel Cancer Therapies Between 2000 and 2016

Clinical trial evidence used to support drug approval is typically the only information on benefits and harms that patients and clinicians can use for decision-making when novel cancer therapies become available. Various evaluations have raised concern about the uncertainty surrounding these data, and a systematic investigation of the available information on treatment outcomes for cancer drugs approved by the US Food and Drug Administration (FDA) is warranted. To describe the clinical trial data available on treatment outcomes at the time of FDA approval of all novel cancer drugs approved for the first time between 2000 and 2016. This comparative effectiveness study analyzed randomized clinical trials and single-arm clinical trials of novel drugs approved for the first time to treat any type of cancer. Approval packages were obtained from drugs@FDA, a publicly available database containing information on drug and biologic products approved for human use in the US. Data from January 2000 to December 2016 were included in this study. Regulatory and clinical trial characteristics were described. For randomized clinical trials, summary treatment outcomes for overall survival, progression-free survival, and tumor response across all therapies were calculated, and median absolute survival increases were estimated. Tumor types and regulatory characteristics were assessed separately. Between 2000 and 2016, 92 novel cancer drugs were approved by the FDA for 100 indications based on data from 127 clinical trials. The 127 clinical trials included a median of 191 participants (interquartile range [IQR], 106-448 participants). Overall, 65 clinical trials (51.2%) were randomized, and 95 clinical trials (74.8%) were open label. Of 100 indications, 44 indications underwent accelerated approval, 42 indications were for hematological cancers, and 58 indications were for solid tumors. Novel drugs had mean hazard ratios of 0.77 (95% CI, 0.73-0.81; I2 = 46%) for overall survival and 0.52 (95% CI, 0.47-0.57; I2 = 88%) for progression-free survival. The median tumor response, expressed as relative risk, was 2.37 (95% CI, 2.00-2.80; I2 = 91%). The median absolute survival benefit was 2.40 months (IQR, 1.25-3.89 months). In this study, data available at the time of FDA drug approval indicated that novel cancer therapies were associated with substantial tumor responses but with prolonging median overall survival by only 2.40 months. Approval data from 17 years of clinical trials suggested that patients and clinicians typically had limited information available regarding the benefits of novel cancer treatments at market entry.

Patient-Centered Approach to Benefit-Risk Characterization Using Number Needed to Benefit and Number Needed to Harm: Advanced Non-Small-Cell Lung Cancer.

This work summarizes the benefit and risk of the results of clinical trials submitted to the US Food and Drug Administration of therapies for the treatment of non-small cell lung cancer (NSCLC) using number needed to benefit (NNB) and number needed to harm (NNH) metrics. NNB and NNH metrics have been reported as potentially being more patient centric and more intuitive to medical practitioners than more common metrics, such as the hazard ratio, and valuable to medical practitioners in complementing other metrics, such as the median time to event. This approach involved the characterization of efficacy and safety results in terms of NNB and NNH of 30 clinical trials in advanced NSCLC supporting US Food and Drug Administration approval decisions from 2003 to 2017. We assessed trends of NNB over time of treatment (eg, for programmed death 1 inhibitors) and variation of NNB across subpopulations (eg, characterized by epidermal growth factor receptor mutation, programmed death ligand 1 expression, Eastern Cooperative Oncology Group performance status, age, and extent of disease progression). Furthermore, the evolution of NNB of treatments for advanced NSCLC was charted from 2003 to 2017. Across subpopulations, NNB, on average, was 4 patients for approved targeted therapies in molecularly enriched populations, 11 patients for approved therapies in nonmolecularly enriched populations, and 23 patients for withdrawn or unapproved therapies. Furthermore, the NNB analysis showed variation for attributes of epidermal growth factor receptor mutations, level of programmed death 1 expression, Eastern Cooperative Oncology Group performance status, etc. When considering the best-case subpopulations and available drugs, the NNB frontier reduced from an estimated value of 7.7 in 2003 to an estimated value of 2.5 in 2017 at the estimated median overall survival-equal to 6 months-of an untreated patient.

Inclusion of Older People Reflective of Real-World Clinical Practice in Cardiovascular Drug Trials.

BackgroundUnderrepresentation of older people in clinical trials remains. This study aimed to examine the inclusion of older people and associated safety and efficacy reports from clinical trials of new molecular entities for cardiovascular disease indications since commencement of the US Food and Drug Administration Drug Trial Snapshot (DTS) Program. The DTS provides concise information on participants included in clinical trials supporting US Food and Drug Administration approval of new drugs.Methods and ResultsA cross‐sectional analysis between January 1, 2015 and April 30, 2019 of DTS data including approval date, indication, number of trials and participants, age distribution, efficacy, and safety statements was conducted. Participation‐to‐prevalence ratio (PPR) was used to describe representation of older participants in trials relative to disease population. Efficacy and safety statements regarding age were compared with drug prescribing information. A total of 72 079 participants from 10 DTS reports were identified and 39 625 (55.0%) were aged ≥65 years old. Overall, 63.6% of cardiovascular disease DTS reports were representative of people aged ≥65 years old for specific cardiovascular disease conditions. Underrepresentation was observed in 4 DTS: 2 for heart failure (PPR 0.48 and 0.62), 1 for pulmonary arterial hypertension (PPR 0.72), and 1 for venous thromboembolism (PPR 0.38). Participants in clinical trials for new drugs for the treatment of atrial fibrillation (PPR 0.99 and 1.21) and hypercholesterolemia (PPR 0.84 and 0.97) were reflective of the older population for these diseases. An increased risk of adverse events in older participants was reported in 40% DTS safety statements but no differences were reported in the drug product information.ConclusionsDespite the fact that >60% of cardiovascular disease trial participants for new molecular entities included in the DTS program were representative of the older population in real‐world clinical practice, concerns remain for conditions including heart failure or venous thromboembolism. Drug product information safety statements regarding age differences in adverse events were not reflective of trial findings. An increased directive is needed to facilitate the generation of real‐world evidence and appropriate reporting within drug product information for these potentially at‐risk patient populations.

Clinical Evidence Supporting US Food and Drug Administration Clearance of Novel Therapeutic Devices via the De Novo Pathway Between 2011 and 2019

This cross-sectional study characterizes the premarket clinical evidence supporting clearance of moderate-risk novel therapeutic medical devices by the US Food and Drug Administration.

Use of data from the Vascular Quality Initiative registry to support regulatory decisions yielded a high return on investment

BackgroundReal-world data (RWD) from the Society for Vascular Surgery Vascular Quality Initiative (VQI) registry has been used to support US Food and Drug Administration (FDA) regulatory decisions regarding vascular devices....

Assessment of Data Sources That Support US Food and Drug Administration Medical Devices Safety Communications

Medical Device Safety Communications (MDSCs) are used by the US Food and Drug Administration (FDA) to convey important new safety information to patients and health care professionals. The sources of initial safety signals that trigger MDSCs have not been described previously. To assess the sources of initial safety signals that trigger publication of MDSCs and the potential associations among MDSC data source, type of safety issue, and subsequent FDA action. In this cross-sectional study, all MDSCs published on the FDA website between January 1, 2011, and December 31, 2019, were assessed. The MDSC characteristics, sources of initiating safety signals, regulatory approval or clearance pathways of the related medical devices, and subsequent FDA actions were collected from the FDA website. The main outcome was the distribution of sources of initial safety signals that led to publication of MDSCs. Secondary aims included exploration of potential associations among safety signal sources (direct reporting vs other), type of safety issue (death vs other), and FDA action (withdrawal vs other). A total of 93 MDSCs were evaluated. Median time from device approval to MDSC posting was 10 years (interquartile range, 6-16 years). The most common data sources that triggered MDSCs were direct reports to the FDA through the Medical Device Reporting (MDR) program (44 of 93 [47%]) followed by regulator-initiated assessments (32 [34%]). Common safety issues included patient injury (25 [27%]), potential wrong diagnoses (19 [20%]), and death (18 [19%]). Frequent FDA action after MDSC posting included recommendation for increased vigilance and caution (47 [51%]), complete device withdrawal (12 [13%]), and warnings of specific lots or clinics (12 [13%]). There was a statistically significant correlation between direct reports of adverse events to the FDA through the MDR program and risk of death as a safety issue (14 of 44 [32%] for direct reporting vs 4 of 49 [8%] for any other data sources, P = .007). In this cross-sectional study, the most common source of initial safety signals that triggered MDSCs was direct reports of real-world adverse events to the FDA through the MDR program. The delayed detection of postmarketing adverse events highlights the importance of proactive identification of emerging device-related safety issues.

Ten-Year Trends in Enrollment of Women and Minorities in Pivotal Trials Supporting Recent US Food and Drug Administration Approval of Novel Cardiometabolic Drugs.

BackgroundIn 1993, the US Food and Drug Administration established guidelines to increase diversity by sex and race/ethnicity of participants in clinical trials supporting novel drug approvals. In this study we investigated the 10‐year trends of participation of women and minorities in pivotal trials supporting approval of new molecular entities in cardiometabolic drugs from January 2008 to December 2017.Methods and ResultsA list of new molecular entities was abstracted from publicly available data at Drugs@Fda. Sex and race/ethnicity data were collected from trial publications. Linear regression analysis was performed to assess the relation between drug approval year and proportion of women and minorities enrolled. Thirty‐five novel cardiovascular (n=24) and diabetes mellitus (n=11) drugs were approved by the US Food and Drug Administration during the study period. The median number of participants supporting each drug was 5930 (interquartile range, 3175–10 942). Women represented 36% (n=108 052) of trial participants (n=296 163). Women were underrepresented compared with their proportion of the disease population in trials of coronary heart disease (participation‐to‐prevalence ratio, 0.52), heart failure (participation‐to‐prevalence ratio, 0.58), and acute coronary syndrome (participation‐to‐prevalence ratio, 0.68). Among trial participants, 81% were white, 4% black, 12% Asian, and 11% Hispanic/Latino. There was no significant association between enrollment of women (P=0.29) or underrepresented minorities (P=0.45) with the drug approval year.ConclusionsOver the past decade (2008–2017), women and minorities, particularly blacks, have continued to be inadequately represented in pivotal cardiometabolic clinical trials that support US Food and Drug Administration approval of new molecular entities. This may have major implications in determining efficacy of such therapies in these groups, and may impair generalizability of trial results to routine clinical practice.

Abstract D081: Geographic relationship between lung cancer clinical trial sites and patient prevalence and demographics in the Medicare Fee-for-service program

Abstract Racial and ethnic minority groups have low rates of inclusion in cancer clinical trials (CCTs). For example, African American patients comprise 5% of patients enrolled in CCTs that support US Food and Drug Administration approval of new drugs but represent 13.3% of the general US population. Though cancer is the leading cause of death for Asian Americans, only 3% of CCTs is composed of Asian American participants. With the promise and rise of precision medicine, it is critical that study populations in clinical research reflect the changing US demographics. Expanding access to health data and analytics empower stakeholders to better understand and advocate for equitable research and treatment access in cancer. Research question: To what extent does the current US CCT site placement for non-small cell lung cancer (NCSLC) and small cell lung cancer (SCLC) reflect the reality of lung cancer patient prevalence and demographics in the US? Methods: Researchers used the following two primary data sources: (1) Medicare Fee-for-Service (FFS) patient-level claims data from 2016, including the following data elements: prevalence, co-morbidities, hospital encounters, and costs for patients with ICD-10 codes for NCSLC and SCLC, by demographic (age, gender, race, and ethnicity). Locations were designated as high (greater than 0.87%) or low (less than 0.87%) prevalence, based on national average prevalence. (2) CCT placement data was sourced from 2018 Clinical Trials.gov to determine ongoing NCLSC and SCLC studies where there are US study sites. Data were mapped on the Lung Cancer Index™, a National Minority Quality Forum (NMQF) geographic information system (GIS) with an interactive data warehouse and data visualization system, including geomapping. Preliminary data conclusions: 1) Of the 2812 interventional CCTs, the study team mapped 495 therapeutic, interventional, currently enrolling CCTs (after excluding trials for behavioral interventions and palliative care). 2) Of the 10015 zip codes mapped, 58.8% of those were designated as zones of high prevalence (HP) of lung cancer. Of the 5888 HP zip codes, only 10.5% had NSCLC trials and 5.6% percent had SCLC trials. 3) When analyzed by counties, of the 59% of counties with high prevalence of African American patients, only 3% and 1% of counties had more than 10 NSCLC trials and 10 SCLC trials respectively. Similarly, of the 24% of counties with high prevalence of Asian American lung cancer patients, only 3% and 1% of counties had more than 10 NSCLC and 10 SCLC trials respectively. Implications: While additional analyses are ongoing, preliminary findings suggest that there is a major disconnect between US lung CCT placement and where patients live. The advent of precision medicine creates urgency to improve CCT enrollment of racial and ethnic minority groups, for equitable benefit of resulting innovation and access to optimal treatment. Lung cancer prevalence, including by population demographics, at the zip code and county level can be a critical guide to CCT site placement. Citation Format: Upal Basu Roy, Liou Xu, Laura Lee Hall, Gary Puckrein, Andrea Ferris, Jeanne Regnante. Geographic relationship between lung cancer clinical trial sites and patient prevalence and demographics in the Medicare Fee-for-service program [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D081.