المؤلفون: Carrigan, Gillis, Bradbury, Brian D., Brookhart, M. Alan, Capra, William B., Chia, Victoria, Rothman, Kenneth J., Sarsour, Khaled, Taylor, Michael D., Brown, Jefferey S.

المصدر: Current Epidemiology Reports ; volume 9, issue 4, page 326-337 ; ISSN 2196-2995

مصطلحات موضوعية: General Earth and Planetary Sciences

الوصف: Real-world data (RWD) from electronic health records (EHRs) and administrative claims databases are used increasingly to generate real-world evidence (RWE). RWE is used to support clinical evidence packages for medicines that inform decision-makers. In this review of current issues in the use of RWD-derived external comparator groups to support regulatory filings, we assess a series of topics that generally apply across many disease indications. However, most of the examples and illustrations focus on the oncology clinical research setting. The topics include an overview of current uses of RWD in drug development, a discussion of regulatory filings using RWD-derived external comparators, a brief overview of guidance documents and white papers pertaining to external comparators, a summary of some limitations and methodological issues in the use of external comparator groups and finally, a look at the future of this area and recommendations.

الإتاحة: https://doi.org/10.1007/s40471-022-00305-9Test

المؤلفون: Tan, W. Katherine, Segal, Brian D., Curtis, Melissa D., Baxi, Shrujal S., Capra, William B., Garrett-Mayer, Elizabeth, Hobbs, Brian P., Hong, David S., Hubbard, Rebecca A., Zhu, Jiawen, Sarkar, Somnath, Samant, Meghna

المصدر: Contemporary Clinical Trials Communications ; volume 30, page 101000 ; ISSN 2451-8654

مصطلحات موضوعية: Pharmacology, General Medicine

الإتاحة: https://doi.org/10.1016/j.conctc.2022.101000Test
https://api.elsevier.com/content/article/PII:S245186542200117X?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S245186542200117X?httpAccept=text/plainTest

المؤلفون: Tan, W. Katherine, Segal, Brian D., Curtis, Melissa D., Baxi, Shrujal S., Capra, William B., Garrett-Mayer, Elizabeth, Hobbs, Brian P., Hong, David S., Hubbard, Rebecca A., Zhu, Jiawen, Sarkar, Somnath, Samant, Meghna

مصطلحات موضوعية: Statistics - Methodology

الوصف: Randomized controlled trials (RCTs) are the gold standard for assessing drug safety and efficacy. However, RCTs have some drawbacks which have led to the use of single-arm studies to make certain internal drug development and regulatory decisions, particularly in oncology. Hybrid controlled trials with real-world data (RWD), in which the control arm is composed of both trial and real-world patients, have the potential to help address some of the shortcomings of both RCTs and single-arm studies in particular situations, such as when a disease has low prevalence or when the standard of care to be used in the control arm is ineffective or highly toxic and an experimental therapy shows early promise. This paper discusses why it may be beneficial to consider hybrid controlled trials with RWD, what such a design entails, when it may be appropriate, and how to conduct the analyses. We propose a novel two-step borrowing method for the construction of hybrid control arms. We use simulations to demonstrate the operating characteristics of dynamic and static borrowing methods, and highlight the trade-offs and analytic decisions that study teams will need to address when designing a hybrid study. ; Comment: 71 pgs (with supplemental) 3 Tables, 4 Figures

العلاقة: http://arxiv.org/abs/2108.07335Test

الإتاحة: http://arxiv.org/abs/2108.07335Test

المؤلفون: Carrigan, Gillis, Whipple, Samuel, Capra, William B., Taylor, Michael D., Brown, Jeffrey S., Lu, Michael, Arnieri, Brandon, Copping, Ryan, Rothman, Kenneth J.

المصدر: Clinical Pharmacology & Therapeutics ; volume 107, issue 2, page 369-377 ; ISSN 0009-9236 1532-6535

الوصف: Oncology drug development increasingly relies on single‐arm clinical trials. External controls ( EC s) derived from electronic health record ( EHR ) databases may provide additional context. Patients from a US ‐based oncology EHR database were aligned with patients from randomized controlled trials ( RCT s) and trial‐specific eligibility criteria were applied to the EHR dataset. Overall survival ( OS ) in the EC ‐derived control arm was compared with OS in the RCT experimental arm. The primary outcome was OS , defined as time from randomization or treatment initiation ( EHR ) to death. Cox regression models were used to obtain effect estimates using EHR data. EC ‐derived hazard ratio estimates aligned closely with those from the corresponding RCT with one exception. Comparing log HR s among all RCT and EC results gave a Pearson correlation coefficient of 0.86. Properly selected control arms from contemporaneous EHR data could be used to put single‐arm trials of OS in advanced non‐small cell lung cancer into context.

الإتاحة: https://doi.org/10.1002/cpt.1586Test

المؤلفون: Carrigan, Gillis, Whipple, Samuel, Taylor, Michael D., Torres, Aracelis Z., Gossai, Anala, Arnieri, Brandon, Tucker, Melisa, Hofmeister, Philip P., Lambert, Peter, Griffith, Sandra D., Capra, William B.

المساهمون: F. Hoffmann-La Roche

المصدر: Pharmacoepidemiology and Drug Safety ; volume 28, issue 5, page 572-581 ; ISSN 1053-8569 1099-1557

الوصف: Purpose The aim of this study was to assess the impact of missing death data on survival analyses conducted in an oncology EHR‐derived database. Methods The study was conducted using the Flatiron Health oncology database and the National Death Index (NDI) as a gold standard. Three analytic frameworks were evaluated in advanced non‐small cell lung cancer (aNSCLC) patients: median overall survival [mOS]), relative risk estimates conducted within the EHR‐derived database, and “external control arm” analyses comparing an experimental group augmented with mortality data from the gold standard to a control group from the EHR‐derived database only. The hazard ratios (HRs) obtained within the EHR‐derived database (91% sensitivity) and the external control arm analyses, were compared with results when both groups were augmented with mortality data from the gold standard. The above analyses were repeated using simulated lower mortality sensitivities to understand the impact of more extreme levels of missing deaths. Results Bias in mOS ranged from modest (0.6–0.9 mos.) in the EHR‐derived cohort with (91% sensitivity) to substantial when lower sensitivities were generated through simulation (3.3–9.7 mos.). Overall, small differences were observed in the HRs for the EHR‐derived cohort across comparative analyses when compared with HRs obtained using the gold standard data source. When only one treatment arm was subject to estimation bias, the bias was slightly more pronounced, but increased substantially when lower sensitivities were simulated. Conclusions The impact on survival analysis is minimal with high mortality sensitivity with only modest impact associated within external control arm applications.

الإتاحة: https://doi.org/10.1002/pds.4758Test

المؤلفون: Curtis, Melissa D., Griffith, Sandra D., Tucker, Melisa, Taylor, Michael D., Capra, William B., Carrigan, Gillis, Holzman, Ben, Torres, Aracelis Z., You, Paul, Arnieri, Brandon, Abernethy, Amy P.

المصدر: Health Services Research ; volume 53, issue 6, page 4460-4476 ; ISSN 0017-9124 1475-6773

الوصف: Objective To create a high‐quality electronic health record ( EHR )–derived mortality dataset for retrospective and prospective real‐world evidence generation. Data Sources/Study Setting Oncology EHR data, supplemented with external commercial and US Social Security Death Index data, benchmarked to the National Death Index ( NDI ). Study Design We developed a recent, linkable, high‐quality mortality variable amalgamated from multiple data sources to supplement EHR data, benchmarked against the highest completeness U.S. mortality data, the NDI . Data quality of the mortality variable version 2.0 is reported here. Principal Findings For advanced non‐small‐cell lung cancer, sensitivity of mortality information improved from 66 percent in EHR structured data to 91 percent in the composite dataset, with high date agreement compared to the NDI . For advanced melanoma, metastatic colorectal cancer, and metastatic breast cancer, sensitivity of the final variable was 85 to 88 percent. Kaplan–Meier survival analyses showed that improving mortality data completeness minimized overestimation of survival relative to NDI ‐based estimates. Conclusions For EHR ‐derived data to yield reliable real‐world evidence, it needs to be of known and sufficiently high quality. Considering the impact of mortality data completeness on survival endpoints, we highlight the importance of data quality assessment and advocate benchmarking to the NDI .

الإتاحة: https://doi.org/10.1111/1475-6773.12872Test

المؤلفون: Tan, W. Katherine, Segal, Brian D., Curtis, Melissa D., Baxi, Shrujal S., Capra, William B., Garrett-Mayer, Elizabeth, Hobbs, Brian P., Hong, David S., Hubbard, Rebecca A., Zhu, Jiawen, Sarkar, Somnath, Samant, Meghna

المصدر: Contemp Clin Trials Commun

مصطلحات موضوعية: Article, demo, envir

الوصف: BACKGROUND: Hybrid controlled trials with real-world data (RWD), where the control arm is composed of both trial and real-world patients, could facilitate research when the feasibility of randomized controlled trials (RCTs) is challenging and single-arm trials would provide insufficient information. METHODS: We propose a frequentist two-step borrowing method to construct hybrid control arms. We use parameters informed by a completed randomized trial in metastatic triple-negative breast cancer to simulate the operating characteristics of dynamic and static borrowing methods, highlighting key trade-offs and analytic decisions in the design of hybrid studies. RESULTS: Simulated data were generated under varying residual-bias assumptions (no bias: HR(RWD) = 1) and experimental treatment effects (target trial scenario: HR(Exp) = 0.78). Under the target scenario with no residual bias, all borrowing methods achieved the desired 88% power, an improvement over the reference model (74% power) that does not borrow information externally. The effective number of external events tended to decrease with higher bias between RWD and RCT (i.e. HR(RWD) away from 1), and with weaker experimental treatment effects (i.e. HR(Exp) closer to 1). All dynamic borrowing methods illustrated (but not the static power prior) cap the maximum Type 1 error over the residual-bias range considered. Our two-step model achieved comparable results for power, type 1 error, and effective number of external events borrowed compared to other borrowing methodologies. CONCLUSION: By pairing high-quality external data with rigorous simulations, researchers have the potential to design hybrid controlled trials that better meet the needs of patients and drug development.

العلاقة: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9519429Test/

الإتاحة: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9519429Test/

المؤلفون: Carrigan, Gillis, Whipple, Samuel, Capra, William B., Taylor, Michael D., Brown, Jeffrey S., Lu, Michael, Arnieri, Brandon, Copping, Ryan, Rothman, Kenneth J.

المصدر: Clinical Pharmacology & Therapeutics ; volume 108, issue 5, page 920-920 ; ISSN 0009-9236 1532-6535

الإتاحة: https://doi.org/10.1002/cpt.1880Test

المؤلفون: Carrigan, Gillis, Whipple, Samuel, Taylor, Michael D., Torres, Aracelis Z., Gossai, Anala, Arnieri, Brandon, Tucker, Melisa, Hofmeister, Philip P., Lambert, Peter, Griffith, Sandra D., Capra, William B.

مصطلحات موضوعية: Original Report, demo, socio

الوصف: PURPOSE: The aim of this study was to assess the impact of missing death data on survival analyses conducted in an oncology EHR‐derived database. METHODS: The study was conducted using the Flatiron Health oncology database and the National Death Index (NDI) as a gold standard. Three analytic frameworks were evaluated in advanced non‐small cell lung cancer (aNSCLC) patients: median overall survival [mOS]), relative risk estimates conducted within the EHR‐derived database, and “external control arm” analyses comparing an experimental group augmented with mortality data from the gold standard to a control group from the EHR‐derived database only. The hazard ratios (HRs) obtained within the EHR‐derived database (91% sensitivity) and the external control arm analyses, were compared with results when both groups were augmented with mortality data from the gold standard. The above analyses were repeated using simulated lower mortality sensitivities to understand the impact of more extreme levels of missing deaths. RESULTS: Bias in mOS ranged from modest (0.6–0.9 mos.) in the EHR‐derived cohort with (91% sensitivity) to substantial when lower sensitivities were generated through simulation (3.3–9.7 mos.). Overall, small differences were observed in the HRs for the EHR‐derived cohort across comparative analyses when compared with HRs obtained using the gold standard data source. When only one treatment arm was subject to estimation bias, the bias was slightly more pronounced, but increased substantially when lower sensitivities were simulated. CONCLUSIONS: The impact on survival analysis is minimal with high mortality sensitivity with only modest impact associated within external control arm applications.

العلاقة: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594237Test/

الإتاحة: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594237Test/

المؤلفون: Emery, Sean, Capra, William B., Cooper, David A., Mitsuyasu, Ronald T., Kovacs, Joseph A., Vig, Pamela, Smolskis, Mary, Saravolatz, Louis D., Lane, H. Clifford, Fyfe, Gwen A., Curtin, Peter T., for the International Interleukin-2 Study Group

مصطلحات موضوعية: Major Articles

الوصف: We collected human immunodeficiency virus (HIV) disease progression, survival, most recent CD4 cell count, and plasma HIV RNA levels from patients ( n = 157) who participated in randomized clinical trials of interleukin (IL)–2 that commenced before 1995. Data were available for 155 (99%) patients. Statistical analyses were based on the intention-to-treat principle. Median follow-up was 28 months and 30 months for control and IL-2 patients, respectively. Twenty-five (16%) patients developed AIDS or died during follow-up (16 control patients vs. 9 IL-2 patients; R 2 = 0.57; P = .22). Mean change from baseline CD4 cell count was significantly higher in patients randomized to receive IL-2 (368 vs. 153 cells/µL; P = .003). Mean change from baseline plasma HIV RNA was significantly lower in patients randomized to receive IL-2 (−0.98 vs. −0.63 log copies/mL; P = .004). Significant improvements in CD4 cell count and plasma HIV RNA in recipients of IL-2 relative to control patients were associated with a nonsignificant trend toward improved clinical outcome.

وصف الملف: text/html

العلاقة: http://jid.oxfordjournals.org/cgi/content/short/182/2/428Test; http://dx.doi.org/10.1086/315736Test

الإتاحة: https://doi.org/10.1086/315736Test
http://jid.oxfordjournals.org/cgi/content/short/182/2/428Test