Abstract
Advanced practice providers in oncology are now likely to encounter real-world data (RWD) studies in addition to data from randomized controlled trials (RCTs) in their practice. Real-world evidence derived from RWD can provide important information about a therapeutic agent’s effectiveness outside of the confines of RCTs. It is important to understand how these studies are conducted and how data from these two types of studies can be interpreted and integrated for practical clinical use and shared decision-making. The goal of this manuscript is to provide an overview of the fundamental aspects of RWD studies and what is required to conduct a robust RWD study. Recently published studies are cited to demonstrate how RWD studies complement RCTs.
References
American Cancer Society. (2023). Cancer facts & figures 2023. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf
Arondekar, B., Duh, M. S., Bhak, R. H., DerSarkissian, M., Huynh, L., Wang, K.,…Demetri, G. D. (2022). Real-world evidence in support of oncology product registration: A systematic review of new drug application and biologics license application approvals from 2015–2020. Clinical Cancer Research, 28(1), 27–35. https://doi.org/10.1158/1078-0432.CCR-21-2639
Austin, P. C. (2014). The use of propensity score methods with survival or time-to-event outcomes: Reporting measures of effect similar to those used in randomized experiments. Statistics in Medicine, 33(7), 1242–1258. https://doi.org/10.1002/sim.5984
Austin, P. C., & Stuart, E. A. (2015). Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Statistics in Medicine, 34(28), 3661–3679. https://doi.org/10.1002/sim.6607
Austin, P. C., White, I. R., Lee, D. S., & van Buuren, S. (2021). Missing data in clinical research: A tutorial on multiple imputation. Canadian Journal of Cardiology, 37(9), 1322–1331. https://doi.org/10.1016/j.cjca.2020.11.010
Berger, M. L., Sox, H., Willke, R. J., Brixner, D. L., Eichler, H. G., Goettsch, W.,…Daniel Mullins, C. (2017). Good practices for real-world data studies of treatment and/or comparative effectiveness: Recommendations from the joint ISPOR-ISPE special task force on real-world evidence in health care decision making. Pharmacoepidemiology and Drug Safety, 26(9), 1033–1039. https://doi.org/10.1002/pds.4297
Blonde, L., Khunti, K., Harris, S. B., Meizinger, C., & Skolnik, N. S. (2018). Interpretation and impact of real-world clinical data for the practicing clinician. Advances in Therapy, 35(11), 1763–1774. https://doi.org/10.1007/s12325-018-0805-y
Broglio, K. R., & Berry, D. A. (2009). Detecting an overall survival benefit that is derived from progression-free survival. Journal of the National Cancer Institute, 101(23), 1642–1649. https://doi.org/10.1093/jnci/djp369
Cummings, J. (2018). Lessons learned from Alzheimer disease: Clinical trials with negative outcomes. Clinical and Translational Science, 11(2), 147–152. https://doi.org/10.1111/cts.12491
Dang, A. (2023). Real-world evidence: A primer. Pharmaceutical Medicine, 37(1), 25–36. https://doi.org/10.1007/s40290-022-00456-6
Deniz, S., Akbolat, M., Cimen, M., & Unal, O. (2021). The mediating role of shared decision-making in the effect of the patient-physician relationship on compliance with treatment. Journal of Patient Experience, 8, 23743735211018066. https://doi.org/10.1177/23743735211018066
Dreyer, N. A., Schneeweiss, S., McNeil, B. J., Berger, M. L., Walker, A. M., Ollendorf, D. A., & Gliklich, R. E. (2010). Grace principles: Recognizing high-quality observational studies of comparative effectiveness. The American Journal of Managed Care, 16(6). https://www.ajmc.com/view/ajmc_10jundreyer_467to471
FDA. (2017). Palbociclib (Ibrance). https://www.fda.gov/drugs/resources-information-approved-drugs/palbociclib-ibrance
FDA. (2018). Framework for FDA’s real-world evidence program [FDA issued guidance]. https://www.fda.gov/media/120060/download
FDA. (2019). FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease
Finn, R. S., Martin, M., Rugo, H. S., Jones, S., Im, S. A., Gelmon, K.,…Slamon, D. J. (2016). Palbociclib and letrozole in advanced breast cancer. New England Journal of Medicine, 375(20), 1925–1936. https://doi.org/10.1056/NEJMoa1607303
Finn, R. S., Rugo, H. S., Dieras, V. C., Harbeck, N., Im, S.-A., Gelmon, K. A.,…Slamon, D. J. (2022). Overall survival (OS) with first-line palbociclib plus letrozole (pal+let) versus placebo plus letrozole (pbo+let) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/HER2− ABC): Analyses from PALOMA-2. Journal of Clinical Oncology, 40(17_suppl), LBA1003. https://doi.org/10.1200/JCO.2022.40.17_suppl.LBA1003
Ford, I., & Norrie, J. (2016). Pragmatic trials. New England Journal of Medicine, 375(5), 454–463. https://doi.org/10.1056/NEJMra1510059
Forstag, E. H. (2019). In C. Shore, A. W. Gee, B. Kahn, & E. H. Forstag (Eds.), Examining the impact of real-world evidence on medical product development: Proceedings of a workshop series. https://doi.org/10.17226/25352
Garrison, L. P., Jr., Neumann, P. J., Erickson, P., Marshall, D., & Mullins, C. D. (2007). Using real-world data for coverage and payment decisions: The ISPOR real-world data task force report. Value in Health, 10(5), 326–335. https://doi.org/10.1111/j.1524-4733.2007.00186.x
Gatto, N. M., Campbell, U. B., Rubinstein, E., Jaksa, A., Mattox, P., Mo, J., & Reynolds, R. F. (2022). The structured process to identify fit-for-purpose data: A data feasibility assessment framework. Clinical Pharmacology & Therapeutics, 111(1), 122–134. https://doi.org/10.1002/cpt.2466
Gokhale, M., Sturmer, T., & Buse, J. B. (2020). Real-world evidence: The devil is in the detail. Diabetologia, 63(9), 1694–1705. https://doi.org/10.1007/s00125-020-05217-1
Haneuse, S., Arterburn, D., & Daniels, M. J. (2021). Assessing missing data assumptions in EHR-based studies: A complex and underappreciated task. JAMA Network Open, 4(2), e210184. https://doi.org/10.1001/jamanetworkopen.2021.0184
Hariton, E., & Locascio, J. J. (2018). Randomised controlled trials - The gold standard for effectiveness research: Study design: Randomised controlled trials. BJOG: An International Journal of Obstetrics & Gynaecology, 125(13), 1716. https://doi.org/10.1111/1471-0528.15199
Jahanshahi, M., Gregg, K., Davis, G., Ndu, A., Miller, V., Vockley, J., Ollivier, C., Franolic, T., & Sakai, S. (2021). The use of external controls in FDA regulatory decision making. Therapeutic Innovation & Regulatory Science, 55(5), 1019–1035. https://doi.org/10.1007/s43441-021-00302-y
Khosla, S., White, R., Medina, J., Ouwens, M., Emmas, C., Koder, T., Male, G., & Leonard, S. (2018). Real world evidence (RWE) - A disruptive innovation or the quiet evolution of medical evidence generation? F1000Research, 7, 111. https://doi.org/10.12688/f1000research.13585.2
Khozin, S., Blumenthal, G. M., & Pazdur, R. (2017). Real-world data for clinical evidence generation in oncology. Journal of the National Cancer Institute, 109(11). https://doi.org/10.1093/jnci/djx187
Kim, H. S., Lee, S., & Kim, J. H. (2018). Real-world evidence versus randomized controlled trial: Clinical research based on electronic medical records. Journal of Korean Medical Sciences, 33(34), e213. https://doi.org/10.3346/jkms.2018.33.e213
Kurtin, S. E., & Taher, R. (2020). Clinical trial design and drug approval in oncology: A primer for the advanced practitioner in oncology. Journal of the Advanced Practitioner in Oncology, 11(7), 736–751. https://doi.org/10.6004/jadpro.2020.11.7.7
Lavertu, A., Vora, B., Giacomini, K. M., Altman, R., & Rensi, S. (2021). A new era in pharmacovigilance: Toward real-world data and digital monitoring. Clinical Pharmacology & Therapeutics, 109(5), 1197–1202. https://doi.org/10.1002/cpt.2172
Mahendraratnam, N., Mercon, K., Eckert, J., Romine, M., Kroetsch, A., Frank, K.,…McClellan, M. (2019). Adding real-world evidence to a totality of evidence approach for evaluating marketed product effectiveness [White Paper]. Duke Margolis Center for Health Policy. https://healthpolicy.duke.edu/sites/default/files/2020-08/Totality%20of%20Evidence%20Approach.pdf
Monti, S., Grosso, V., Todoerti, M., & Caporali, R. (2018). Randomized controlled trials and real-world data: Differences and similarities to untangle literature data. Rheumatology (Oxford), 57(57 Suppl 7), vii54–vii58. https://doi.org/10.1093/rheumatology/key109
O’Leary, C. P., & Cavender, M. A. (2020). Emerging opportunities to harness real-world data: An introduction to data sources, concepts, and applications. Diabetes, Obesity & Metabolism, 22(Suppl 3), 3–12. https://doi.org/10.1111/dom.13948
Rare Diseases International. (2023). Infographic-operational-description-of-rare-diseases. https://www.rarediseasesinternational.org/wp-content/uploads/2022/08/INFOGRAPHIC-OPERATIONAL-DESCRIPTION-OF-RARE-DISEASES.pdf
Rifkin, R., Singer, D., Aguilar, K. M., Baidoo, B., & Maiese, E. M. (2019). Daratumumab split first versus single dosing schedule among patients with multiple myeloma treated in a US community oncology setting: A retrospective observational study. Clinical Therapeutics, 41(5), 866–881 e867. https://doi.org/10.1016/j.clinthera.2019.03.013
Rohrig, B., du Prel, J. B., Wachtlin, D., Kwiecien, R., & Blettner, M. (2010). Sample size calculation in clinical trials: Part 13 of a series on evaluation of scientific publications. Deutsches Ärzteblatt International, 107(31–32), 552–556. https://doi.org/10.3238/arztebl.2010.0552
Rothman, K. J., Greenland, S., & Lash, T. (2008). Modern Epidemiology (Third Edition ed.). Lippincott Williams & Wilkins. http://students.aiu.edu/submissions/profiles/resources/onlineBook/a9c7D5_Modern_Epidemiology_3.pdf
Rugo, H. S., Brufsky, A., Liu, X., Li, B., McRoy, L., Chen, C.,…DeMichele, A. (2022). Real-world study of overall survival with palbociclib plus aromatase inhibitor in HR+/HER2- metastatic breast cancer. NPJ Breast Cancer, 8(1), 114. https://doi.org/10.1038/s41523-022-00479-x
Rugo, H. S., Finn, R. S., Dieras, V., Ettl, J., Lipatov, O., Joy, A. A.,…Slamon, D. J. (2019). Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Research and Treatment, 174(3), 719–729. https://doi.org/10.1007/s10549-018-05125-4
Schad, F., & Thronicke, A. (2022). Real-world evidence-current developments and perspectives. International Journal of Environmental Research and Public Health, 19(16). https://doi.org/10.3390/ijerph191610159
Setia, M. S. (2016). Methodology series module 3: Cross-sectional studies. Indian Journal of Dermatology, 61(3), 261–264. https://doi.org/10.4103/0019-5154.182410
Singal, A. G., Higgins, P. D., & Waljee, A. K. (2014). A primer on effectiveness and efficacy trials. Clinical and Translational Gastroenterology, 5(1), e45. https://doi.org/10.1038/ctg.2013.13
Singh, G. K., & Jemal, A. (2017). Socioeconomic and racial/ethnic disparities in cancer mortality, incidence, and survival in the United States, 1950–2014: Over six decades of changing patterns and widening inequalities. Journal of Environmental and Public Health, 2017, 2819372. https://doi.org/10.1155/2017/2819372
Singh, H., Kanapuru, B., Smith, C., Fashoyin-Aje, L. A., Myers, A., Kim, G., & Pazdur, R. (2017). FDA analysis of enrollment of older adults in clinical trials for cancer drug registration: A 10-year experience by the U.S. Food and Drug Administration. Journal of Clinical Oncology, 35(15_suppl), 10009–10009. https://doi.org/10.1200/JCO.2017.35.15_suppl.10009
Subbiah, V. (2023). The next generation of evidence-based medicine. Nature Medicine, 29(1), 49–58. https://doi.org/10.1038/s41591-022-02160-z
Talarico, L., Chen, G., & Pazdur, R. (2004). Enrollment of elderly patients in clinical trials for cancer drug registration: A 7-year experience by the US Food and Drug Administration. Journal of Clinical Oncology, 22(22), 4626–4631. https://doi.org/10.1200/JCO.2004.02.175
Tang, M., Pearson, S. A., Simes, R. J., & Chua, B. H. (2023). Harnessing real-world evidence to advance cancer research. Current Oncology, 30(2), 1844–1859. https://doi.org/10.3390/curroncol30020143
Taur, S. R. (2022). Observational designs for real-world evidence studies. Perspectives in Clinical Research, 13(1), 12–16. https://doi.org/10.4103/picr.picr_217_21
Thorlund, K., Dron, L., Park, J. J. H., & Mills, E. J. (2020). Synthetic and external controls in clinical trials - a primer for researchers. Clinical Epidemiology, 12, 457–467. https://doi.org/10.2147/CLEP.S242097
Turner, B. E., Steinberg, J. R., Weeks, B. T., Rodriguez, F., & Cullen, M. R. (2022). Race/ethnicity reporting and representation in US clinical trials: A cohort study. The Lancet Regional Health – Americas, 11. https://doi.org/10.1016/j.lana.2022.100252
US Congress. (2016). 21st Century Cures Act. https://www.federalregister.gov/documents/2020/05/01/2020-07419/21st-century-cures-act-interoperability-information-blocking-and-the-onc-health-it-certification
Wang, S. V., Pinheiro, S., Hua, W., Arlett, P., Uyama, Y., Berlin, J. A.,…Schneeweiss, S. (2021). Start-RWE: Structured template for planning and reporting on the implementation of real-world evidence studies. BMJ, 372, m4856. https://doi.org/10.1136/bmj.m4856
Wang, S. V., & Schneeweiss, S. (2022). Assessing and interpreting real-world evidence studies: Introductory points for new reviewers. Clinical Pharmacology & Therapeutics, 111(1), 145–149. https://doi.org/10.1002/cpt.2398
Wedam, S., Fashoyin-Aje, L., Bloomquist, E., Tang, S., Sridhara, R., Goldberg, K. B,…Beaver, J. A. (2020). FDA approval summary: Palbociclib for male patients with metastatic breast cancer. Clinical Cancer Research, 26(6), 1208–1212. https://doi.org/10.1158/1078-0432.CCR-19-2580
Wouters, O. J., McKee, M., & Luyten, J. (2020). Estimated research and development investment needed to bring a new medicine to market, 2009-2018. JAMA, 323(9), 844–853. https://doi.org/10.1001/jama.2020.1166
Xia, A. D., Schaefer, C. P., Szende, A., Jahn, E., & Hirst, M. J. (2019). RWE framework: An interactive visual tool to support a real-world evidence study design. Drugs - Real World Outcomes, 6(4), 193–203. https://doi.org/10.1007/s40801-019-00167-6