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The Case for Real-world Evidence in the Future of Clinical Research on Chronic Myeloid Leukemia

  • Jonathan Webster
    Affiliations
    Sidney Kimmel Comprehensive Cancer Center, Division of Hematologic Malignancies, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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  • B. Douglas Smith
    Correspondence
    Address correspondence to: B. Douglas Smith, MD, Sidney Kimmel Comprehensive Cancer Center, Division of Hematologic Malignancies, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1—Room 246, Baltimore, MD 21287, USA.
    Affiliations
    Sidney Kimmel Comprehensive Cancer Center, Division of Hematologic Malignancies, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Open AccessPublished:January 29, 2019DOI:https://doi.org/10.1016/j.clinthera.2018.12.013

      Abstract

      Purpose

      In light of recently published guidelines from the US Food and Drug Administration (FDA) on the communication of real-world data (RWD) and real-world evidence (RWE) to support regulatory decision making, it is important to understand how such data are developed, the limitations of these data, and how to best use RWD to improve patient care. Historically, the use of RWE has been approached with skepticism because of its often-retrospective nature compared with data from conventional randomized controlled trials (RCTs). This review discusses the role and function of RWE and RWD in clinical research. We summarize the types of RWE used in clinical research, outline the challenges and limitations involved with these data, and suggest how these types of analyses can supplement results from clinical trials to foster a more complete understanding of a drug or disease area of interest. In particular, we focus on the role of RWE in investigating chronic myeloid leukemia (CML) and tyrosine kinase inhibitor therapy for CML.

      Methods

      We reviewed FDA guidance on the use of RWE and conducted a PubMed literature search to evaluate published data from real-world studies in CML.

      Findings

      RWE includes analysis of RWD gathered from nonconventional sources, including patient registries, observational studies, and social media, among others. Importantly, although real-world studies do not adhere to the same degree of controlled conditions and predefined patient-management strategies as do conventional clinical trials, analyses resulting from these studies can be held to a high degree of validation and standardization, making them as meaningful as those from RCTs. In CML, RWE has informed early treatment milestones and has provided a window into patient perspectives regarding treatment. These types of analyses have already informed and can continue to inform disease management. These improvements in disease management, in turn, will help clinicians to better forecast treatment challenges and allow for the optimization of future treatment paradigms.

      Implications

      Real-world studies are different from conventional RCTs and therefore provide insight into distinct aspects of treatment and patient outcomes. Together with results from clinical trials, RWE can help to illustrate a more complete picture of the tolerability, effectiveness, and impact of a drug. The recently published guidelines indicate that the FDA expects a growing role for RWE.

      Key words

      Introduction

      Conventional randomized controlled trials (RCTs) are rigorous scientific examinations of the tolerability and efficacy of potential new therapies.
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.
      RCTs define precise clinical end points, maximize adherence, minimize variance of clinical conditions, and are limited to relatively homogeneous patient populations through strict eligibility criteria and controlled conditions.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
      During RCTs, patients are managed according to study-defined protocols and typically undergo more intensive monitoring than in routine practice, with more detailed collection and recording of data than is typical in ordinary medical records.
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.
      In addition, randomization in RCTs aims to minimize bias by balancing patient characteristics between treatment groups and thereby maximizes the likelihood that any observed differences result from differences in assigned study treatments.
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
      Although RCTs can provide crucial information on the tolerability and efficacy of a treatment, certain aspects of RCTs limit the applicability of their results to all patients.
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
      RCTs typically comprise patient populations that are relatively homogenous and not identical to patient populations outside of RCTs.
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
      The use of large-scale, highly selected patient populations in RCTs creates high statistical power, which can lead to the detection of statistically significant but small differences in patient outcomes.
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
      Patient education and tightly controlled treatment administration are standard in many RCTs and may result in higher rates of treatment adherence and, therefore, improved response rates compared with those in routine clinical practice.
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      • Ibrahim A.R.
      • Eliasson L.
      • Apperley J.F.
      • Milojkovic D.
      • Bua M.
      • Szydlo R.
      • et al.
      Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy.
      Real-world data (RWD) are data regarding patient health status and health care delivery that are routinely collected from a variety of sources, including patient registries, databases, clinical case reports, claims and billing reports, medical devices, and electronic health records; RWD are analyzed in accordance with high-quality research methods and can be valuable for complementing the information obtained from conventional clinical trials.
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.

      US Food and Drug Administration. Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: Guidance for Industry and Food and Drug Administration Staff. Available at: https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm513027.pdf. Accessed 2 October 2017.

      In addition, social media as well as electronic devices and apps that continuously monitor patient biometrics are massive data sources that can be used for epidemiologic purposes.
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.
      Results from certain types of clinical trials (those with less stringent enrollment criteria and patient-management guidelines than in conventional RCTs) can also be considered RWD.
      • Price D.
      • Bateman E.D.
      • Chisholm A.
      • Papadopoulos N.G.
      • Bosnic-Anticevich S.
      • Pizzichini E.
      • et al.
      Complementing the randomized controlled trial evidence base. evolution not revolution.
      Real-world evidence (RWE) is clinical evidence derived from the analysis of RWD regarding the use, as well as the benefits and risks associated with the use, of a medical product.
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.

      US Food and Drug Administration. Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: Guidance for Industry and Food and Drug Administration Staff. Available at: https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm513027.pdf. Accessed 2 October 2017.

      Importantly, RWE is not anecdotal but requires validation and standardization of data.

      Berger M, Daniel G, Frank K, et al; Duke-Margolis Center for Health Policy. A Framework for Regulatory Use of Real-World Evidence. Available at: https://healthpolicy.duke.edu/sites/default/files/atoms/files/rwe_white_paper_2017.09.06.pdf. Accessed 3 April 2018.

      RWD may uncover aspects of disease management that could be optimized to improve patient care.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      Analysis and interpretation of RWD may also help to guide the development of improved health plan operations, health system administration, patient or provider communications, cost management, and epidemiologic research. RWD can also contribute to the design of more efficient RCTs.

      Berger M, Daniel G, Frank K, et al; Duke-Margolis Center for Health Policy. A Framework for Regulatory Use of Real-World Evidence. Available at: https://healthpolicy.duke.edu/sites/default/files/atoms/files/rwe_white_paper_2017.09.06.pdf. Accessed 3 April 2018.

      In the chronic myeloid leukemia (CML) field, RWE can potentially contribute substantially to the understanding and optimization of real-life treatment patterns and patient outcomes. RWE can reveal insights into patient quality of life, the actual frequency of disease monitoring in clinical practice, factors that contribute to treatment intolerance or discontinuation, factors that determine treatment choice, patterns of treatment switching and associated outcomes, and health care resource utilization and costs.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      • Latremouille-Viau D.
      • Guerin A.
      • Gagnon-Sanschagrin P.
      • Dea K.
      • Cohen B.G.
      • Joseph G.J.
      Health care resource utilization and costs in patients with chronic myeloid leukemia with better adherence to tyrosine kinase inhibitors and increased molecular monitoring frequency.
      • Goldberg S.L.
      • Cortes J.E.
      • Gambacorti-Passerini C.
      • Hehlmann R.
      • Khoury H.J.
      • Michallet M.
      • et al.
      First-line treatment selection and early monitoring patterns in chronic phase-chronic myeloid leukemia in routine clinical practice: SIMPLICITY.
      • Latagliata R.
      • Breccia M.
      • Carmosino I.
      • Cannella L.
      • De Cuia R.
      • Diverio D.
      • et al.
      Real-life" results of front-line treatment with imatinib in older patients (≥ 65 years) with newly diagnosed chronic myelogenous leukemia.
      • Michallet M.
      • Tulliez M.
      • Corm S.
      • Gardembas M.
      • Huguet F.
      • Oukessou A.
      • et al.
      Management of chronic myeloid leukaemia in clinical practice in France: results of the French subset of patients from the UNIC study.
      Results from RWE studies, as well as those from RCTs, must be interpreted with consideration of their limitations,
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
      and the quality of RWD should be assessed according to the specific clinical or regulatory context that the data are intended to serve.

      Berger M, Daniel G, Frank K, et al; Duke-Margolis Center for Health Policy. A Framework for Regulatory Use of Real-World Evidence. Available at: https://healthpolicy.duke.edu/sites/default/files/atoms/files/rwe_white_paper_2017.09.06.pdf. Accessed 3 April 2018.

      Materials and Methods

      In this analysis, the US Food and Drug Administration (FDA) guidance documents on the use of RWE in regulatory decision making (Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: Guidance for Industry and FDA Staff

      US Food and Drug Administration. Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: Guidance for Industry and Food and Drug Administration Staff. Available at: https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm513027.pdf. Accessed 2 October 2017.

      and Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities—Questions and Answers: Guidance for Industry and Review Staff

      US Food and Drug Administration. Drug and device manufacturer communications with payors, formulary committees, and similar entities—questions and answers: guidance for industry and review staff. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm537347.pdf. Accessed 10 August 2017.

      ) were reviewed. To identify studies using RWD and RWE in CML, a PubMed literature search was conducted using search terms including ‘chronic myeloid leukemia’ AND (‘real-world’ OR ‘registry’). Recent congress abstracts reporting the results from real-world analyses were also reviewed. Representative publications were selected for inclusion in this review. No predefined criteria were established to select publications; rather, publications were selected that would allow for the presentation of a broad summary of the use of RWD and RWE in the CML field.

      Results

       FDA Guidance on RWE

      The FDA has issued guidance documents on the use of RWE to support regulatory decision making with regard to medical devices and on the communication of certain types of RWD (namely, health care economic information) between manufacturers and payers and formulary committees.

      US Food and Drug Administration. Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: Guidance for Industry and Food and Drug Administration Staff. Available at: https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm513027.pdf. Accessed 2 October 2017.

      US Food and Drug Administration. Drug and device manufacturer communications with payors, formulary committees, and similar entities—questions and answers: guidance for industry and review staff. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm537347.pdf. Accessed 10 August 2017.

      Additionally, contributors from several offices within the FDA published an editorial article in The New England Journal of Medicine in 2016 discussing RWE and its place in medical research.
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.
      The specific recommendations in the FDA guidance document on the use of RWE in regulatory decision making focus on medical devices; however, the definitions and characteristics of valid RWD included in this guidance are relevant to research on pharmaceutical approaches as well.

      21st Century Cures act, Publication no. 114–255, 130 Stat 1033.

      The FDA states that RWE can support and inform conclusions on the performance of medical products if the RWD that generate RWE meet certain evidentiary standards. The FDA notes that potential sources of RWD are to be selected based on the ability of these sources to address a specific question, and the FDA emphasizes the importance of ensuring accuracy, relevance, and reliability when evaluating RWD.

      US Food and Drug Administration. Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: Guidance for Industry and Food and Drug Administration Staff. Available at: https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm513027.pdf. Accessed 2 October 2017.

      In its guidance on communication of health care economic information, the FDA carefully outlines the information about a study that must be communicated to ensure understanding and appropriate interpretation of the results; the study information includes background and contextual information as well as clear and prominent explanations of the study design and methodology (eg, type of analysis, patient population, time horizon, and assumptions), generalizability, limitations, associated sensitivity analyses, and other supporting information.

      US Food and Drug Administration. Drug and device manufacturer communications with payors, formulary committees, and similar entities—questions and answers: guidance for industry and review staff. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm537347.pdf. Accessed 10 August 2017.

       Types of RWE Studies

      RWE studies can be prospective (eg, observational reports from patient registries or pragmatic trials) or retrospective (eg, analyses of claims databases or medical records).

      US Food and Drug Administration. Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: Guidance for Industry and Food and Drug Administration Staff. Available at: https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm513027.pdf. Accessed 2 October 2017.

      Prospective observational studies using data from patient registries offer a mechanism to follow up on a large cohort of patients and collect information on outcomes of interest over time.
      • Hoffmann V.S.
      • Baccarani M.
      • Hasford J.
      • Castagnetti F.
      • Di Raimondo F.
      • Casado L.F.
      • et al.
      Treatment and outcome of 2904 CML patients from the EUTOS population-based registry.
      Patient registries can be used to address several research questions by prospectively collecting information on many topics, such as compliance, patient experience, the frequency of rare events, health care access, and outcomes among heterogeneous patient populations.
      Some prospective clinical trials can also be considered RWE studies.
      • Price D.
      • Bateman E.D.
      • Chisholm A.
      • Papadopoulos N.G.
      • Bosnic-Anticevich S.
      • Pizzichini E.
      • et al.
      Complementing the randomized controlled trial evidence base. evolution not revolution.
      These clinical trials, sometimes referred to as pragmatic trials, are distinct from conventional RCTs in that they typically have less stringent enrollment criteria and on-study management protocols. As a result, they are expected to better reflect routine clinical practice.
      • Price D.
      • Bateman E.D.
      • Chisholm A.
      • Papadopoulos N.G.
      • Bosnic-Anticevich S.
      • Pizzichini E.
      • et al.
      Complementing the randomized controlled trial evidence base. evolution not revolution.
      Retrospective cohort analyses use previously recorded information from insurance claims databases or patient medical records to analyze outcomes in a patient cohort of interest or to compare outcomes among cohorts.
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.
      • Motheral B.
      • Brooks J.
      • Clark M.A.
      • Crown W.H.
      • Davey P.
      • Hutchins D.
      • et al.
      A checklist for retrospective database studies--report of the ISPOR task force on retrospective databases.
      • Henk H.J.
      • Woloj M.
      • Shapiro M.
      • Whiteley J.
      Real-world analysis of tyrosine kinase inhibitor treatment patterns among patients with chronic myeloid leukemia in the United States.
      • Latremouille-Viau D.
      • Guerin A.
      • Nitulescu R.
      • Gagnon P.S.
      • Joseph G.J.
      • Chen L.
      Treatment patterns and healthcare costs among newly-diagnosed patients with chronic myeloid leukemia receiving dasatinib or nilotinib as first-line therapy in the United States.
      • Häyrinen K.
      • Saranto K.
      • Nykänen P.
      Definition, structure, content, use and impacts of electronic health records: a review of the research literature.
      One type of retrospective cohort analysis is a retrospective claims database study, in which data on treatments and outcomes are gathered from billing codes submitted to payers; these databases can be a robust, expedient, and inexpensive source of data.
      • Motheral B.
      • Brooks J.
      • Clark M.A.
      • Crown W.H.
      • Davey P.
      • Hutchins D.
      • et al.
      A checklist for retrospective database studies--report of the ISPOR task force on retrospective databases.
      Analyses of patient medical records, including electronic health records, can capture data on management practices.
      • Häyrinen K.
      • Saranto K.
      • Nykänen P.
      Definition, structure, content, use and impacts of electronic health records: a review of the research literature.
      Medical records contain information such as symptoms and impact of various treatment strategies and provide clinical or operational data that can guide future clinical practice and reveal epidemiologic trends.
      • Häyrinen K.
      • Saranto K.
      • Nykänen P.
      Definition, structure, content, use and impacts of electronic health records: a review of the research literature.
      Longitudinal studies of medical records enable the evaluation of patient variables that may not be included in RCTs.
      • Häyrinen K.
      • Saranto K.
      • Nykänen P.
      Definition, structure, content, use and impacts of electronic health records: a review of the research literature.
      Another source of RWD is patient surveys, which are designed to assess patient experiences or opinions.
      • Geissler J.
      • Sharf G.
      • Bombaci F.
      • Daban M.
      • De Jong J.
      • Gavin T.
      • et al.
      Factors influencing adherence in CML and ways to improvement: results of a patient-driven survey of 2546 patients in 63 countries.
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      • Mullins C.D.
      Using real-world data for coverage and payment decisions: the ISPOR Real-World Data Task Force report.

       Role of RWE

       Data Gaps Not Addressed in RCTs

      RWE can provide insights not readily attainable from RCTs (Table I).
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
      Specific patient populations, such as elderly patients, pregnant patients, or patients with specific comorbidities, are often excluded from clinical trials.
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
      • Hutchins L.F.
      • Unger J.M.
      • Crowley J.J.
      • Coltman C.A.
      • Albain K.S.
      Underrepresentation of patients 65 years of age or older in cancer-treatment trials.
      RWE studies can provide insight into the outcomes of patient populations that may be underrepresented in RCTs.
      • Bach P.B.
      • Cramer L.D.
      • Warren J.L.
      • Begg C.B.
      Racial differences in the treatment of early-stage lung cancer.
      • Hershman D.
      • McBride R.
      • Jacobson J.S.
      • Lamerato L.
      • Roberts K.
      • Grann V.R.
      • et al.
      Racial disparities in treatment and survival among women with early-stage breast cancer.
      • Tyldesley S.
      • Zhang-Salomons J.
      • Groome P.A.
      • Zhou S.
      • Schulze K.
      • Paszat L.F.
      • et al.
      Association between age and the utilization of radiotherapy in Ontario.
      • Unger J.M.
      • Hershman D.L.
      • Albain K.S.
      • Moinpour C.M.
      • Petersen J.A.
      • Burg K.
      • et al.
      Patient income level and cancer clinical trial participation.
      These analyses are important supplements to the data obtained in conventional RCTs; for example, patients with comorbidities may experience greater toxicity in clinical practice than is observed in trials.
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
      Most RCTs focus on therapeutic efficacy and short-term toxicity; long-term tolerability and patient-centered outcomes, such as quality of life, may not be fully captured.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
      In contrast, longer study durations and large-scale databases used in RWE studies can reveal rare adverse events (AEs), assess the true incidence and impact of AEs in routine clinical practice, and monitor AEs that emerge after long-term treatment; they can also be a valuable source of information on patient-centered outcomes.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      • Ligthelm R.J.
      • Borzì V.
      • Gumprecht J.
      • Kawamori R.
      • Wenying Y.
      • Valensi P.
      Importance of observational studies in clinical practice.
      Small differences in response rates or survival that are evident in a large-scale RCT may not be observed in routine practice with a less homogeneous patient population.
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
      RWE studies can follow RCTs to report on patterns of patient management, toxicity, and treatment outcomes in routine clinical practice; assess how outcomes evolve in a real-world setting; and determine whether clinical practice changed as a result of the study's findings.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
      • Ligthelm R.J.
      • Borzì V.
      • Gumprecht J.
      • Kawamori R.
      • Wenying Y.
      • Valensi P.
      Importance of observational studies in clinical practice.
      RWE can also be used to evaluate the cost-effectiveness of available treatments.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      Table IContributions of conventional clinical trials and real-world evidence (RWE) to end points used generally in research and specifically in chronic myeloid leukemia (CML).
      End PointClinical TrialsRWE
      Research studies
       ResponseShort-term treatment effects
      • Cortes J.E.
      • Kim D.W.
      • Pinilla-Ibarz J.
      • le Coutre P.
      • Paquette R.
      • Chuah C.
      • et al.
      A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.


      Impact on risk for developing a condition or disease complication
      • Banerji A.
      • Riedl M.A.
      • Bernstein J.A.
      • Cicardi M.
      • Longhurst H.J.
      • Zuraw B.L.
      • et al.
      Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks: a randomized clinical trial.


      Impact on disease symptoms
      • Agar M.R.
      • Lawlor P.G.
      • Quinn S.
      • Draper B.
      • Caplan G.A.
      • Rowett D.
      • et al.
      Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial.


      Response rate at discrete time points
      • Cortes J.E.
      • Kim D.W.
      • Pinilla-Ibarz J.
      • le Coutre P.
      • Paquette R.
      • Chuah C.
      • et al.
      A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • Larson R.A.
      • Kim D.W.
      • Issaragrisil S.
      • et al.
      Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • Baccarani M.
      • Mayer J.
      • Boqué C.
      • et al.
      Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial.
      Long-term treatment effects
      • Ganesan P.
      • Sagar T.G.
      • Dubashi B.
      • Rajendranath R.
      • Kannan K.
      • Cyriac S.
      • et al.
      Nonadherence to imatinib adversely affects event free survival in chronic phase-chronic myeloid leukemia.


      Impact on risk for developing a condition or disease complication over time
      • Chi N.F.
      • Wen C.P.
      • Liu C.H.
      • Li J.Y.
      • Jeng J.S.
      • Chen C.H.
      • et al.
      Comparison between aspirin and clopidogrel in secondary stroke prevention based on real-world data.


      Outcomes in patients not typically included in RCTs
      • Assi R.
      • Kantarjian H.M.
      • Keating M.J.
      • Pemmaraju N.
      • Verstovsek S.
      • Garcia-Manero G.
      • et al.
      Management of chronic myeloid leukemia (CML) during pregnancy among patients (pts) treated with a tyrosine kinase inhibitor (TKI): a single-center experience.
      • Smith B.D.
      • Liu J.
      • Latremouille-Viau D.
      • Guerin A.
      • Fernandez D.
      • Chen L.
      Treatment patterns, overall survival, healthcare resource use and costs in elderly Medicare beneficiaries with chronic myeloid leukemia using second-generation tyrosine kinase inhibitors as second-line therapy.


      Response rates in clinical practice
      • Goldberg S.L.
      • Chen L.
      • Guerin A.
      • Macalalad A.R.
      • Liu N.
      • Kaminsky M.
      • et al.
      Association between molecular monitoring and long-term outcomes in chronic myelogenous leukemia patients treated with first line imatinib.


      Real-world disease-management practices
      • Goldberg S.L.
      • Chen L.
      • Guerin A.
      • Macalalad A.R.
      • Liu N.
      • Kaminsky M.
      • et al.
      Association between molecular monitoring and long-term outcomes in chronic myelogenous leukemia patients treated with first line imatinib.
       SurvivalOS at discrete time points
      • Cortes J.E.
      • Kim D.W.
      • Pinilla-Ibarz J.
      • le Coutre P.
      • Paquette R.
      • Chuah C.
      • et al.
      A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • Larson R.A.
      • Kim D.W.
      • Issaragrisil S.
      • et al.
      Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • Baccarani M.
      • Mayer J.
      • Boqué C.
      • et al.
      Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial.


      Reported causes of death
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • Larson R.A.
      • Kim D.W.
      • Issaragrisil S.
      • et al.
      Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.
      Long-term survival
      • Haque R.
      • Shi J.
      • Chung J.
      • Xu X.
      • Avila C.
      • Campbell C.
      • et al.
      Medication adherence, molecular monitoring, and clinical outcomes in patients with chronic myelogenous leukemia in a large HMO.
      • Pfirrmann M.
      • Baccarani M.
      • Saussele S.
      • Guilhot J.
      • Cervantes F.
      • Ossenkoppele G.
      • et al.
      Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia.


      Survival in patients not typically included in RCTs
      • Smith B.D.
      • Liu J.
      • Latremouille-Viau D.
      • Guerin A.
      • Fernandez D.
      • Chen L.
      Treatment patterns, overall survival, healthcare resource use and costs in elderly Medicare beneficiaries with chronic myeloid leukemia using second-generation tyrosine kinase inhibitors as second-line therapy.
       QOLQOL at start of analysis and discrete short-term time points
      • Hochhaus A.
      • Masszi T.
      • Giles F.J.
      • Radich J.P.
      • Ross D.M.
      • Gómez Casares M.T.
      • et al.
      Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.
      • Mahon F.X.
      • Boquimpani C.M.
      • Takahashi N.
      • Benyamini N.
      • Clementino N.C.D.
      • Shuvaev V.
      • et al.
      Patient-reported quality of life before and after stopping treatment in the ENESTop trial of treatment-free remission for patients with chronic myeloid leukemia in chronic phase.
      • Trask P.C.
      • Cella D.
      • Powell C.
      • Reisman A.
      • Whiteley J.
      • Kelly V.
      Health-related quality of life in chronic myeloid leukemia.
      • Trask P.C.
      • Cella D.
      • Besson N.
      • Kelly V.
      • Masszi T.
      • Kim D.W.
      Health-related quality of life of bosutinib (SKI-606) in imatinib-resistant or imatinib-intolerant chronic phase chronic myeloid leukemia.
      QOL
      • Williams L.A.
      • Gonzalez A.G.G.
      • Ault P.
      • Mendoza T.R.
      • Sailors M.L.
      • Williams J.L.
      • et al.
      Measuring the symptom burden associated with the treatment of chronic myeloid leukemia.
       TolerabilityDetailed data on adverse events occurring early during treatment
      • Cortes J.E.
      • Kim D.W.
      • Pinilla-Ibarz J.
      • le Coutre P.
      • Paquette R.
      • Chuah C.
      • et al.
      A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.


      Treatment discontinuation
      • Cortes J.E.
      • Kim D.W.
      • Pinilla-Ibarz J.
      • le Coutre P.
      • Paquette R.
      • Chuah C.
      • et al.
      A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • Larson R.A.
      • Kim D.W.
      • Issaragrisil S.
      • et al.
      Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • Baccarani M.
      • Mayer J.
      • Boqué C.
      • et al.
      Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial.
      Long-term treatment side effects and complications
      • Sam P.Y.
      • Ahaneku H.
      • Nogueras-Gonzalez G.M.
      • Jabbour E.
      • Garcia-Manero G.
      • Borthakur G.
      • et al.
      Cardiovascular events among patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs).
      CML research studies
       ResponseMolecular, cytogenetic, and hematologic response rates at discrete time points
      • Cortes J.E.
      • Kim D.W.
      • Pinilla-Ibarz J.
      • le Coutre P.
      • Paquette R.
      • Chuah C.
      • et al.
      A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • Larson R.A.
      • Kim D.W.
      • Issaragrisil S.
      • et al.
      Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • Baccarani M.
      • Mayer J.
      • Boqué C.
      • et al.
      Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial.


      Kinetics of reduction in BCR-ABL1 transcript levels
      • Cortes J.E.
      • Gambacorti-Passerini C.
      • Deininger M.W.
      • Mauro M.J.
      • Chuah C.
      • Kim D.W.
      • et al.
      Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial.


      Assessment of whether a patient meets designated treatment response landmarks (eg, target response levels at 3, 6, and 12 months from the start of treatment)
      • Cortes J.E.
      • Gambacorti-Passerini C.
      • Deininger M.W.
      • Mauro M.J.
      • Chuah C.
      • Kim D.W.
      • et al.
      Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial.


      Rates of CML progression at early time points
      • Cortes J.E.
      • Gambacorti-Passerini C.
      • Deininger M.W.
      • Mauro M.J.
      • Chuah C.
      • Kim D.W.
      • et al.
      Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial.


      Development of evidence supporting new treatment practices, such as criteria for attempting treatment-free remission
      • Hochhaus A.
      • Masszi T.
      • Giles F.J.
      • Radich J.P.
      • Ross D.M.
      • Gómez Casares M.T.
      • et al.
      Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.
      • National Comprehensive Cancer Network
      Clinical practice guidelines in oncology. Chronic myeloid leukemia. V1..
      • Saussele S.
      • Richter J.
      • Hochhaus A.
      • Mahon F.X.
      The concept of treatment-free remission in chronic myeloid leukemia.
      • Etienne G.
      • Guilhot J.
      • Rea D.
      • Rigal-Huguet F.
      • Nicolini F.
      • Charbonnier A.
      • et al.
      Long-term follow-up of the French Stop Imatinib (STIM1) study in patients with chronic myeloid leukemia.
      • Hochhaus A.
      • Saussele S.
      • Rosti G.
      • Mahon F.X.
      • Janssen J.J.W.M.
      • Hjorth-Hansen H.
      • et al.
      Chronic myeloid leukemia: EMSO Clinical Practice Guidelines for diagnosis, treatment, and follow-up.
      • Mahon F.X.
      • Boquimpani C.
      • Kim D.W.
      • Benyamini N.
      • Clementino N.C.D.
      • Shuvaev V.
      • et al.
      Treatment-free remission after second-line nilotinib treatment in patients with chronic myeloid leukemia in chronic phase: results from a single-group, phase 2, open-label study.
      • Ross D.M.
      • Masszi T.
      • Gómez Casares M.T.
      • Hellmann A.
      • Stentoft J.
      • Conneally E.
      • et al.
      Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study.
      • Rousselot P.
      • Charbonnier A.
      • Cony-Makhoul P.
      • Agape P.
      • Nicolini F.E.
      • Varet B.
      • et al.
      Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease.
      Long-term treatment effects
      • Ganesan P.
      • Sagar T.G.
      • Dubashi B.
      • Rajendranath R.
      • Kannan K.
      • Cyriac S.
      • et al.
      Nonadherence to imatinib adversely affects event free survival in chronic phase-chronic myeloid leukemia.


      Long-term rates of CML progression
      • Haque R.
      • Shi J.
      • Chung J.
      • Xu X.
      • Avila C.
      • Campbell C.
      • et al.
      Medication adherence, molecular monitoring, and clinical outcomes in patients with chronic myelogenous leukemia in a large HMO.


      Rates of treatment failure in clinical practice
      • Hoffmann V.S.
      • Baccarani M.
      • Hasford J.
      • Castagnetti F.
      • Di Raimondo F.
      • Casado L.F.
      • et al.
      Treatment and outcome of 2904 CML patients from the EUTOS population-based registry.
      • Smith B.D.
      • Liu J.
      • Latremouille-Viau D.
      • Guerin A.
      • Fernandez D.
      • Chen L.
      Treatment patterns, overall survival, healthcare resource use and costs in elderly Medicare beneficiaries with chronic myeloid leukemia using second-generation tyrosine kinase inhibitors as second-line therapy.


      Analysis of treatment switching patterns, including rates of treatment switch due to treatment failure
      • Hoffmann V.S.
      • Baccarani M.
      • Hasford J.
      • Castagnetti F.
      • Di Raimondo F.
      • Casado L.F.
      • et al.
      Treatment and outcome of 2904 CML patients from the EUTOS population-based registry.
      • Smith B.D.
      • Liu J.
      • Latremouille-Viau D.
      • Guerin A.
      • Fernandez D.
      • Chen L.
      Treatment patterns, overall survival, healthcare resource use and costs in elderly Medicare beneficiaries with chronic myeloid leukemia using second-generation tyrosine kinase inhibitors as second-line therapy.


      Analysis of treatment-free remission practices and outcomes in clinical practice
      • Ritchie E.K.
      • Wolff J.E.
      • Latremouille-Viau D.
      • Guerin A.
      • Pivneva I.
      • Briggs O.
      • et al.
      Tyrosine kinase inhibitor (TKI) therapy discontinuation in patients with CML in chronic phase: a US clinical practice perspective.


      Outcomes in patients not typically included in RCTs
      • Assi R.
      • Kantarjian H.M.
      • Keating M.J.
      • Pemmaraju N.
      • Verstovsek S.
      • Garcia-Manero G.
      • et al.
      Management of chronic myeloid leukemia (CML) during pregnancy among patients (pts) treated with a tyrosine kinase inhibitor (TKI): a single-center experience.
      • Smith B.D.
      • Liu J.
      • Latremouille-Viau D.
      • Guerin A.
      • Fernandez D.
      • Chen L.
      Treatment patterns, overall survival, healthcare resource use and costs in elderly Medicare beneficiaries with chronic myeloid leukemia using second-generation tyrosine kinase inhibitors as second-line therapy.


      Response rates in clinical practice
      • Goldberg S.L.
      • Chen L.
      • Guerin A.
      • Macalalad A.R.
      • Liu N.
      • Kaminsky M.
      • et al.
      Association between molecular monitoring and long-term outcomes in chronic myelogenous leukemia patients treated with first line imatinib.


      Real-world disease management practices
      • Goldberg S.L.
      • Chen L.
      • Guerin A.
      • Macalalad A.R.
      • Liu N.
      • Kaminsky M.
      • et al.
      Association between molecular monitoring and long-term outcomes in chronic myelogenous leukemia patients treated with first line imatinib.
       SurvivalOS at discrete time points
      • Cortes J.E.
      • Kim D.W.
      • Pinilla-Ibarz J.
      • le Coutre P.
      • Paquette R.
      • Chuah C.
      • et al.
      A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • Larson R.A.
      • Kim D.W.
      • Issaragrisil S.
      • et al.
      Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • Baccarani M.
      • Mayer J.
      • Boqué C.
      • et al.
      Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial.


      Reported causes of death
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • Larson R.A.
      • Kim D.W.
      • Issaragrisil S.
      • et al.
      Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.
      Long-term survival
      • Haque R.
      • Shi J.
      • Chung J.
      • Xu X.
      • Avila C.
      • Campbell C.
      • et al.
      Medication adherence, molecular monitoring, and clinical outcomes in patients with chronic myelogenous leukemia in a large HMO.
      • Pfirrmann M.
      • Baccarani M.
      • Saussele S.
      • Guilhot J.
      • Cervantes F.
      • Ossenkoppele G.
      • et al.
      Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia.


      Long-term rate of CML-related deaths
      • Pfirrmann M.
      • Baccarani M.
      • Saussele S.
      • Guilhot J.
      • Cervantes F.
      • Ossenkoppele G.
      • et al.
      Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia.


      Survival in patients not typically included in RCTs
      • Smith B.D.
      • Liu J.
      • Latremouille-Viau D.
      • Guerin A.
      • Fernandez D.
      • Chen L.
      Treatment patterns, overall survival, healthcare resource use and costs in elderly Medicare beneficiaries with chronic myeloid leukemia using second-generation tyrosine kinase inhibitors as second-line therapy.
       QOLQOL at start of analysis and discrete short-term time points
      • Hochhaus A.
      • Masszi T.
      • Giles F.J.
      • Radich J.P.
      • Ross D.M.
      • Gómez Casares M.T.
      • et al.
      Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.
      • Mahon F.X.
      • Boquimpani C.M.
      • Takahashi N.
      • Benyamini N.
      • Clementino N.C.D.
      • Shuvaev V.
      • et al.
      Patient-reported quality of life before and after stopping treatment in the ENESTop trial of treatment-free remission for patients with chronic myeloid leukemia in chronic phase.
      • Trask P.C.
      • Cella D.
      • Powell C.
      • Reisman A.
      • Whiteley J.
      • Kelly V.
      Health-related quality of life in chronic myeloid leukemia.
      • Trask P.C.
      • Cella D.
      • Besson N.
      • Kelly V.
      • Masszi T.
      • Kim D.W.
      Health-related quality of life of bosutinib (SKI-606) in imatinib-resistant or imatinib-intolerant chronic phase chronic myeloid leukemia.
      QOL
      • Williams L.A.
      • Gonzalez A.G.G.
      • Ault P.
      • Mendoza T.R.
      • Sailors M.L.
      • Williams J.L.
      • et al.
      Measuring the symptom burden associated with the treatment of chronic myeloid leukemia.
       TolerabilityDetailed data on adverse events occurring early during treatment
      • Cortes J.E.
      • Kim D.W.
      • Pinilla-Ibarz J.
      • le Coutre P.
      • Paquette R.
      • Chuah C.
      • et al.
      A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.


      Treatment discontinuation
      • Cortes J.E.
      • Kim D.W.
      • Pinilla-Ibarz J.
      • le Coutre P.
      • Paquette R.
      • Chuah C.
      • et al.
      A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • Larson R.A.
      • Kim D.W.
      • Issaragrisil S.
      • et al.
      Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • Baccarani M.
      • Mayer J.
      • Boqué C.
      • et al.
      Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial.
      Long-term treatment side effects and complications
      • Sam P.Y.
      • Ahaneku H.
      • Nogueras-Gonzalez G.M.
      • Jabbour E.
      • Garcia-Manero G.
      • Borthakur G.
      • et al.
      Cardiovascular events among patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs).
      OS, overall survival; QOL, quality of life; RCT, randomized controlled trial; RWE, real-world evidence.

       Weaknesses and Challenges Associated With RWE

      Observational studies are important in epidemiologic investigations and surveillance; however, when treatment effects are assessed, it is difficult to conclusively determine whether any observed differences were due to the treatment rather than confounding factors.
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.
      Because of their relatively flexible study designs and heterogeneous patient populations, RWE studies may not detect small differences between treatment groups.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      A nonrandomized design limits the internal validity of RWD and increases the risk for bias, which may increase the risk for generating unreliable conclusions.
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
      • Ligthelm R.J.
      • Borzì V.
      • Gumprecht J.
      • Kawamori R.
      • Wenying Y.
      • Valensi P.
      Importance of observational studies in clinical practice.
      Observational studies are associated with an increased risk for incomplete datasets, which complicate statistical analysis.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      Many RWD sources are not designed for research purposes; therefore, the accuracy and reliability of data collected from these sources may be unknown.
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.
      Researchers must be clear about how RWE can be used most effectively; RWE studies are intended to complement, not compete with or replace, RCTs.
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.
      • Ligthelm R.J.
      • Borzì V.
      • Gumprecht J.
      • Kawamori R.
      • Wenying Y.
      • Valensi P.
      Importance of observational studies in clinical practice.

       RWE Studies in CML

      CML accounts for ∼15% of all cases of leukemia in adults.
      • National Comprehensive Cancer Network
      Clinical practice guidelines in oncology. Chronic myeloid leukemia. V1..
      The disease is characterized by 3 phases: chronic phase, accelerated phase, and blast crisis. The treatment landscape in patients with CML changed after the approval of imatinib, a tyrosine kinase inhibitor (TKI), in 2001.
      Since then, several newer TKIs have also been approved, and TKI therapy is now the recommended treatment for patients with CML.
      • National Comprehensive Cancer Network
      Clinical practice guidelines in oncology. Chronic myeloid leukemia. V1..
      Due to the substantial efficacy of TKI therapy, life expectancy in patients with CML now approaches that of the general population.
      • Bower H.
      • Björkholm M.
      • Dickman P.W.
      • Höglund M.
      • Lambert P.C.
      • Andersson T.M.
      Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population.
      The management of TKI therapy over time and the possibility of permanently stopping therapy have been, and are still, topics of much investigation.
      There are several areas in which RWE can contribute to the understanding and optimization of CML-management practices. Many RWE studies have informed early treatment milestones in CML. An RWE study in 483 patients (median age, 48 years) with newly diagnosed CML treated with first-line TKIs showed that 3-month BCR-ABL1 level significantly predicted 3-year event-free survival (EFS); 3-year EFS rates based on BCR-ABL1 transcript levels on the International Scale (IS) at 3 months were 95% if BCR-ABL1IS was ≤1%, 98% if BCR-ABL1IS was >1% to 10%, and 61% if BCR-ABL1IS was >10%.
      • Jain P.
      • Kantarjian H.
      • Nazha A.
      • O'Brien S.
      • Jabbour E.
      • Romo C.G.
      • et al.
      Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities.
      A similar result was seen in a study in 282 patients (median age, 46 years; female, 44.3%) treated with imatinib as first-line therapy, which showed that of BCR-ABL1 transcript levels at 3, 6, and 12 months, the transcript level at 3 months was the most strongly predictive of progression-free survival, overall survival, and complete molecular response; additionally, at 6 and 12 months, BCR-ABL1 transcript levels were more predictive of outcomes than were cytogenetic responses.
      • Marin D.
      • Ibrahim A.R.
      • Lucas C.
      • Gerrard G.
      • Wang L.
      • Szydlo R.M.
      • et al.
      Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors.
      RWE studies can also be useful for helping to better understand the actual patterns of TKI use and CML management in clinical practice, as well as patient perspectives on their disease and treatment. One example of such a study is SIMPLICITY (Studying Interventions for Managing Patients With Chronic Myeloid Leukemia (CML) in Chronic Phase: The 5-Year Prospective Cohort Study), an observational study in 1242 patients (median age, 57 years; female, 45.3%) with CML treated with imatinib, nilotinib, or dasatinib as front-line therapy.
      • Goldberg S.L.
      • Cortes J.E.
      • Gambacorti-Passerini C.
      • Hehlmann R.
      • Khoury H.J.
      • Michallet M.
      • et al.
      First-line treatment selection and early monitoring patterns in chronic phase-chronic myeloid leukemia in routine clinical practice: SIMPLICITY.
      SIMPLICITY was designed to assess patterns of TKI use, resource utilization, and patient-reported outcomes such as quality of life and patient satisfaction in routine clinical practice.
      • Goldberg S.L.
      • Cortes J.E.
      • Gambacorti-Passerini C.
      • Hehlmann R.
      • Khoury H.J.
      • Michallet M.
      • et al.
      First-line treatment selection and early monitoring patterns in chronic phase-chronic myeloid leukemia in routine clinical practice: SIMPLICITY.

      ClinicalTrials.gov. Studying first line treatment of chronic myeloid leukemia (CML) in a real-world setting (SIMPLICITY). Available at: https://clinicaltrials.gov/ct2/show/NCT01244750. Accessed 7 May 2018.

      Early results from this study have suggested that disease-monitoring practices are rarely as rigorous as those recommended by the National Comprehensive Cancer Network or European LeukemiaNet and that many factors influence monitoring, such as where the patient is treated (Europe vs United States), type of practice (community vs academic), patient age (<65 vs ≥65 years), and whether the patient is receiving first- or second-line therapy.
      • Goldberg S.L.
      • Cortes J.E.
      • Gambacorti-Passerini C.
      • Hehlmann R.
      • Khoury H.J.
      • Michallet M.
      • et al.
      First-line treatment selection and early monitoring patterns in chronic phase-chronic myeloid leukemia in routine clinical practice: SIMPLICITY.
      Another example of an informative RWE study is the EUTOS (European Treatment Outcome Study) registry (N = 2904),
      • Hoffmann V.S.
      • Baccarani M.
      • Hasford J.
      • Lindoerfer D.
      • Burgstaller S.
      • Sertic D.
      • et al.
      The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in twenty European countries.
      which was created to gain a better understanding of patient treatment and outcome patterns in clinical practice. For the EUTOS registry, baseline, treatment, and outcomes data were collected from the records of all adult patients (no exclusion criteria; median age, 55 years; female, 46%) with newly diagnosed CML across several European countries.
      • Hoffmann V.S.
      • Baccarani M.
      • Hasford J.
      • Castagnetti F.
      • Di Raimondo F.
      • Casado L.F.
      • et al.
      Treatment and outcome of 2904 CML patients from the EUTOS population-based registry.
      • Hoffmann V.S.
      • Baccarani M.
      • Hasford J.
      • Lindoerfer D.
      • Burgstaller S.
      • Sertic D.
      • et al.
      The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in twenty European countries.
      One outcome in EUTOS was the development of the EUTOS prognostic score, a novel method of predicting a patient's likelihood of achieving a complete cytogenetic response and of identifying patients at a higher risk for progression and impaired survival based on patient baseline characteristics.
      • Hasford J.
      • Baccarani M.
      • Hoffmann V.
      • Guilhot J.
      • Saussele S.
      • Rosti G.
      • et al.
      Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score.
      • Hoffmann V.S.
      • Baccarani M.
      • Lindoerfer D.
      • Castagnetti F.
      • Turkina A.
      • Zaritsky A.
      • et al.
      The EUTOS prognostic score: review and validation in 1288 patients with CML treated frontline with imatinib.
      Because clinical trials generally enroll younger patients who are taking fewer medications, large-scale registries provide the opportunity to assess the impact of polypharmacy, and potentially specific drug–drug interactions, on CML outcomes. Notably, to this point, such studies have not shown polypharmacy to be a risk factor for poorer CML-related outcomes among elderly patients.
      • Iurlo A.
      • Nobili A.
      • Latagliata R.
      • Bucelli C.
      • Castagnetti F.
      • Breccia M.
      • et al.
      Imatinib and polypharmacy in very old patients with chronic myeloid leukemia: effects on response rate, toxicity and outcome.
      Factors associated with the long-term burden of CML, including treatment satisfaction and adherence, and the impact of chronic AEs on quality of life can be informed by RWE studies.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      • Williams L.A.
      • Gonzalez A.G.G.
      • Ault P.
      • Mendoza T.R.
      • Sailors M.L.
      • Williams J.L.
      • et al.
      Measuring the symptom burden associated with the treatment of chronic myeloid leukemia.
      The potential utility of RWE studies in this regard is highlighted by the development of the MD Anderson Symptom Inventory for CML, a questionnaire used for evaluating a patient's quality of life.
      • Williams L.A.
      • Gonzalez A.G.G.
      • Ault P.
      • Mendoza T.R.
      • Sailors M.L.
      • Williams J.L.
      • et al.
      Measuring the symptom burden associated with the treatment of chronic myeloid leukemia.
      This questionnaire was developed based on interviews and surveys of multiple cohorts of patients and CML experts.
      • Williams L.A.
      • Gonzalez A.G.G.
      • Ault P.
      • Mendoza T.R.
      • Sailors M.L.
      • Williams J.L.
      • et al.
      Measuring the symptom burden associated with the treatment of chronic myeloid leukemia.
      Interestingly, in 2 studies of patients stopping nilotinib treatment to attempt treatment-free remission (TFR), there was little change in quality of life following treatment discontinuation or treatment resumption, although pain/discomfort was notably more common after stopping treatment.
      • Hochhaus A.
      • Masszi T.
      • Giles F.J.
      • Radich J.P.
      • Ross D.M.
      • Gómez Casares M.T.
      • et al.
      Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.
      • Mahon F.X.
      • Boquimpani C.M.
      • Takahashi N.
      • Benyamini N.
      • Clementino N.C.D.
      • Shuvaev V.
      • et al.
      Patient-reported quality of life before and after stopping treatment in the ENESTop trial of treatment-free remission for patients with chronic myeloid leukemia in chronic phase.
      TFR has recently emerged as a treatment goal in CML on the basis of several clinical trials demonstrating that some patients with sustained deep molecular responses on long-term TKI therapy could stop treatment without losing their response.
      • Hochhaus A.
      • Masszi T.
      • Giles F.J.
      • Radich J.P.
      • Ross D.M.
      • Gómez Casares M.T.
      • et al.
      Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.
      • National Comprehensive Cancer Network
      Clinical practice guidelines in oncology. Chronic myeloid leukemia. V1..
      • Saussele S.
      • Richter J.
      • Hochhaus A.
      • Mahon F.X.
      The concept of treatment-free remission in chronic myeloid leukemia.
      • Etienne G.
      • Guilhot J.
      • Rea D.
      • Rigal-Huguet F.
      • Nicolini F.
      • Charbonnier A.
      • et al.
      Long-term follow-up of the French Stop Imatinib (STIM1) study in patients with chronic myeloid leukemia.
      • Hochhaus A.
      • Saussele S.
      • Rosti G.
      • Mahon F.X.
      • Janssen J.J.W.M.
      • Hjorth-Hansen H.
      • et al.
      Chronic myeloid leukemia: EMSO Clinical Practice Guidelines for diagnosis, treatment, and follow-up.
      • Mahon F.X.
      • Boquimpani C.
      • Kim D.W.
      • Benyamini N.
      • Clementino N.C.D.
      • Shuvaev V.
      • et al.
      Treatment-free remission after second-line nilotinib treatment in patients with chronic myeloid leukemia in chronic phase: results from a single-group, phase 2, open-label study.
      • Ross D.M.
      • Masszi T.
      • Gómez Casares M.T.
      • Hellmann A.
      • Stentoft J.
      • Conneally E.
      • et al.
      Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study.
      • Rousselot P.
      • Charbonnier A.
      • Cony-Makhoul P.
      • Agape P.
      • Nicolini F.E.
      • Varet B.
      • et al.
      Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease.
      The feasibility of TFR has been reproducibly demonstrated in several clinical trials; however, all of these trials have used stringent eligibility criteria.
      • Hochhaus A.
      • Masszi T.
      • Giles F.J.
      • Radich J.P.
      • Ross D.M.
      • Gómez Casares M.T.
      • et al.
      Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.
      • Saussele S.
      • Richter J.
      • Hochhaus A.
      • Mahon F.X.
      The concept of treatment-free remission in chronic myeloid leukemia.
      • Etienne G.
      • Guilhot J.
      • Rea D.
      • Rigal-Huguet F.
      • Nicolini F.
      • Charbonnier A.
      • et al.
      Long-term follow-up of the French Stop Imatinib (STIM1) study in patients with chronic myeloid leukemia.
      • Mahon F.X.
      • Boquimpani C.
      • Kim D.W.
      • Benyamini N.
      • Clementino N.C.D.
      • Shuvaev V.
      • et al.
      Treatment-free remission after second-line nilotinib treatment in patients with chronic myeloid leukemia in chronic phase: results from a single-group, phase 2, open-label study.
      • Ross D.M.
      • Masszi T.
      • Gómez Casares M.T.
      • Hellmann A.
      • Stentoft J.
      • Conneally E.
      • et al.
      Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study.
      • Rousselot P.
      • Charbonnier A.
      • Cony-Makhoul P.
      • Agape P.
      • Nicolini F.E.
      • Varet B.
      • et al.
      Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease.
      • Hughes T.P.
      • Ross D.M.
      Moving treatment-free remission into mainstream clinical practice in CML.
      Thus, analyses of RWD on TFR are important for understanding how this new concept can be incorporated into routine clinical practice,
      • Ritchie E.K.
      • Wolff J.E.
      • Latremouille-Viau D.
      • Guerin A.
      • Pivneva I.
      • Briggs O.
      • et al.
      Tyrosine kinase inhibitor (TKI) therapy discontinuation in patients with CML in chronic phase: a US clinical practice perspective.
      • Ritchie E.K.
      • Latremouille-Viau D.
      • Guerin A.
      • Pivneva I.
      • Habucky K.
      • Ndife B.
      • et al.
      Treatment patterns in patients with chronic myeloid leukemia in chronic phase in US clinical practice, with a focus on tyrosine kinase inhibitor therapy discontinuation.
      particularly following the addition, in the National Comprehensive Cancer Network guidelines on CML, of recommendations on the use of TFR in clinical practice, and the incorporation of TFR data into the labeling of nilotinib in the United States.
      • National Comprehensive Cancer Network
      Clinical practice guidelines in oncology. Chronic myeloid leukemia. V1..
      Notably, a survey of US physicians found that one-third reported having attempted TKI discontinuation prior to the availability of the National Comprehensive Cancer Network TFR guideline,
      • Ritchie E.K.
      • Wolff J.E.
      • Latremouille-Viau D.
      • Guerin A.
      • Pivneva I.
      • Briggs O.
      • et al.
      Tyrosine kinase inhibitor (TKI) therapy discontinuation in patients with CML in chronic phase: a US clinical practice perspective.
      further demonstrating the need for analyzing real-world treatment and management patterns.
      Long-term or late outcomes may not be captured during RCTs, whereas RWE studies can provide a picture of long-term outcomes with CML treatment.
      • Mauro M.J.
      • Davis C.
      • Zyczynski T.
      • Khoury H.J.
      The role of observational studies in optimizing the clinical management of chronic myeloid leukemia.
      For example, RWE studies may help to reveal whether the relative risk for short-term cardiovascular AEs reported in clinical trials
      • Cortes J.E.
      • Kim D.W.
      • Pinilla-Ibarz J.
      • le Coutre P.
      • Paquette R.
      • Chuah C.
      • et al.
      A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • Larson R.A.
      • Kim D.W.
      • Issaragrisil S.
      • et al.
      Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • Baccarani M.
      • Mayer J.
      • Boqué C.
      • et al.
      Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial.
      translates into a real risk for long-term cardiovascular toxicity in a wider population of patients with CML. One such retrospective RWE cohort study followed up 896 patients with CML (mean age at diagnosis, 58 years; female, 46%; 94.4% with documented TKI treatment) for a median of 4.2 years and compared the incidence of vascular events in these patients with the incidence of vascular events in age- and sex-matched patients in a control cohort.
      • Dahlén T.
      • Edgren G.
      • Lambe M.
      • Höglund M.
      • Björkholm M.
      • Sandin F.
      • et al.
      Cardiovascular events associated with use of tyrosine kinase inhibitors in chronic myeloid leukemia: a population-based cohort study.
      Patients with CML had greater risks for both arterial and venous vascular events than did patients in the control population. Data from an analysis comparing different types of TKI therapy were limited due to too few events for meaningful statistical evaluation; however, Dahlén et al.
      • Dahlén T.
      • Edgren G.
      • Lambe M.
      • Höglund M.
      • Björkholm M.
      • Sandin F.
      • et al.
      Cardiovascular events associated with use of tyrosine kinase inhibitors in chronic myeloid leukemia: a population-based cohort study.
      reported that patients treated with nilotinib or dasatinib had an increased rate of myocardial infarction events compared with patients who received imatinib. Another retrospective study examining RWD in 584 patients with CML treated with TKIs (median age at start of treatment, 49 years; female, 41%) reported that cardiovascular events occurred in 53% of patients, and the highest risk ratio for the incidence of treatment-emergent cardiovascular and arteriothrombotic AEs was in patients who received second- or third-generation TKIs rather than imatinib.
      • Sam P.Y.
      • Ahaneku H.
      • Nogueras-Gonzalez G.M.
      • Jabbour E.
      • Garcia-Manero G.
      • Borthakur G.
      • et al.
      Cardiovascular events among patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs).
      Notably, findings from a recent study suggest that cardiovascular disease–related mortality is lower among patients with CML who are treated with TKIs than among patients diagnosed in the pre-TKI era, raising the possibility that TKIs may increase the incidence but not the severity of cardiovascular events. This study also demonstrated that African American patients with CML treated with TKIs have an increased risk for cardiovascular disease–related mortality compared with white patients (P = .004), suggesting that African Americans may represent a particularly vulnerable population requiring more careful monitoring for cardiovascular disease.
      • Molenaar R.J.
      • Radivoyevitch T.
      • Nazha A.
      • Advani A.S.
      • Gerds A.T.
      • Maciejewski J.P.
      • et al.
      Atherosclerotic arterial disease-related mortality in chronic myeloid patients treated with tyrosine kinase inhibitors.
      RWE studies can also be used to evaluate the impact of treatment adherence on clinical outcomes. For example, a prospective, single-institution cohort analysis of data from 87 consecutive patients with CML treated with imatinib found that poor treatment adherence was significantly associated with a lower likelihood of achieving a complete molecular response (P < .001) and higher risk for loss of cytogenetic response (P < .0001) and treatment failure (P < .0001).
      • Ibrahim A.R.
      • Eliasson L.
      • Apperley J.F.
      • Milojkovic D.
      • Bua M.
      • Szydlo R.
      • et al.
      Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy.
      • Marin D.
      • Bazeos A.
      • Mahon F.X.
      • Eliasson L.
      • Milojkovic D.
      • Bua M.
      • et al.
      Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib.
      Additionally, a retrospective cohort analysis found that patients with a medication possession ratio (MPR) of ≥90%, considered a high level of adherence, had lower rates of progression to accelerated phase/blast crisis and mortality than did patients with an MPR of <90%.
      • Haque R.
      • Shi J.
      • Chung J.
      • Xu X.
      • Avila C.
      • Campbell C.
      • et al.
      Medication adherence, molecular monitoring, and clinical outcomes in patients with chronic myelogenous leukemia in a large HMO.
      Retrospective cohort analyses can be used to evaluate disease-management practices and the impact of these practices on patient outcomes.
      • Latremouille-Viau D.
      • Guerin A.
      • Gagnon-Sanschagrin P.
      • Dea K.
      • Cohen B.G.
      • Joseph G.J.
      Health care resource utilization and costs in patients with chronic myeloid leukemia with better adherence to tyrosine kinase inhibitors and increased molecular monitoring frequency.
      For example, a retrospective claims analysis of data from 1431 patients with CML in the United States found that 16% had 4 molecular monitoring tests, the recommended number of tests,
      • National Comprehensive Cancer Network
      Clinical practice guidelines in oncology. Chronic myeloid leukemia. V1..
      during the first year after diagnosis, while the majority of patients had fewer tests.
      • Latremouille-Viau D.
      • Guerin A.
      • Gagnon-Sanschagrin P.
      • Dea K.
      • Cohen B.G.
      • Joseph G.J.
      Health care resource utilization and costs in patients with chronic myeloid leukemia with better adherence to tyrosine kinase inhibitors and increased molecular monitoring frequency.
      Notably, patients with fewer tests had poorer treatment adherence (P < .001) and had higher health care resource utilization and costs overall, including a higher number of inpatient days (P = .010), although an increase of 1 molecular monitoring test was also associated with a 3.0% increase in outpatient service days (P = .002).
      • Latremouille-Viau D.
      • Guerin A.
      • Gagnon-Sanschagrin P.
      • Dea K.
      • Cohen B.G.
      • Joseph G.J.
      Health care resource utilization and costs in patients with chronic myeloid leukemia with better adherence to tyrosine kinase inhibitors and increased molecular monitoring frequency.
      Most importantly, the frequency of testing has been linked to outcomes, whereby patients who underwent more testing had an improved progression-free survival (P = .001).
      • Goldberg S.L.
      • Chen L.
      • Guerin A.
      • Macalalad A.R.
      • Liu N.
      • Kaminsky M.
      • et al.
      Association between molecular monitoring and long-term outcomes in chronic myelogenous leukemia patients treated with first line imatinib.
      Similarly, in a retrospective study of data from 516 patients with CML in chronic phase in India who received imatinib free of cost, the impact of treatment adherence was investigated on the basis of whether patients attended regular clinic visits at which the drug was dispensed; results showed significantly worse 5-year EFS among nonadherent patients compared with that in adherent patients (P = .011).
      • Ganesan P.
      • Sagar T.G.
      • Dubashi B.
      • Rajendranath R.
      • Kannan K.
      • Cyriac S.
      • et al.
      Nonadherence to imatinib adversely affects event free survival in chronic phase-chronic myeloid leukemia.
      Pregnant patients have been excluded from TKI clinical trials due to concerns about the teratogenicity of TKIs as demonstrated in animal models.
      Unfortunately, CML is a disease that affects women of reproductive age, and health care providers are often faced with questions about how to treat patients prior to and during pregnancy. A retrospective study of RWD examined data from 13 women who were diagnosed with CML during pregnancy and an additional 15 who conceived while receiving TKIs. Among the women who were diagnosed with CML during pregnancy, 10 successfully carried infants to term, and all but 1 had an adequate response to TKI treatment initiated within 1 month of delivery. The 15 women who conceived while receiving TKIs stopped treatment upon learning of their pregnancies, which led to 12 live births, including 2 infants with minor abnormalities (hypospadias and rotation of the small intestine). These patients remained off TKIs for a median of 10 months, during which time 40% lost their responses, but all subsequently achieved at least a complete cytogenetic response upon resuming TKI treatment. That study provided important information that clinicians can use to assure patients who are diagnosed with CML during pregnancy or who become pregnant while receiving a TKI.
      • Assi R.
      • Kantarjian H.M.
      • Keating M.J.
      • Pemmaraju N.
      • Verstovsek S.
      • Garcia-Manero G.
      • et al.
      Management of chronic myeloid leukemia (CML) during pregnancy among patients (pts) treated with a tyrosine kinase inhibitor (TKI): a single-center experience.

       Vignette: RWE Analysis of Data From Elderly Patients With CML

      To better understand how elderly Medicare beneficiaries with CML respond to second-line nilotinib or dasatinib therapy following initial treatment with imatinib, our group
      • Smith B.D.
      • Liu J.
      • Latremouille-Viau D.
      • Guerin A.
      • Fernandez D.
      • Chen L.
      Treatment patterns, overall survival, healthcare resource use and costs in elderly Medicare beneficiaries with chronic myeloid leukemia using second-generation tyrosine kinase inhibitors as second-line therapy.
      conducted a retrospective cross-sectional cohort study of data from the US Centers for Medicare & Medicaid Services national administrative claims database. The analysis included patients with continuous Medicare Parts A, B, and D coverage, and data were sourced from the Medicare Research Identifiable Files (2006–2012). These files contain information on patient demographics as well as claims data relating to inpatient and outpatient care (from Medicare Part A), carrier and medical equipment files (from Medicare Part B), and therapeutic interventions (from Medicare Part D). The patient selection sample process is illustrated in Figure 1. Briefly, eligible patients had ≥2 recorded CML diagnoses (International Classification of Diseases, Ninth Revision—Clinical Modification code 205.1×), were treated with front-line imatinib and second-line nilotinib or dasatinib, and were aged ≥65 years at the start of second-line therapy. Patients previously enrolled in a clinical trial or who received a stem cell transplant or chemotherapy other than hydroxyurea were excluded. A total of 379 dasatinib-treated patients and 280 nilotinib-treated patients were identified for inclusion. The study period began when second-line TKI therapy was initiated (the index date) and ended at the date of the patient's death, the conclusion of continuous Medicare enrollment, or when data became unavailable. Outcomes in dasatinib- and nilotinib-treated patients were compared using multivariate regression models adjusted for potential confounding factors, including age, sex, region, Darkow CML complexity and Quan-Charlson Comorbidity Index
      • Quan H.
      • Sundararajan V.
      • Halfon P.
      • Fong A.
      • Burnand B.
      • Luthi J.C.
      • et al.
      Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.
      scores, and whether patients were initiated on TKI therapy at the recommended starting dose or at a different dose.
      Figure 1
      Figure 1Patient selection sample process. CML, chronic myeloid leukemia; HMO, health maintenance organization. Reprinted by permission of Taylor & Francis Ltd.
      • Smith B.D.
      • Liu J.
      • Latremouille-Viau D.
      • Guerin A.
      • Fernandez D.
      • Chen L.
      Treatment patterns, overall survival, healthcare resource use and costs in elderly Medicare beneficiaries with chronic myeloid leukemia using second-generation tyrosine kinase inhibitors as second-line therapy.
      Results of this analysis revealed that the dasatinib-treated and nilotinib-treated cohorts had similar patient demographics and comorbidities (Table II
      • Smith B.D.
      • Liu J.
      • Latremouille-Viau D.
      • Guerin A.
      • Fernandez D.
      • Chen L.
      Treatment patterns, overall survival, healthcare resource use and costs in elderly Medicare beneficiaries with chronic myeloid leukemia using second-generation tyrosine kinase inhibitors as second-line therapy.
      ), although preexisting cardiovascular disease was more common among nilotinib-treated patients (38.6% and 28.8% of patients in the nilotinib and dasatinib cohorts, respectively; P = 0.008); the durations of available follow-up data were similar between cohorts (both: median, 22 months). Patients receiving dasatinib more often started at the recommended dose (74.1% vs 53.2%; P < 0.001), but they also had more dose reductions (P = .002) or increases (P = .048) than patients receiving nilotinib. Compared with dasatinib-treated patients, those treated with nilotinib had lower likelihoods of treatment switch (21% [nilotinib] vs 29% [dasatinib]; P = 0.044) and discontinuation (59% vs 67%, respectively; P = 0.026). Patients treated with either drug had similar levels of treatment adherence. During the 6-month period after the index date, the mean MPRs were 0.79 and 0.81 in the nilotinib and dasatinib groups, respectively. There was a longer median overall survival and lower risk for mortality in patients treated with nilotinib than in patients treated with dasatinib (median duration of survival: nilotinib, not reached after 4.9 years; dasatinib, 4.0 years [P = 0.032]; mortality risk after adjusting for potential confounding factors: 18% vs 28% [P = 0.008]). After adjustment for potential confounding factors, patients treated with nilotinib also had fewer inpatient, outpatient, and emergency department visits (all P < .05), and the per-patient per-month total medical costs were $513 lower with nilotinib than with dasatinib (P = 0.024) (data not shown).
      • Smith B.D.
      • Liu J.
      • Latremouille-Viau D.
      • Guerin A.
      • Fernandez D.
      • Chen L.
      Treatment patterns, overall survival, healthcare resource use and costs in elderly Medicare beneficiaries with chronic myeloid leukemia using second-generation tyrosine kinase inhibitors as second-line therapy.
      Table IIComparison of patient characteristics between the nilotinib and dasatinib cohorts
      Smith BD, et al. Curr Med Res Opin. 2016; 32(5):817–827, reprinted by permission of Taylor & Francis Ltd.
      .
      CharacteristicNilotinib (n = 280)Dasatinib (n = 379)P
      P values were calculated using χ2 tests for binary variables and Wilcoxon tests for continuous variables.
      Mean age (SD), years
      Age was calculated as of the index date.
      76.25 (6.95)75.36 (6.70).097
       65–69 years, n (%)57 (20.4)82 (21.6).691
       70–74 years, n (%)69 (24.6)123 (32.5).029
      Significant at the 5% level.
       75–79 years, n (%)57 (20.4)71 (18.7).603
       80+ years, n (%)97 (34.6)103 (27.2).039
      Significant at the 5% level.
      Female, n (%)177 (63.2)232 (61.2).601
      Region, n (%)
       South131 (46.8)167 (44.1).488
       Northeast47 (16.8)68 (17.9).699
       West38 (13.6)61 (16.1).370
       Midwest64 (22.9)83 (21.9).770
      Index year, n (%)
       200837 (13.2)71 (18.7).058
       200932 (11.4)67 (17.7).026
      Significant at the 5% level.
       201082 (29.3)91 (24.0).128
       201170 (25.0)84 (22.2).395
       201259 (21.1)66 (17.4).237
      Mean observed duration of CML, days [median] (SD)
      Observed duration of CML was calculated between the first observed CML diagnosis and the index date.
      866 [698] (648)873 [786] (633).879
      Mean imatinib duration prior to index date, days [median] (SD)
      Observed duration of imatinib use was calculated between the first observed imatinib prescription and the index date.
      801 [637] (632)776 [666] (598).789
      Mean length follow-up period, days [median] (SD)702 [673] (420)717 [665] (469).950
       Follow-up period ≥6 months, n (%)253 (90.4)324 (85.5).061
       Follow-up period ≥12 months, n (%)204 (72.9)276 (72.8).992
       Follow-up period ≥18 months, n (%)175 (62.5)227 (59.9).498
       Follow-up period ≥24 months, n (%)128 (45.7)173 (45.6).986
      Adjusted disease complexity since CML diagnosis
       Mild152 (54.3)220 (58.0).336
       Moderate65 (23.2)81 (21.4).573
       Severe63 (22.5)78 (20.6).553
      CML remission37 (13.2)44 (11.6).535
      CML relapse5 (1.8)7 (1.8).954
      Initiated the index TKI on the recommended dose, n (%)149 (53.2)281 (74.1)<.001
      Significant at the 5% level.
      Quan-Charlson Comorbidity Index (CCI) score, excluding CML, mean (SD)
      • Quan H.
      • Sundararajan V.
      • Halfon P.
      • Fong A.
      • Burnand B.
      • Luthi J.C.
      • et al.
      Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.
      1.40 (1.71)1.21 (1.60).100
       Quan-CCI score ≥1164 (58.6)196 (51.7).081
       Quan-CCI score ≥299 (35.4)120 (31.7).32
       Quan-CCI score ≥363 (22.5)69 (18.2).173
      Comorbidities before the index date, n (%)
      The list of comorbidities was based on Agency for Health care Research and Quality. Healthcare Cost and Utilization Project Elixhauser Comorbidity Software, version 3.7. https://www.hcup-us.ahrq.gov/toolssoftware/comorbidity/comorbidity.jsp. Accessed 18 August 2015.
       Anemia125 (44.6)167 (44.1).882
       Chronic pulmonary disease52 (18.6)65 (17.2).637
       Cardiovascular disease108 (38.6)109 (28.8).008
      Significant at the 5% level.
       Congestive heart failure63 (22.5)51 (13.5).002
      Significant at the 5% level.
       Coagulopathy27 (9.6)29 (7.7).365
       Depression13 (4.6)24 (6.3).352
       Diabetes86 (30.7)109 (28.8).587
       Fluid electrolyte disorders48 (17.1)56 (14.8).410
       Hyperlipidemia93 (33.2)127 (33.5).937
       Hypertension156 (55.7)219 (57.8).596
       Hypothyroidism39 (13.9)52 (13.7).939
       Macular degeneration15 (5.4)6 (1.6).006
      Significant at the 5% level.
       Neurological disorders17 (6.1)16 (4.2).282
       Osteoporosis13 (4.6)29 (7.7).118
       Peripheral vascular disease23 (8.2)31 (8.2).987
       Pulmonary circulation disorder14 (5.0)8 (2.1).041
      Significant at the 5% level.
       QTc prolongation36 (12.9)35 (9.2).138
       Renal failure49 (17.5)64 (16.9).836
       Solid tumor43 (15.4)65 (17.2).539
       Valvular disease25 (8.9)22 (5.8).123
       Weight loss16 (5.7)17 (4.5).475
      CML, chronic myeloid leukemia; TKI, tyrosine kinase inhibitor.
      a Smith BD, et al. Curr Med Res Opin. 2016; 32(5):817–827, reprinted by permission of Taylor & Francis Ltd.
      b P values were calculated using χ2 tests for binary variables and Wilcoxon tests for continuous variables.
      c Age was calculated as of the index date.
      d Significant at the 5% level.
      e Observed duration of CML was calculated between the first observed CML diagnosis and the index date.
      f Observed duration of imatinib use was calculated between the first observed imatinib prescription and the index date.
      g The list of comorbidities was based on Agency for Health care Research and Quality. Healthcare Cost and Utilization Project Elixhauser Comorbidity Software, version 3.7. https://www.hcup-us.ahrq.gov/toolssoftware/comorbidity/comorbidity.jsp. Accessed 18 August 2015.
      The results from that study highlight several potential contributions of RWE analyses to medical research. No randomized head-to-head trials comparing second-line nilotinib with dasatinib have been conducted; thus, RWE studies such as this one are an important avenue for obtaining comparative analyses. The retrospective collection of information on health care resource utilization and costs provides important insight into the overall economic impact of therapies. Comparable data cannot be readily obtained from RCTs in which patients are treated according to the management policies outlined in the study protocol rather than a physician's professional discretion.
      Although retrospective observational health care claims analyses such as the one by our group
      • Smith B.D.
      • Liu J.
      • Latremouille-Viau D.
      • Guerin A.
      • Fernandez D.
      • Chen L.
      Treatment patterns, overall survival, healthcare resource use and costs in elderly Medicare beneficiaries with chronic myeloid leukemia using second-generation tyrosine kinase inhibitors as second-line therapy.
      are valuable, their inherent limitations must also be considered. Variable dosing patterns may have been a factor in the outcomes reported in that study, and the data were limited to those from patients covered by Medicare and information recorded in the Medicare database. Important disease and patient characteristics, such as CML phase, were not included in many claims. Dasatinib is indicated for the treatment of CML in blast crisis, whereas nilotinib is not, and an inability to control for this variable may have skewed the results.

      Conclusions and Future Directions

      Conventional RCTs and RWE studies are distinct types of research that produce distinct types of data. Each type is best suited to answering different research questions. When used together, they can provide a fuller picture of the tolerability, efficacy, and overall impact of a drug. Considering the recent publication of guidance documents and commentary from the FDA on topics related to RWE,
      • Sherman R.E.
      • Anderson S.A.
      • Dal Pan G.J.
      • Gray G.W.
      • Gross T.
      • Hunter N.L.
      • et al.
      Real-world evidence—what is it and what can it tell us?.

      US Food and Drug Administration. Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: Guidance for Industry and Food and Drug Administration Staff. Available at: https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm513027.pdf. Accessed 2 October 2017.

      US Food and Drug Administration. Drug and device manufacturer communications with payors, formulary committees, and similar entities—questions and answers: guidance for industry and review staff. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm537347.pdf. Accessed 10 August 2017.

      it can be expected that RWE will play a growing role in the development of new and existing medical products in the coming years.

      Acknowledgments

      We thank Amarallys Cintron, PhD, and Karen Kaluza Smith, PhD, of ArticulateScience LLC, for their medical editorial assistance with the manuscript.
      Both authors wrote and critically reviewed the manuscript. The authors had full control of the content and made the final decisions on all aspects of this article.

      Conflicts of Interest

      Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation .
      B.D. Smith has received consultant's fees from Bristol-Myers Squibb, Novartis, Jazz Pharmaceuticals, and Pfizer. The authors have indicated that they have no other conflicts of interest with regard to the content of this article.

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