Patient-reported outcomes in drug development forhematology

Catherine Acquadro1 and Antoine Regnault2

1Mapi Research Trust, Lyon, France; and 2Mapi, Lyon, France

Patient-reported outcomes (PROs) are any outcome evaluated directly by the patient himself and based on thepatient’s perception of a disease and its treatment(s). PROs are direct outcome measures that can be used as clinicalmeaningful endpoints to characterize treatment benefit. They provide unique and important information about theeffect of treatment from a patient’s view. However, PROs will only be considered adequate if the assessment iswell-defined and reliable. In 2009, the FDA has issued a guidance, which defines good measurement principles toconsider for PRO measures intended to give evidence of treatment benefit in drug development. In hematologic clinicaltrials, when applied rigorously, they may be used to evaluate overall treatment effectiveness, treatment toxicity, andquality of patient’s well-being at short-term and long-term after treatment from a patient’s perspective. In situations inwhich multiple treatment options exist with similar survival outcome or if a new therapeutic strategy needs to beevaluated, the inclusion of PROs as an endpoint can provide additional data and help in clinical decision making. Giventhe diversity of the hematological field, the approach to measurement needs to be tailored for each specific situation.The importance of PROs in hematologic diseases has been highlighted in a number of international recommendations.In addition, new perspectives in the regulatory field will enhance the inclusion of PRO endpoints in clinical trials inhematology, allowing the voice of the patients with hematologic diseases to be taken into greater consideration in thedevelopment of new drugs.

Learning Objectives

● Understand the general principles around the assessment ofpatient-reported outcomes in drug development

● Understand the importance of the patient’s perspective indrug development for hematology and the most recentadvances in assessment and regulatory issues

Our purpose with this paper was to give an overview of theassessment of patient-reported outcomes (PROs) in the context ofdrug development in hematology. First we present the generalprinciples around the assessment of PROs in a drug developmentcontext. In a second part, we present how this general frameworkapplies specifically to the field of hematology. Finally, we introducesome recent developments that will likely drive the field forward inthe near future.

Patient-reported outcomes in drug developmentAs defined by the US Food and Drug Administration (FDA), apatient-reported outcome “is any report of the status of apatient’s health condition that comes directly from the patient,without interpretation of the patient’s response by a clinician oranyone else.”1 For the European Medicines Agency (EMA), “anyoutcome evaluated directly by the patient himself and based onpatient’s perception of a disease and its treatment(s) is calledpatient-reported outcome (PRO). The term PRO is proposed asan umbrella term to cover both single-dimension and multi-dimension measures of symptoms, health-related quality-of-life

(HRQL), health status, adherence to treatment, satisfaction withtreatment, etc.”2

Treatment benefit is demonstrated by evidence that the treatmenthas a positive impact on a meaningful concept of interest.1,3,4 On theregulatory standpoint, clinically meaningful endpoints for thecharacterization of treatment benefits are direct measures of how apatient feels, functions, or survives, and are expected to predict theeffect of therapy.5 They represent or characterize the clinicaloutcome of interest, either objective (eg, survival, disease exacerba-tion, clinical event) or subjective (eg, symptoms, health-relatedquality-of-life). Indirect outcome measures or surrogate endpoints,such as physical signs, observations, or laboratory tests/biomarkers,are substitute for direct outcome measures, and therefore do notconfer full evidence on clinical benefit to the patient. Treatmentbenefit can be demonstrated as either a comparative advantage inhow patients survive, feel, or function, or a comparative reduction intreatment-related toxicity. Thus, well-defined PROs are directoutcome measures, and can be used as clinical meaningful end-points to characterize treatment benefit.

As a result of the FDA PRO Harmonization meetings in the early2000s, a consensus on the value of the patient’s perspective and therationale for its inclusion in drug development emerged and wasstructured around 4 key points6 i.e., the patient’s perspective is:

(1) A unique indicator for assessing disease impact: as such, PROsmay be the sole indicator of disease activity (eg, in migraine,

Conflict-of-interest disclosures: C.A. declares no competing financial interests; A.R. is employed by Mapi.

Off-label drug use: None disclosed.

PATIENT-REPORTED OUTCOMES IN HEMATOLOGY

496 American Society of Hematology

rhinitis, etc), a key indicator (eg, in asthma, psoriasis, etc) or maysupplement other indicators (eg, FEV1 and daily functioning).

(2) Essential for evaluating treatment efficacy: in clinical trials,patients’ report is the sole source of data on the frequency andseverity of symptoms and side effects, and the impact of treatmenton functioning and well-being.

(3) Useful for interpreting clinical outcomes: PRO data fromclinical trials contribute to the comprehensive evaluation of thebenefits of a new treatment.

(4) A key element in treatment decision making: a number ofspecialty groups and organizations recommend the use of PROs inclinical trials and have published guidelines for selecting outcomemeasures specific to the unique characteristics and evaluation needsof the underlying disease.

However, a PRO measure will only be considered adequate tocharacterize a treatment benefit if the assessment is well-definedand reliable.7 The FDA guidance on the use of PRO measures inmedical product development to support labeling claims,1 whichwas issued in 2009, defines good measurement principles toconsider for well-defined and reliable PRO measures intended toprovide evidence of treatment benefit. In brief, the evaluation ofa PRO in a clinical research setting should address the followingconsiderations:

The PRO instrument should be clearly defined (conceptual frame-work, number of items, scoring rules, etc) and should be under-pinned by rigorous measurement science supporting primarily itscontent validity but also the other measurement properties (reliabil-ity, validity, ability to detect change); if used in an internationalcontext, its translation or cultural adaptation should be the outcomeof a robust methodology.

The objectives, design and analyses of the clinical trial(s) in whichthe PRO is an endpoint should be appropriately specified; the sameclinical trial design principles that apply to other endpoint measuresalso apply to PROs. More specifically, the position of the PROendpoint in the endpoint model (and hierarchy) should be carefullydefined: the role the PRO endpoint in the clinical trial (ie, primary,key secondary, or supportive) is key in the evaluation of theinstrument. Furthermore, the data analysis of PRO endpoints in aclinical trial should be cautious regarding the management ofmultiple, possibly composite, endpoints, and of missing data andshould provide ways to support the meaningful interpretation ofresults (eg, responder analysis, cumulative distribution functions).

In addition to the FDA PRO guidance, a roadmap to Patient-Focused Outcome Measurement in Clinical Trials8 was issued bythe FDA to illustrate how one might embark upon a sound, orderly,instrument selection or development pathway that is in alignmentwith the objectives of the drug development program and theclinical trial context of use (Figure 1). It shows that properassessment of an outcome in a clinical trial should be underpinnedby sound understanding of the disease (Column 1) and a precise andspecific conceptualization of the expected treatment benefit (Col-umn 2).

Patient-reported outcomes in hematologyGeneral issuesHematology covers a wide spectrum of blood disorders which canbe classified in 2 categories: non-neoplastic and neoplastic.9 Thewide variety of disorders involves various treatment strategies withvery different therapeutic implications (in terms of duration oftreatment or side effects); each of which with a different impact onpatients’ lives. The evaluation of the patient’s perspective in clinicalresearch in hematology, whatever the disorder is, is certainlyimportant and should follow the same rules as those described in theFDA PRO guidance1 and the Roadmap.8 Hence the approach needs

Figure 1. Roadmap to patient-focused outcome measurement in clinical trials. Adapted from http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/UCM370174.pdf.

Hematology 2015 497

to be tailored for each specific situation, and there is no “one-size-fits-all’ solution given the diversity of the hematologic field.Nonetheless applying rigorously the approaches described abovewill undoubtedly allow the proper demonstration of treatmentbenefits based on PRO endpoints in hematology.

Novik et al indicate that PROs are often used in hematology tocomplement primary outcomes such as survival, clinician assess-ments and physiologic or laboratory-based measures.10 In manysituations, the patient’s perspective brings different informationfrom the clinician or biological perspectives, and according to thevery definition of treatment benefit, it should not be overlooked. Forexample, PROs were shown to be complementary to survival,clinical response, and adverse effects in characterizing treatmentbenefit in multiple myeloma.11,12 In situations in which multipletreatment options exist with similar survival outcome or if a newtherapeutic strategy needs to be evaluated, the inclusion of PROs orhealth-related quality-of-life as an endpoint can provide additionaldata and help in clinical decision making. In palliative care, PROassessment may be the sole indicator of treatment assignment orchange.

The importance of PRO evaluation is stated in a number ofinternational recommendations for various hematologic diseases,namely, for hemophilia,13 immune thrombocytopenia,14,15 myelodys-plastic syndromes,16 chronic lymphocytic leukemia,17 acute leuke-mia,18 non-Hodgkin’s lymphoma,19 Hodgkin’s lymphoma,20,21 andmultiple myeloma.22 It is beyond the scope of this paper to describecomprehensively the PRO evaluation in all hematologic disorders;however, in 2012, the European Hematology Association (EHA)Scientific Working Group on Quality and Life and Symptoms hasbeen working with clinicians and researchers from 17 countries and9 patients’ organizations on Guidelines on PROs in hematology.10

The guidelines provide recommendations on PRO assessments inclinical studies for patients with hematologic diseases such asleukemias, lymphomas, multiple myeloma, myelodysplastic syn-dromes, hemophilia, Von Willebrand disease, immune thrombocy-topenia, and anemia of chronic disease. They also present theevaluation of quality-of-life and symptoms in patients undergoingbone marrow transplantation, in patients receiving anticoagulanttherapy, in long-term blood cancer survivors, and in children andadolescents with hematologic malignancies. These EHA guidelinesare an excellent starting point in the endeavor of assessing a PROendpoint in a clinical trial. In contrast, on the regulatory side, verylittle guidance has been published by the FDA and the EMA inbenign hematology. There is a greater focus on PROs inmalignancies.23-25

A success story: the approval of JakafiOn November 2011, Jakafi (ruxolitinib) was approved by FDA forthe treatment of intermediate or high-risk myelofibrosis (MF)including primary MF, post-polycythemia vera MF (PPV-MF), andpostessential thrombocythemia MF (PET-MF). Prior to this date,there were no approved products for this indication, and thereforethere were no regulatory precedent on the endpoints required in thisorphan disease. The regulatory endpoints that provided the basisfor a full FDA approval of ruxolitinib were: (1) a decrease insplenomegaly, and (2) an improvement in MF-related symptoms asmeasured by a novel PRO instrument, the modified MyelofibrosisSymptom Assessment Form (MFSAF) version 2.0 diary.

Several meetings with the FDA were held in 2008 and in 2009 todiscuss endpoint strategy. After several rounds of discussion and no

agreement on 2 previous Special Protocol Assessments (SPAs), theFDA advised to use objectively measured spleen size reduction as aprimary endpoint, and a clinically relevant benefit, such as symptomimprovement measured daily, as a secondary endpoint, to supportregistration. Symptom improvement was measured using a revisedversion of the MFSAF published by Mesa et al.26 The changes madeto the MFSAF followed the requirements of the FDA PROguidance1: qualitative patient interviews and cognitive testing wereperformed and demonstrated the content validity of the new versionof the MFSAF, ie, the modified MFSAF version 2.0 diary. Theinstrument was composed of 7 questions: 6 questions asking aboutthe severity of symptoms such as night sweats, itchiness, abdominaldiscomfort, pain under the ribs, early satiety and bone or musclepain, and 1 question asking about inactivity. Scores ranged from 0 to10 with 0 representing “absent” and 10 representing “worstimaginable”. The 6 symptomatic questions were scored in acomposite referred to as the Total Symptom Score (TSS). However,the instrument was not demonstrated as “fit for purpose” yet, asrequired by the PRO guidance. To achieve this, evidence onmeasurement properties, as well as information to support meaning-ful interpretation of the results of the TSS, were generated usingblinded data at 1 month of the 6 month randomized, placebo-controlled phase III trial and also the unblended data obtained at theend of the study.

The phase III trial was a double-blind, randomized, placebo-controlled study in 309 patients who were refractory to or were notcandidates for available therapy. Patients were dosed with Jakafi ormatching placebo. The primary efficacy endpoint was the propor-tion of patients achieving �35% reduction from baseline in spleenvolume at Week 24 as measured by MRI or CT. Secondaryendpoints included duration of a 35% or greater reduction in spleenvolume and proportion of patients with a 50% or greater reductionin TTS from baseline to week 24 as measured by the MFSAF v2.0diary. Electronic handheld diaries were used to collect the patient-reported symptom data. At baseline, the mean TSS was 18.0 in theruxolitinib group and 16.5 in the placebo group. A higher proportionof patients in the ruxolitinib group (45.9%) had a 50% or greaterreduction in TSS than in the placebo group (5.3%, P � 0.001), witha median time to response of �4 weeks.

It was decided to include the TSS in the final product label becausethe endpoint was alpha-controlled, the data collected was complete,the treatment effect size was clinically meaningful, and all of theMF symptoms were driving the TSS (not just 1 or 2 symptoms). Fullapproval was obtained with FDA, indicating that, without thedemonstration of clinical benefit using the data produced by themodified MFSAF v2.0 diary, it would have been hard to justifyanything but accelerated approval.

ChallengesSome of the main challenges in the evaluation of PROs inhematology include the following: (1) the design of oncology trialsis not always optimized for PROs (ie, single arm or open-labeldesign), (2) difficulty in collecting data from patients that haveadvanced or progressive disease due to failing health or cognitivechallenges, and (3) high levels of missing data.23,27 Challenges alsoinclude assessment of PRO endpoints in rare diseases, such ashemophilia28 or Willebrand’s disease, where the limited number ofavailable patients make the conduct of a comprehensive PROresearch agenda difficult. Similarly, assessment of PROs in pediat-ric context require particular care.

498 American Society of Hematology

Another challenge is represented by the globalization of clinicalresearch. In 2007, over 60% of pivotal studies submitted to theCenter for Drug Evaluation and Research (CDER) contained datafrom 1 or more international study sites.29 From October 2007 toSeptember 2008, clinical trials for medical products were conductedat nearly 6500 international sites. This situation has implications forPRO measures, which need to be appropriately translated andcross-culturally adapted to be used globally. A methodology (ie,linguistic validation) has been developed30-32 which is advised to befollowed for all PRO measures to ensure conceptual equivalencebetween the original and the translations. Several PRO measuresused in hematology have been translated using this process (eg, theHaemoQOL,33 or the QLQ-C30 and QLQ-MY2034).

New perspectives: PDUFA V and new FDAorganization in hematology and oncologyThe Prescription Drug User Fee Act (PDUFA) was first authorizedin 1992 and was conceived to overcome the “drug lag” of the 1980sby providing the FDA with increased staffing and resources, and byencouraging medical innovation. PDUFA was reauthorized (asPDUFA V) as part of the Food and Drug Administration Safety andInnovation Act, enacted in July 2012, and went into effect onOctober 1, 2012. The FDA’s Patient-Focused Drug Developmentinitiative is a commitment under PDUFA V that aims to moresystematically gather patients’ perspectives on their condition andavailable therapies to treat their condition. This initiative clearlydemonstrates that the central position of the patients in the drugdevelopment is now acknowledged by regulatory agencies, inparticular the FDA. One of the goals of this initiative is to increasethe use of PROs in clinical trials. Twenty public meetings over thecourse of PDUFA V were planned, each focused on a specificdisease area. At the moment, 2 meetings were held in hematology,ie, in sickle cell disease, on February 2, 201435, and in hemophiliaA, hemophilia B, von Willebrand disease, and other heritablebleeding disorders, on September 22, 2014.36 These meetings gaveFDA and the pharmaceutical industry a unique opportunity to heardirectly from patients and caregivers about their experiences withtheir disease and its treatments. Discussion focused on 2 key topics:(1) the effects of the disease that matter most to patients, and (2)patients’ perspectives on treatments and on clinical trial participa-tion. The input generated through these meetings enhanced the FDAunderstanding of the burden of the disease on patients and theirexperiences with the treatment and their perspectives for the future.The outcome of these meetings will be used to enhance drugdevelopment programs in each disease area, by informing thediscussion between the regulators and sponsors that submit productsfor marketing approval in the US. This input may also be of value tothe drug development process more broadly. For example, thereport may be useful to drug developers as they explore potentialareas of unmet needs. It could also point to the potential need fordevelopment and qualification of new outcome measures in clinicaltrials.

In a recent presentation at the FDA Clinical Outcome Assessments(COA) workshop,37 organizational changes at the Office of Hematol-ogy and Oncology Products (OHOP) were introduced with thedeclared objective to advance PRO evaluation in hematology andoncology and facilitate the review of PROs in the dossiers submittedto OHOP. Over the last 2 years, interactions with the StudyEndpoints and Labeling Development (SEALD) team were in-creased, with the organization of OHOP-SEALD working groupswith monthly meetings. OHOP PRO and labeling expertise has beenimproved with an Office level dedication, PRO leads, and associate

directors of labeling in each OHOP clinical division providing PROand labeling expertise and interacting with SEALD to improveconsistency between OHOP Divisions, and finally overall OHOPeducational opportunities for reviewers with monthly hematologyoncology case series. The goal is to provide more detailed,consistent, and proactive PRO advice to sponsors.

ConclusionPatient-reported outcomes provide unique and important informa-tion about the effect of a treatment from a patient’s view inhematology, as in other fields. In hematologic clinical trials, theymay be used to evaluate overall treatment effectiveness, treatmenttoxicity, and quality of patient’s well-being at short-term andlong-term after treatment from a patient’s perspective. The inclusionof PRO endpoints in clinical trials in hematology will certainlycontinue to grow in the future allowing the voice of the patients withhematologic diseases to be taken into greater consideration in thedevelopment of new drugs, which it is always important to keep inmind, aims to address patients’ needs.

CorrespondenceCatherine Acquadro, Mapi Research Trust, 27 rue de la Villette,69003 Lyon, France; Phone: 04-72-13-65-75; Fax: 04-72-13-66-82; e-mail: cacquadro@mapigroup.com.

References1. US Department of Health, Food and Drug Administration (2009).

Patient-reported outcome measures: use in medical product develop-ment to support labeling claims. Federal Register. 2009;74(35):65132-65133 (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf). Accessed April23, 2015.

2. European Medicines Agency. Reflection paper on the regulatory guidancefor the use of health-related quality of life (HRQL) measures in theevaluation of medicinal products (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003637.pdf). Ac-cessed April 23, 2015.

3. Papadopoulos EJ. Establishing evidence of treatment benefit: focus onoutcome assessment (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM375588.pdf). Accessed April 23, 2015.

4. Papadopoulos EJ. An approach to outcome measure development: aregulatory perspective (http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2014/12/WC500177921.pdf). AccessedApril 24, 2015.

5. Temple R. Are surrogate markers adequate to assess cardiovasculardisease drugs? JAMA. 1999;282(8):790-795.

6. Acquadro C, Berzon R, Dubois D, et al. Incorporating the patient’sperspective into drug development and communication: an ad hoc taskforce report of the Patient-Reported Outcomes (PRO) HarmonizationGroup meeting at the Food and Drug Administration, February 16,2001. Value Health. 2000;5:522-531.

7. CFR: Code of Federal Regulations Title 21. 21CFR 314.126 (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr�314.126). Accessed April 25, 2015.

8. US Department of Health and Human Services, Food and Drug Administra-tion. Roadmap to Patient-Focused Outcome Measurement in Clinical Trials(http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/UCM370174.pdf). AccessedApril 28, 2015.

9. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification ofTumours of Haematopoietic and Lymphoid Tissues. Ed 4th. Lyon,France: IARC Press; 2008.

10. Novik A, Salek S, Ionova T. Guidelines Patient-Reported outcomes inHematology. The Hague, The Netherlands; 2012 (https://www.ehaweb.

Hematology 2015 499

org/assets/documents/Guidelines-PRO-SWG-QoL.pdf). Accessed April20, 2015.

11. Viala M, Bhakar AL, de la Loge C, et al. Patient-reported outcomeshelped predict survival in multiple myeloma using partial least squaresanalysis. J Clin Epidemiol. 2007;60(7):670-679.

12. Delforge M, Dhawan R, Robinson D Jr, et al. Health-related quality oflife in elderly, newly diagnosed multiple myeloma patients treated withVMP vs. MP: results from the VISTA trial. Eur J Haematol. 2012;89(1):16-27.

13. Guidelines for the management of hemophilia. Ed 2d. Montreal,Quebec: World Federation of Hemophilia; 2012.

14. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization ofterminology, definitions and outcome criteria in immune thrombocyto-penic purpura (ITP) of adults and children: report from an internationalworking group. Blood. 2009;113(11):2386-2393.

15. Kirsch M, Klaassen RJ, De Geest S, Matzdorff A, Ionova T, Dobbels F.Understanding the importance of using patient-reported outcome mea-sures in patients with immune thrombocytopenia. Semin Hematol.2013;50(Suppl 1):39-42.

16. Tefferi A, Barosi G, Mesa RA, et al. International working group (IWG)consensus criteria for treatment response in myelofibrosis with myeloidmetaplasia, for the IWG for myelofibrosis research and treatment(IWG-MRT). Blood. 2006;108(5):1497-1503.

17. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosisand treatment of chronic lymphocytic leukemia: a report from theInternational Workshop on Chronic Lymphocytic Leukemia updatingthe National Cancer Institute-Working Group 1996 guidelines. Blood.2008;111(12):5446-5456.

18. Appelbaum FR. The acute leukemias. In: Goldman L, Ausiello D, eds.Cecil Medicine. Ch 194. Ed 23. Philadelphia, PA: Saunders; 2007.

19. Mauch PM, Armitage JON, Harris R, et al. Non-Hodgkin’s Lympho-mas. Philadelphia, PA: Lippincott Williams & Wilkins; 2004.

20. Hoppe R, Mauch PM, Armitage JON. Hodgkin Lymphoma. Philadel-phia, PA: Lippincott Williams & Wilkins; 2007.

21. Engert A, Horning SJ. Hodgkin lymphoma: a comprehensive update ondiagnostics and clinics. Berlin: Springer; 2011.

22. Morgan GP, Krishnan B, Jenner M, Davies, FE. Advances in oraltherapy for multiple myeloma. Lancet Oncol. 2006;7(4):316-325.

23. European Medicines Agency. Oncology Working Party. Guideline on theevaluation of anticancer medicinal products in man (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/01/WC500137128.pdf). Accessed April 25, 2015.

24. European Medicines Agency. Oncology Working Party. ReflectionPaper on the use of patient reported outcome (PRO) measures inoncology studies (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/06/WC500168852.pdf). Accessed April25, 2015.

25. US Department of Health and Human Services, Food and DrugAdministration. Clinical trials endpoints for the approval of cancerdrugs and biologics (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071590.pdf). Ac-cessed April 25, 2015.

26. Mesa RA, Schwager S, Radia D, et al. The Myelofibrosis SymptomAssessment Form (MFSAF): an evidence-based brief inventory tomeasure quality of life and symptomatic response to treatment inmyelofibrosis. Leuk Res. 2009;33(9):1199-1203.

27. Basch E, Geoghegan C, Coons SJ, et al. Patient-reported outcomes incancer drug development and US regulatory review: perspectives fromindustry, the Food and Drug Administration, and the patient. JAMAOncol. 2015;1(3):375-379.

28. Santagostino E, Lentz SR, Busk AK, Regnault A, Iorio A. Assessmentof the impact of treatment on quality of life of patients with haemophiliaA at different ages: insights from two clinical trials on turoctocog alfa.Haemophilia. 2014;20(4):527-534.

29. Ayalew K. FDA perspective on international clinical trials (http://www.fda.gov/downloads/Training/ClinicalInvestigatorTrainingCourse/UCM378499.pdf). Accessed April 27, 2015.

30. Acquadro C, Conway K, Giroudet C, Mear I. Linguistic ValidationManual for Health Outcome Assessments. Ed 2. Lyon, France: MAPIInstitute; 2012.

31. Wild D, Grove A, Martin ML, et al. ISPOR principles of good practice:the cross-cultural adaptation process for patient reported. Value Health.2005;8(2):94-110.

32. Wild D, Eremenco S, Mear I, et al. Multinational trials: recommenda-tions on the translations required, approaches to using the samelanguage in different countries, and the approaches to support poolingthe data: the ISPOR Patient Reported Outcomes Translation & Linguis-tic Validation Good Research Practices Task Force Report. ValueHealth. 2009;12:430-440.

33. von Mackensen S, Campos IG, Acquadro C, Strandberg-Larsen M.Cross-cultural adaptation and linguistic validation of age-group-specifichaemophilia patient-reported outcome (PRO) instruments for patientsand parents. Haemophilia. 2013;19(2):73-83.

34. Cocks K, Cohen D, Wisløff F, et al. An international field study of thereliability and validity of a disease-specific questionnaire module (theQLQ-MY20) in assessing the quality of life of patients with multiplemyeloma. Eur J Cancer. 2007;43(11):1670-1678.

35. US Department of Health and Human Services, Food and DrugAdministration. The Voice of the Patient: Sickle Cell Report. Publicmeeting: 2/07/2014; Report date: 10/2014 (http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM418430.pdf). Accessed April 26, 2015.

36. US Department of Health and Human Services, Food and Drug Administra-tion. Patient-Focused Drug Development for Hemophilia A, Hemophilia B,von Willebrand Disease and other Heritable Bleeding Disorders. Publicmeeting: 09/22/2014 (http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm401758.htm). Accessed April30, 2015.

37. US Department of Health and Human Services, Food and DrugAdministration. PDUFA V Clinical Outcome Assessments PublicWorkshop. April 1, 2015 (http://www.fda.gov/Drugs/NewsEvents/ucm431040.htm). Accessed April 26, 2015.

500 American Society of Hematology