Patient-reported Outcomes Endpoints Research Articles

One Programme, Four Stakeholders: An Overview of the Utilisation of Patient-Reported Outcomes in Intervention Development to Meet the Needs of Regulators, Payers, Healthcare Professionals and Patients

For a new intervention to achieve commercial success, regulators (to provide marketing authorisation), payers (for reimbursement and formulary placement), healthcare professionals (HCPs; to prescribe) and patients (to adhere and persist) must all consider the intervention to be valuable. These stakeholders are increasingly using the patient’s perspective on a condition and its treatment—measured through patient-reported outcome (PRO) instruments—to define the value of a treatment. However, there is common confusion about the most appropriate way to incorporate the patient’s perspective into the clinical development of pharmaceutical interventions in a way that will resonate with these four key stakeholder groups. This article briefly summarises the perspectives of regulators, payers, HCPs and patients regarding PRO endpoints, and examines how a robust, comprehensive and systematic PRO endpoint strategy can be developed to meet the needs of all stakeholders in a single development programme. Such an endpoint strategy may include PRO assessments of first-order signs and symptoms using a disease-specific measure, health-related quality of life using both a disease-specific measure and generic utility measure, and general quality of life. Other PRO endpoints (e.g. preference/satisfaction, ease of use, HCP contact time, absenteeism) may be useful with some stakeholders to provide further differentiation between interventions.

Anxiety and health-related quality of life among patients with low-tumor burden non-Hodgkin lymphoma randomly assigned to two different rituximab dosing regimens: results from ECOG trial E4402 (RESORT).

The purpose of this study was to compare illness-related anxiety among participants in the Rituximab Extended Schedule or Retreatment Trial (RESORT) randomly assigned to maintenance rituximab (MR) versus rituximab re-treatment (RR). A secondary objective was to examine whether the superiority of MR versus RR on anxiety depended on illness-related coping style. Patients (N = 253) completed patient-reported outcome (PRO) measures at random assignment to MR or RR (baseline); at 3, 6, 12, 24, 36, and 48 months after random assignment; and at rituximab failure. PRO measures assessed illness-related anxiety and coping style, and secondary end points including general anxiety, worry and interference with emotional well-being, depression, and health-related quality of life (HRQoL). Patients were classified as using an active or avoidant illness-related coping style. Independent sample t tests and linear mixed-effects models were used to identify treatment arm differences on PRO end points and differences based on coping style. Illness-related anxiety was comparable between treatment arms at all time points (P > .05), regardless of coping style (active or avoidant). Illness-related anxiety and general anxiety significantly decreased over time on both arms. HRQoL scores were relatively stable and did not change significantly from baseline for both arms. An avoidant coping style was associated with significantly higher anxiety (18% and 13% exceeded clinical cutoff points at baseline and 6 months, respectively) and poorer HRQoL compared with an active coping style (P < .001), regardless of treatment arm assignment. Surveillance until RR at progression was not associated with increased anxiety compared with MR, regardless of coping style. Avoidant coping was associated with higher anxiety and poorer HRQoL.

Quality of Life and Patient-Reported Outcomes in Endometrial Cancer Clinical Trials

There is increasing recognition that quality of life (QoL) and patient-reported outcomes (PROs) are of fundamental importance and particularly relevant given the relatively high likelihood of long-term survival in most women with endometrial cancer (EC). However, there has been relatively little research focused on this topic. Our objective was to analyze our current knowledge and identify research questions to be included in the design of next clinical trials. Analyze and critically assess reported clinical trials in EC that have included QoL and PROs as primary or secondary end points. Surgery has a significant impact on physical and functional domains of QoL particularly in the first 6 months after diagnosis. Minimally invasive surgery is associated with less acute morbidity than open procedures and this persists over time. Lymphadenectomy is associated with increased incidence of lymphedema, important late effect. Adjuvant external irradiation may cause gastrointestinal and genitourinary symptoms that impact on physical functioning and which can persist over time. In contrast, vaginal brachytherapy has less toxicity and fewer late effects than external irradiation. The impact of treatment on sexuality has been poorly evaluated in EC survivors. There are few published data on QoL and PROs in patients treated with chemotherapy and the long-term impact has not been addressed. There is no evidence that palliative chemotherapy reduces symptoms and improves QoL. There are very few longitudinal studies on survivorship that is an important concern in EC survivors. Although there have been some studies addressing QoL and PROs in EC, we have identified deficiencies and gaps in our knowledge. Careful consideration of QoL and PROs end points and how to include them in clinical trials will result in a better appreciation of how treatments can impact on patients QoL and lead to conduct interventions to reduce late effects.

Patient-reported outcome (PRO) assessment in clinical trials: a systematic review of guidance for trial protocol writers.

BackgroundEvidence suggests there are inconsistencies in patient-reported outcome (PRO) assessment and reporting in clinical trials, which may limit the use of these data to inform patient care. For trials with a PRO endpoint, routine inclusion of key PRO information in the protocol may help improve trial conduct and the reporting and appraisal of PRO results; however, it is currently unclear exactly what PRO-specific information should be included. The aim of this review was to summarize the current PRO-specific guidance for clinical trial protocol developers.Methods and FindingsWe searched the MEDLINE, EMBASE, CINHAL and Cochrane Library databases (inception to February 2013) for PRO-specific guidance regarding trial protocol development. Further guidance documents were identified via Google, Google scholar, requests to members of the UK Clinical Research Collaboration registered clinical trials units and international experts. Two independent investigators undertook title/abstract screening, full text review and data extraction, with a third involved in the event of disagreement. 21,175 citations were screened and 54 met the inclusion criteria. Guidance documents were difficult to access: electronic database searches identified just 8 documents, with the remaining 46 sourced elsewhere (5 from citation tracking, 27 from hand searching, 7 from the grey literature review and 7 from experts). 162 unique PRO-specific protocol recommendations were extracted from included documents. A further 10 PRO recommendations were identified relating to supporting trial documentation. Only 5/162 (3%) recommendations appeared in ≥50% of guidance documents reviewed, indicating a lack of consistency.ConclusionsPRO-specific protocol guidelines were difficult to access, lacked consistency and may be challenging to implement in practice. There is a need to develop easily accessible consensus-driven PRO protocol guidance. Guidance should be aimed at ensuring key PRO information is routinely included in appropriate trial protocols, in order to facilitate rigorous collection/reporting of PRO data, to effectively inform patient care.

Promotion of Patient-Reported Outcome Label Claims Based on Nonprimary Endpoints.

Patient-reported outcomes (PROs) play an increasingly pivotal role in confirmatory clinical trials with pressures to develop drug differentiation strategies. Claims based on primary endpoints that are included in the product label are likely to be fully promoted by the manufacturers; however, the extent to which manufacturers promote claims based on secondary PRO endpoints is unknown. The purpose of this review is to assess the extent of promotion of PRO label claims for 6 pharmaceutical products with nonprimary PRO endpoints. Six products were reviewed that received PRO label claims based on nonprimary PRO endpoints between 2006 and 2008. Promotional documents distributed in the United States by the drug manufacturers between the year of launch and 2011 were identified from a PharmaVoxx database. Circulation of these documents was calculated according to quarterly distributions. Two researchers reviewed the documents using standard criteria. Promotional activities based on nonprimary PRO endpoint claims were compared with total number of messages. Manufacturers of the 6 products distributed 973 unique promotional documents 2998 times. Messages based on primary endpoints were distributed 1798 times, whereas messages relating to nonprimary PRO endpoints were distributed 1200 times (40% of distributions) and varied among products (4%-70%). Messages relating to PROs were targeted mostly at patients and consumers (65%) versus physicians and health care professionals (34%). Promotion of PRO messages based on nonprimary endpoints is much lower than those based on primary endpoints, suggesting that manufacturers do not always optimize the potential of PRO messages.

Including Patient-Reported Outcomes and Patient-Reported Resource-Use Questionnaires in Studies

More efficient and better informed healthcare systems are expected to have improved knowledge of the impact of interventions on patient outcomes and resources used by patients and providers in specific health conditions. To describe trends related to putting patients at the center of healthcare decision making, regulatory trends and best practice recommendations for developing high-quality patient-reported outcomes (PROs), and strategic issues related to including PROs in studies. We summarize PRO concepts, definitions, and broadly-accepted scientific standards for developing, assessing, and interpreting PROs. Three conceptual models are presented as examples for assessing PROs in relation to other outcomes. We discuss different perspectives for stakeholders, including regulatory issues pertaining to formal guidance for PRO development and for use in trials. We provide examples of PROs used in studies for assessing health outcomes in oncology and resource-use outcomes in low back pain patients. Psychometric scientists working closely with multi-disciplinary teams and regulatory authorities have greatly improved the science of collecting, assessing, and understanding patient-reported outcomes in clinical trials. A simplified framework is presented for strategic considerations for including PROs in studies, such as the appropriate timing for PRO endpoints. Asking patients about their health status and/or use of resources improves our understanding of how interventions and care processes may impact their lives and their budgets. We provide examples from a back pain trial of patient-reported resource-use questionnaires for medicines taken and other services or products used by patients. Healthcare stakeholders are placing increased emphasis on resource use and the impact of interventions on patients, including effects associated with diagnostic tests. Patient-reported outcomes are being used in clinical practice and in clinical research, supported by formal best-practice guidelines. Radiology has a role as an engaged stakeholder in the design, conduct, and interpretation of patient-based evidence, and in its relevance to health policy implementation.

FRI0004 Randomization to Patient-Reported RAPID3 versus Physician-Based CDAI Tools for Prediction of Treatment Response and Assessment of Patient-Reported Outcomes in Rheumatoid Arthritis Patients Receiving Certolizumab Pegol: Results from the PREDICT Study

BackgroundGuidelines support regular quantitative disease activity monitoring and early intervention in rheumatoid arthritis (RA), but there is no uniform agreement on the best measurement tool.1,2 While physician-based tools like the...

OP0152 Effects of Tofacitinib Monotherapy versus Methotrexate on Patient-Reported Outcomes in the 2-Year Phase 3 Oral Start TRIAL in Methotrexate-NaÏVe Patients with Rheumatoid Arthritis

BackgroundTofacitinib is a novel, oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA).ObjectivesTo compare the effects of twice daily (BID) tofacitinib 5 mg and 10 mg monotherapy versus...

An overview of current trends and gaps in patient-reported outcome measures used in haemophilia.

This review summarises the importance, recent progress and issues in measuring patient-reported outcomes (PROs) in haemophilia research. A critical review of recent advances and trends in measuring haemophilia-related PROs was conducted, using current regulatory guidelines and methodological recommendations to evaluate these instruments. Although regulators, payers and policymakers increasingly consider the patient's perspective to be important in treatment decision-making, to date, few haemophilia intervention studies have meaningfully applied PRO endpoints. Condition-specific PRO instruments have been developed, but most are not fully validated; sensitivity to subgroup differences and changes over time is unclear. Generic PROs and instruments developed for other conditions have been used to measure health-related quality of life (HRQL) in haemophilia patients, but little evidence of their validity for this purpose exists. Haemophilia presents a number of challenges to developing valid, reliable and responsive PRO instruments, including the rarity of the disorder; necessitating research in multiple counties to attain sufficient sample size; the chronic nature of the condition; acute exacerbations of illness; age and geographical region variations with respect to treatment; differences in treatment regimens, range of disease severity and phenotypes; and changes in patients' perceived health status over time. Given that haemophilia begins at birth, the illness has an impact on the lives of caregivers, although the extent of the impact is largely unknown. Patient perspectives are crucial to understanding the best and most cost-effective haemophilia treatment approaches. More research is needed on the ability of current disease-specific and generic PRO instruments to capture responsiveness to treatments over time and subgroup differences in outcomes. Inclusion of PROs in clinical trials is necessary to answer these questions.

PIH67 - A Review Of Patient-Reported Outcome Orphan Drug Labels In The United States From January 2006-September 2013: Analysis Of Evidence For Orphan Drug Pro Label Claims

Objectives: Previous reviews of patient-reported outcome (PRO) label claims did not distinguish products with orphan designation. Literature suggests that less evidence is required for orphan drug approvals compared with non-orphan drugs. This study aimed to identify orphan drug products approved by the US Food and Drug Administration (FDA) between 2006 and 2013, the prevalence of PRO label claims for these products, and levels of evidence supporting PRO claim approval. Methods: Using the Drugs@FDA website, new molecular entities and biologic licensed agents approved between January 2006 and September 2013 with orphan review classification were identified, with subsequent label review. Priority or standard review was also noted. For products with PRO claims, labels and medical and summary review sections from FDA drug approval packages were reviewed to identify indication, reviewing division, PRO endpoint status, PRO measure type, number of phase 3 trials supporting claims, and PRO-related comments from the Study Endpoints and Labeling Development (SEALD) team. Descriptive data were recorded in Microsoft Excel; frequency of measured characteristics was analyzed. Results: For the 43 products identified, a total of 7 PRO label claims were granted to 5(12%) products. Five orphan products achieved 7 PRO claims. Priority and standard review prevalence were similar (44% vs. 40%, respectively) for orphan products; most products (4 of 5) with PRO claims had priority review. A slight majority (60%; 3 of 5 orphan products) included PRO claims supported by ≤ 1 phase 3 trial. Signs/symptoms measures and secondary PRO endpoints were most common (57% each). FDA reviewing division varied. One product had documented comments from SEALD. Conclusions: For the time period evaluated, orphan products rarely included a PRO label claim. These claims may not be needed for orphan product differentiation to the degree that they are for nonorphan products. PRO claims achieved for orphan products appear to require less supporting evidence for approval than non-orphan products, consistent with orphan drug approval expectations.

Patient‐reported outcomes from EMILIA, a randomized phase 3 study of trastuzumab emtansine (T‐DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2–positive locally advanced or metastatic breast cancer

This report describes the results of an analysis of patient-reported outcomes from EMILIA (TDM4370g/BO21977), a randomized phase 3 study of the antibody-drug conjugate trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer. A secondary endpoint of the EMILIA study was time to symptom worsening (time from randomization to the first documentation of a ≥ 5-point decrease from baseline) as measured by the Trial Outcome Index Physical/Functional/Breast (TOI-PFB) subset of the Functional Assessment of Cancer Therapy-Breast questionnaire. Predefined exploratory patient-reported outcome endpoints included proportion of patients with a clinically significant improvement in symptoms (per TOI-PFB) and proportion of patients with diarrhea symptoms (per Diarrhea Assessment Scale). In the T-DM1 arm, 450 of 495 patients had a baseline and ≥ 1 postbaseline TOI-PFB score versus 445 of 496 patients in the capecitabine-plus-lapatinib arm. Time to symptom worsening was delayed in the T-DM1 arm versus the capecitabine-plus-lapatinib arm (7.1 months versus 4.6 months, respectively; hazard ratio = 0.796; P = .0121). In the T-DM1 arm, 55.3% of patients developed clinically significant improvement in symptoms from baseline versus 49.4% in the capecitabine-plus-lapatinib arm (P = .0842). Although similar at baseline, the number of patients reporting diarrhea symptoms increased 1.5- to 2-fold during treatment with capecitabine and lapatinib but remained near baseline levels in the T-DM1 arm. Together with the EMILIA primary data, these results support the concept that T-DM1 has greater efficacy and tolerability than capecitabine plus lapatinib, which may translate into improvements in health-related quality of life.

PSS42 - A Systematic Review of Patient Reported Outcomes in Glaucoma

Patient reported outcomes (PRO) are becoming useful tools for collecting and generating evidence for new medical products to show improvements in health-related quality of life (HRQoL). Glaucoma is a chronic disease with high importance for patient HRQoL. The objective of this study was to review, analyze, and understand trends in the PRO instruments used in patients with Glaucoma. A systematic literature search for Glaucoma trials with PROs endpoints was undertaken for the databases Pubmed, Embase, Biosis, Google Scholar and Cochrane. Data was collected for the study size, interventions, year, PRO instrument and results for PROs. Analysis for conducted to identify trends in commonly used PRO instruments and categorize results as positive, neutral or negative. A total of 31 studies with a total of 9819 patients were identified. In these studies there were eleven different PROs instruments were identified that were Glaucoma health perception index, Glaucoma quality of life questionnaire (Glau-QoL), Glaucoma utility index, Impact of vision impairment, Low vision quality of life questionnaire, National eye institute visual function index-19 items, National eye institute visual function index-51 items, Nursing home vision quality of life questionnaire, Quality of life and visual function questionnaire, Vision core module 1, and Vision quality of life index. The most commonly used instruments were Impact of vision impairment (used in 7 studies) and Low vision quality of life questionnaire (used in 4 studies). Patients with glaucoma have significant impairment in their QoL, hence collection of such data is important for new medical products. PRO instruments such as Impact of vision impairment and Low vision quality of life questionnaire have been commonly used to generate evidence to show which therapies improve patient QoL.

Open-ended concept elicitation with breast cancer (BC) patient advocates to inform patient-reported outcome (PRO) endpoints in neoadjuvant and adjuvant trials of trastuzumab emtansine (T-DM1).

172 Background: There is no standard for measuring health-related quality of life (HRQoL) using PROs in (neo)adjuvant BC clinical trials. Further, in (neo)adjuvant treatment (tx), pre-surgical cytotoxic therapy may initially worsen HRQoL. The development of tools to measure PRO endpoints in (neo)adjuvant clinical trials could be improved with a better understanding of the issues that impact HRQoL in this population. Patient (Pt) advocates, many of whom are BC survivors, may provide valuable insight to inform PRO strategy and optimal selection of PRO endpoints in clinical trials. Methods: A workshop with BC pt advocates was conducted to inform T-DM1 BC PRO strategy. It consisted of open-ended concept elicitation to identify symptomatology, tx-related side effects, and common reasons for tx discontinuation during (neo)adjuvant therapy for BC. Results: For younger pts, hot flashes and issues with sexuality and fertility were described as the most concerning issues. For older pts, peripheral neuropathy was described as the most concerning issue. Regardless of age, most pts reportedly struggle with cognitive dysfunction, anxiety, and depression. Chemotherapy-associated side effects considered most distressing to pts of all ages were alopecia, fatigue, diarrhea, neutropenia, peripheral neuropathy, and hand-foot syndrome (HFS). Neutropenia was considered most likely to cause a physician-instigated tx break, and HFS was most likely to precipitate a pt-instigated tx break. Assessing post-operative pain and satisfaction with post-surgical tx outcome (whether breast conserving or mastectomy) were emphasized. Conclusions: Open-ended concept elicitation with pt advocates is a collaborative and informative way to identify the most relevant concepts for further study. Increased collaboration with advocates to support qualitative research may improve the ability of trial results to assist pts in making informed tx decisions. Earlier engagement of pts and advocates can support the development of new PROs that offer more precision and inform PRO instrument selection to adequately quantify tx impact.

Potential of patient-reported outcomes as nonprimary endpoints in clinical trials.

BackgroundThe purpose of this research was to fully explore the impact of endpoint type (primary vs. nonprimary) on decisions related to patient-reported outcome (PRO) labeling claims supported by PRO measures and to determine if nonprimary PRO endpoints are being fully optimized.This review examines the use of PROs as both primary and nonprimary endpoints in support of demonstration of treatment benefit of new molecular entities (NMEs) and biologic license applications (BLAs) in the United States in the years 2000 to 2012.MethodsAll NMEs and BLAs approved by the Food and Drug Administration (FDA) between January 2000 and June 2012 were identified using the FDA Drug Approval Reports Web page. Generic products granted tentative approvals were excluded. For all identified products, medical review sections from publicly available drug approval packages were reviewed to identify PRO endpoint status. Product labels (indication, clinical trials sections) were reviewed to determine the number and type of PRO claim.ResultsA total of 308 NMEs/BLAs were identified. Of these, 70 NMEs/BLAs (23%) were granted PRO claims. The majority of product claims were for disease- or condition-specific signs and symptoms. Of the 70 products with PRO claims, a PRO was a primary endpoint for the vast majority (57 [81%]). A total of 19 of the 70 products were granted a PRO claim based on a nonprimary endpoint. While nonprimary endpoints were used most often to support claims of improved signs or symptoms, nonprimary endpoints were much more likely to support claims of higher order impacts.ConclusionsSuccessful PRO labeling claims are typically based on primary endpoints assessing signs and symptoms. Based on this research, studies with PROs as primary endpoints are far more likely to facilitate positive regulatory review and acceptance of PROs in support of labeling claims. Although inclusion of PROs as nonprimary endpoints in clinical trials has its challenges, recent PRO labels granted by the FDA show that they can indeed be candidates for PRO labeling claims as long as they are supported by evidence.

The Use of Patient-reported Outcomes (PRO) Within Comparative Effectiveness Research

The goal of comparative effectiveness research (CER) is to explain the differential benefits and harms of alternate methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care. To inform decision making, information from the patient's perspective that reflects outcomes that patients care about are needed and can be collected rigorously using appropriate patient-reported outcomes (PRO). It can be challenging to select the most appropriate PRO measure given the proliferation of such questionnaires over the past 20 years. In this paper, we discuss the value of PROs within CER, types of measures that are likely to be useful in the CER context, PRO instrument selection, and key challenges associated with using PROs in CER. We delineate important considerations for defining the CER context, selecting the appropriate measures, and for the analysis and interpretation of PRO data. Emerging changes that may facilitate CER using PROs as an outcome are also reviewed including implementation of electronic and personal health records, hospital and population-based registries, and the use of PROs in national monitoring initiatives. The potential benefits of linking the information derived from PRO endpoints in CER to decision making is also reviewed. The recommendations presented for incorporating PROs in CER are intended to provide a guide to researchers, clinicians, and policy makers to ensure that information derived from PROs is applicable and interpretable for a given CER context. In turn, CER will provide information that is necessary for clinicians, patients, and families to make informed care decisions.

695P - Quality of Life in Flags Trial a Randomized, Comparative, Open Label, Multicenter, Phase 3 of S-1 + Cisplatin (CS) Compared to 5-Fu + Cisplatin (CF) in Untreated advanced Gastric Cancer (AGC) Patients

ABSTRACT Background FLAGS' primary objective was overall survival. We report below the Patient-Reported Outcomes (PRO) (i.e., Quality-of-Life [QoL]) which was one of the secondary objectives. Methods All patients who completed at least one PRO assessment were eligible for analysis. The primary PRO endpoint was the Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy – Gastric (FACT-Ga). Patients completed the FACT-Ga at the beginning of Cycles 1, 2, 3, 4, 6 and then every 3 cycles prior to treatment administration. All individual subscales in the FACT-Ga were also evaluated as secondary endpoints. The Chemotherapy Convenience and Satisfaction Questionnaire (CCSQ) was administered at the beginning of the first 4 cycles. Results Of the 508 patients dosed at cycle 1 in the CF arm, and the 521 in the CS arm, 456 and 498 respectively completed at least one question on the FACT-Ga and 445 and 486 respectively completed at least 37 items. Compliance to questionnaire fulfillment was more than 80% through Cycle 9. Although there were no overall difference in FACT-Ga scores between the treatment arms and minimal changes over time, an advantage for CS relative to CF was observed for Physical Well-Being (PWB) (51.7% versus 45.1%, p = 0.044). CS treated patients experienced significantly longer time to worsening in PWB scores, with a median time of 4.5 months (95% CI: 3.0 – 5.1) compared to 3.0 months (2.8 – 4.6) with CF (p = 0.014).Patients receiving CS reported higher best and worst score of PWB, Chemotherapy Convenience and Chemotherapy Concerns scores. Conclusions Even if there is little evidence to indicate any difference in FACT-Ga scores, some advantage to CS relative to CF was observed for PWB, one of the secondary PRO endpoints. This advantage was generally consistent across analysis method: time to worsening, best post-baseline score, and worst post-baseline score. CS treated patients did report significantly better Chemotherapy Convenience and Concerns scores, the difference was approximately one-half of a standard deviation generally considered to be a meaningful difference. Disclosure All authors have declared no conflicts of interest.

A Review of Patient-Reported Outcome Labels in the United States: 2006 to 2010

ObjectiveIn 2004, Willke and colleagues reviewed the efficacy endpoints reported in the labels of new drugs approved in the United States from 1997 through 2002 to evaluate the use of patient-reported outcome (PRO) endpoints. Of the labels reviewed, 30% included PROs. Our study aimed to build on this work by describing the current state of PRO label claims granted for new molecular entities (and biologic license applications since February 2006 after the release of the US Food and Drug Administration (FDA) draft PRO guidance. MethodsAll new molecular entities and biologic license applications approved by the FDA from January 2006 through December 2010 were identified by using the Web page of the FDA Drug Approval Reports. For all identified products, drug approval packages and approved product labels were reviewed to identify PRO endpoint status and to determine the number and type of PRO claims. ResultsOf the 116 products identified, 28 (24%) were granted PRO claims; 24 (86%) were for symptoms, and, of these, 9 (38%) claims were pain related. Of the 28 products with PRO claims, a PRO was a primary endpoint for 20 (71%), all symptom related. ConclusionsThe FDA continues to approve PRO claims, with 24% of new molecular entities and biologic license applications being granted. Successful PRO label claims over the past 5 years have generally supported treatment benefit for symptoms specified as primary endpoints.

Review of patient-reported outcome measures in chronic hepatitis C.

BackgroundChronic hepatitis C (CHC) and its treatment are associated with a variety of patient-reported symptoms and impacts. Some CHC symptoms and impacts may be difficult to evaluate through objective clinical testing, and more easily measured through patient self-report. This literature review identified concepts raised by CHC patients related to symptoms, impacts, and treatment effects, and evaluated integration of these concepts within patient-reported outcome (PRO) measures. The goal of this work was to provide recommendations for incorporation of PRO measurement of concepts that are relevant to the CHC experience into CHC clinical trial design.MethodsA three-tiered literature search was conducted. This included searches on concepts of importance, PRO measures used in clinical trials, and existing PRO measures. The PRO Concept Search focused on reviewing issues raised by CHC patients about CHC symptoms, disease impact, and treatment effects. The CHC Trials with PRO Endpoints Search reviewed clinical trials with PRO endpoints to assess differences between treatments over time. The PRO Measure Search reviewed existing PRO measures associated with the concepts of interest.ResultsThis multi-tiered approach identified five key concepts of interest: depression/anxiety, fatigue, flu-like symptoms, cognitive function, insomnia. Comparing these five concepts of interest to the PRO measures in published CHC clinical trials showed that, while treatment of CHC may decrease health-related quality of life in a number of mental and physical domains, the PRO measures that were utilized in published clinical trials inadequately covered the concepts of interest. Further review of 18 existing PRO measures of the concepts of interest showed only four of the 18 were validated in CHC populations.ConclusionsThis review identified several gaps in the literature regarding assessment of symptoms and outcomes reported as important by CHC patients. Further research is needed to ensure that CHC clinical trials evaluate concepts that are important to patients and include measures that have evidence supporting content validity, reliability, construct validity, and responsiveness.

PCN199 An Evaluation of Statistical Methods Used to Analyse Patient-Reported Outcomes (PRO) Data in Published Metastatic Cancer Studies

As metastatic cancers are generally incurable, treatment goal is to control the cancer and relieve symptoms with minimal side effects, making patient-reported outcomes (PRO) of particular interest in addition to traditional clinical outcomes. The objective of this literature review was to explore and evaluate the PRO data analyses reported in published metastatic cancer studies. The literature search was conducted on Medline and Embase databases (1999-2009). The search focused on two types of PRO analyses: the association between PRO scores and clinical outcomes, and the assessment of treatment benefit in terms of PROs. General keywords related to the tumour site and PROs, and keywords specific to each type of analysis were defined. A total of 931 different abstracts were reviewed by one statistician, among which 47 were finally selected for in-depth review based on their relevance to review objectives. The relationship between PRO scores and clinical outcomes was mainly analysed with Cox models, since clinical endpoint was generally survival. When analyses did not involve survival, the association between PRO and clinical outcomes and the use of PRO scores as endpoints were appropriately analysed with various descriptive, non-parametric and parametric statistical methods, depending on parameters like study objectives, design, PRO endpoints used and sample size. Only a few studies discussed the clinical meaningfulness of results alongside statistical significance. While a clear consistency was found in the statistical method for the analysis of the link between PRO scores and survival measures, a large heterogeneity of statistical methodologies was observed for other types of PRO analysis. In most studies, the method was appropriate from a statistical perspective but not adapted to the specific nature of PRO data, including under-use of clinically meaningful interpretation of statistical results and absence of specific PRO approaches such as cumulative distribution curves.

The Patient-Reported Outcome (PRO) Consortium: Filling Measurement Gaps for PRO End Points to Support Labeling Claims

The importance of appropriately and effectively incorporating the patient's voice into the evaluation of new medical products has been recognized and affirmed by regulators.(1,2,3) Patient-reported outcomes (PROs) are increasingly being assessed in clinical trials to quantify treatment benefits such as symptom relief and improved functioning. Translating PRO-based treatment benefits into labeling claims can provide information to physicians and patients and assist in prescribing decisions.(4,5) Hence, standardizing the valid and reliable measurement of PRO end points is critical.