Patient-reported Outcome Claims Research Articles

Concerns with Patient Reported Outcome Measurement and Value Claims for Therapy Response: The Case of Mavacamten and Symptomatic Hypertrophic Cardiomyopathy (SHCM).

Fundamental measurement is the basis for a rational assessment of patient reported outcome (PRO) value claims; both as response to therapy and the submission of credible and evaluable value claims to formulary committees and other health system decision makers. It is important to emphasize the importance of creating interval and ratio scales as opposed to nominal and ordinal scales to support value claims; a recognition that follows from acceptance of conjoint simultaneous measurement and the contribution of Rasch or modern measurement theory (RMT). Failure to appreciate the role of RMT has led thousands of researchers simply to apply numerals to events, inappropriately applying the techniques of classical statistical analysis, with the result that all that is produced are ordinal PRO scores. Instead, we should be aiming for interval and ratio scores based on a comprehensible latent trait and the application of the Rasch model. The purpose of this brief commentary is to review the measurement properties of PRO value claims for mavacamten (Camzyos; Bristol Myers Squibb) in symptomatic hypertrophic cardiomyopathy (SHCM) and to judge whether they have any validity when judged against the requirements of modern measurement theory. The assessment includes both the recent evidence report by the Institute for Clinical and Economic Review (ICER) for mavacamten as well as pivotal randomized trial (RCT) value claims that combine clinical endpoints with PROs that fail the standards of fundamental evidence. These include the Kansas City Cardiomyopathy Questionnaire (KCCQ), the New York Heart Association (NYHA) functional classification and the EuroQuol EQ-5D-5L multiattribute health related quality of life (HRQoL) preference instrument. The review concludes that apart from purely clinical claims based on the various pivotal trials, there are no PRO claims for mavacamten in SHCM that meet the required measurement standards.

Fundamental Outcome Measurement: Selecting Patient Reported Outcome Instruments and Interpreting the Data they Produce.

Over the past 40 years literally thousands of generic and disease specific patient reported outcome (PRO) instruments have been developed. While most were developed for a specific study and were never used again, there is still the question of how manufacturers and others should select a PRO instrument for a study. These studies may be clinical pivotal trials or observational tracking studies to support therapy response. Formulary committees also need to be able to interpret PRO data to make decisions about whether to accept claims for therapy response. It is possible to argue that the many different approaches to outcome measurement have resulted from the lack of agreed methodologies. However, a more likely explanation is that the authors have failed to apply the axioms of fundamental measurement when creating their measures. The result is a plethora of ordinal PRO instruments that inform little about the impact of interventions. Clinical trials rarely report PRO data. Where they do, analyses are generally restricted to (for example) changes in the experimental group's scores. Comparisons between the treatment and placebo groups or between active groups are infrequently reported, most likely due to the failure of the instrument to show differences or changes in outcome. This is unfortunate as it means no assessment is made of the value that patients gain from the intervention. This commentary is intended to make researchers and formulary committees aware of the issues that need to be addressed when selecting PRO instruments for a study or evaluating publications and claims for therapy response. The latter is crucial as reported data influence the selection of medicines and healthcare products. In the latter case a particular concern is with PRO claims embedded in simulation models.

PSY21 - Rates of Patient-Reported Outcome Claims for Orphan Drugs Approved by the European Medicines Agency

To evaluate and characterize the usage of patient-reported outcome (PRO) claims in orphan drug approvals from the European Medicines Agency (EMA) dated between 1/1/2012 and 31/12/2016. Orphan drug approval documentation was obtained from the EMA website. PRO-related language was extracted from the Summaries of Product Characteristics (SmPCs). Among 60 approvals that met the inclusion criteria, 12 products approved by the EMA for 13 (21.7%) orphan indications contained PRO language in the Clinical Studies section of the SmPC. Twelve SmPCs contained PRO instruments based on symptoms, of which five also concerned patient functioning. Eight approvals included PRO claims related to quality of life (QoL); most commonly for cancer treatment. The rate of PRO claims was lower for orphan drugs specifically than for all drug approvals by the EMA. Further, the EMA was particularly inclined to grant PRO claims concerning Health-Related QoL; mostly for cancer treatments.

PSY22 - Patient-Reported Outcome Claims in European and United States Orphan Drug Approvals

PSY22 - Patient-Reported Outcome Claims in European and United States Orphan Drug Approvals

PSY70 - Role of Patient-Reported Outcome Evaluation in the Approval of Orphan Drugs: A Review of 15 Year Approvals by the FDA and the EMA

In 2016, the IRDiRC concluded that the use of patient-reported outcome (PRO) measures is a necessity in clinical research on rare diseases because they measure the real benefits of the treatment from the patient's point of view. The objective of our study was to evaluate the extent to which PROs were used in the evaluation of orphan drugs authorized by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in the last 15 years. The FDA and EMA websites were reviewed to retrieve all products approved with an orphan designation from 01/2002 to 06/2017 included. The label (FDA) and the summary of product characteristics (EMA) of all products were analyzed to find any mention of PROs used and found relevant by the agencies. The review of both data sets (FDA/EMA), excluding duplicate records, led to a single data set of 452 distinct designations. Designations for products indicated for oncology purpose were excluded, leaving 258 designations to review. Among those, only 45 designations included PRO claims in their labeling, i.e., 17.4% of the total designations of non-oncology products. These 45 designations represented 42 different products of which 10 were common to both agencies. The PRO measures mentioned in the label were primarily focused on symptoms (e.g., dyspnea, fatigue, pain), rarely on functioning or health-related quality of life. In few cases (e.g., CAPS, cystic fibrosis, acromegaly), measures were specific and developed for the rare condition. This review shows that the patient’s perspective in the evaluation of orphan drugs is not fully implemented. The high number of rare diseases, the small number of patients for each pathology, the lack of information on the natural history of certain diseases, or the association with significant disability and cognitive impairments, make the development of specific PROs an arduous task.

Patient-reported outcome claims in European and United States orphan drug approvals

ABSTRACTPurpose: We aimed to evaluate the rate of usage and the kind of patient-reported outcome (PRO) claims in orphan drug approvals from the European Medicines Agency (EMA) dated between 1/1/2012 and 31/12/2016 and to compare them to those from the US Food and Drug Administration (FDA).Methods: Orphan drug approval documentation was obtained from the EMA website. PRO-related language was extracted from the Summaries of Product Characteristics (SmPCs). Data were compared to a previously published analysis of the FDA approvals from the same time period.Results: Out of 60 approvals that met the inclusion criteria, 12 products approved by the EMA for 13 (21.7%) orphan indications contained PRO language in the Clinical Studies section of the SmPC. Twelve SmPCs contained PRO instruments based on symptoms, five of which also concerned patient functioning. Eight approvals included PRO claims related to quality of life (QoL) most commonly in cancer treatment.Conclusion: The rate of PRO claims was lower for orphan drugs specifically than for all drug approvals by the EMA. However, in accordance with previous findings, the EMA appeared more inclined to grant PRO claims including health-related QoL than the FDA.

Patient-reported outcome labeling claims and measurement approach for metastatic castration-resistant prostate cancer treatments in the United States and European Union

BackgroundMetastatic castration-resistant prostate cancer (mCRPC) and its treatment significantly affect health-related quality of life (HRQOL). Our objectives were to evaluate and compare patient-reported outcome (PRO) claims granted by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for 5 recently approved mCRPC treatments and to examine key characteristics, development, and measurement properties of the PRO measures supporting these claims against current regulatory standards.MethodsFive products approved for treatment of mCRPC by the FDA and the EMA (2010–2013) were examined: enzalutamide, abiraterone, sipuleucel-T, cabazitaxel, and radium Ra 223 dichloride. United States (US) drug approval packages and European Public Assessment Reports were reviewed. PRO claims in the US labels and European Summaries of Product Characteristics and supporting measures were identified. For PRO measures supporting claims, a targeted literature review was conducted to identify information on key characteristics and measurement properties; this information was compared against FDA PRO guidance criteria.ResultsNine PRO “claims” were granted across 4 of 5 products reviewed. The EMA granted more claims (7 claims—4 for pain, 3 for HRQOL) than the FDA (2 claims, both for pain). The Brief Pain Inventory–Short Form (BPI-SF) worst pain item supported most pain claims and was the only measure supporting US claims. EMA pain claims were supported by BPI-SF worst pain (n = 2) and average pain (n = 1) items and the McGill Pain Questionnaire Present Pain Intensity component (n = 1). EMA HRQOL claims were supported by the Functional Assessment of Cancer Therapy–Prostate Module (n = 2) and the EuroQol 5 Dimensions with visual analogue scale (n = 1). Pain and prostate cancer–specific HRQOL measures supporting claims met US regulatory standards for construct validity, reliability, and responsiveness; these properties were strongest for the BPI-SF worst pain item. Only the BPI-SF worst pain item has documented content validity in mCRPC.ConclusionsPRO label claims were commonly granted across the mCRPC products reviewed. Among the measures reviewed, only the BPI-SF worst pain item supported US label claims. The BPI-SF worst pain item is recommended for pain assessment for the evaluation of new mCRPC treatments.

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.

Role of Patient-Reported Outcome Measures in the Assessment of Central Nervous System Agents

This work aimed to provide an understanding of the current use and regulatory acceptability of patient-reported outcome (PRO) measures in labeling claims for central nervous system (CNS) agents. A subset of CNS agents was identified from all New Drug Approvals and Biologic License Applications for new drugs approved in the US from January 2006 to June 2012. Clinician-reported outcomes (ClinROs) (62%) and PROs (38%) were the most widely used primary outcome measures. The PROs were frequently used in combination with ClinROs. Twelve PRO claims were granted across 41% of CNS drug approvals: 83%, symptoms; 17%, functioning. The PROs are frequently utilized as primary and secondary end points in CNS agents, and labeling claims are granted at higher levels than for non-CNS agents (41% vs 24%, respectively). These claims are granted at a lower rate than expected, given that direct patient input may lend valuable insight to treatment impacts in most CNS diseases.

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.

Reasons for Rejection of Patient-Reported Outcome Label Claims: A Compilation Based on a Review of Patient-Reported Outcome Use among New Molecular Entities and Biologic License Applications, 2006–2010

ObjectivesPrevious analyses of patient-reported outcome (PRO) label claims concentrated only on successful label claims. The goal of this research was to explore the reasons why PRO label claims were denied and to compile regulatory feedback regarding the use of PROs in clinical trials. MethodsBy using the Food and Drug Administration's Drug Approval Report Web page, all new molecular entities and biologic license applications approved between January 2006 and December 2010 were identified. For identified drug products, medical review sections from publicly available drug approval packages were reviewed to identify PRO end-point status and any Study Endpoints and Label Development team comments. ResultsOf the 116 new molecular entities and biologic license applications with accompanying drug approval packages identified and reviewed, 44.8% of the products included PROs as part of the pivotal studies; however, only 24.1% received PRO label claims. Primary reasons for denial included issues of fit for purpose, issues of study design, data quality or interpretation, statistical issues, administrative issues, and lack of demonstrated treatment benefit. ConclusionsBased on drug approval packages, nearly half (45%) of new molecular entitity/biologic license application products in the years 2006 to 2010 included PROs in the clinical trials supporting their approval, yet this rate is not reflected by claims granted. Understanding the nature of PRO claims granted under the current regulatory guidance is important. In addition, a clear understanding of denied claims yields valuable insight into where sponsors may improve implementation of PROs in clinical trials and submission of PRO evidence to increase the likelihood of obtaining PRO label claims.

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.

Patient-reported outcomes in support of oncology product labeling claims: regulatory context and challenges

The US FDA has advocated the patient-reported outcome (PRO) draft guidance as the main vehicle for evaluating PRO-based labeling claims for oncology drugs. In addition, FDA-affiliated researchers have identified factors inhibiting acceptance of health-related quality of life (HRQoL)-based claims for oncology product labels. The views of the FDA on PRO claims are extensive and prescriptive. By contrast, the European Medicines Agency (EMA) has conducted authorizations without an explicitly defined approach for evaluating HRQoL data. A reflective paper released in 2005 offered only broad recommendations on HRQoL labeling claims. The different approaches between the two regulatory agencies partly stem from underlying, divergent organizational characteristics. Moreover, general issues inherent in PRO research in oncology trials including trial design, missing data, multiplicity of end points and inconsistent findings of HRQoL data are discussed.

PCN137 ONCOLOGY PATIENT-REPORTED CLAIMS: MAXIMISING THE CHANCE FOR SUCCESS

Objectives/purpose: To review Patient Reported Outcome (PRO) labelling claims achieved in oncology in Europe and in the United States and consider the benefits, and challenges faced. Methods: PROLabels database was searched to identify oncology products with PRO labelling approved in Europe since 1995 or in the United States since 1998. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) websites and guidance documents were reviewed. PUBMED was searched for articles on PRO claims in oncology. Results: Among all oncology products approved, 22 were identified with PRO claims; 10 in the United States, 7 in Europe, and 5 in both. The language used in the labelling was limited to benefit (e.g. “…resulted in symptom benefits by significantly prolonging time to deterioration in cough, dyspnoea, and pain, versus placebo”) and equivalence (e.g. “no statistical differences were observed between treatment groups for global QoL”). Seven products used a validated HRQoL tool; two used symptom tools; two used both; seven used single-item symptom measures (one was unknown). The following emerged as likely reasons for success: ensuring systematic PRO data collection; clear rationale for pre-specified endpoints; adequately powered trials to detect differences and clinically significant changes; adjusting for multiplicity; developing an a priori statistical analysis plan including primary and subgroup analyses, dealing with missing data, pooling multiple-site data; establishing clinical versus statistical significance; interpreting failure to detect change. End-stage patient drop-out rates and cessation of trials due to exceptional therapeutic benefit pose significant challenges to demonstrating treatment PRO improvement. Conclusions: PRO labelling claims demonstrate treatment impact and the trade-off between efficacy and side effects ultimately facilitating product differentiation. Reliable and valid instruments specific to the desired language, claim, and target population are required. Practical considerations include rationale for study endpoints, transparency in assumptions, and attention to subtle variations in data.

Health-Related Quality of Life and Other Patient-Reported Outcomes in the European Centralized Drug Regulatory Process: A Review of Guidance Documents and Performed Authorizations of Medicinal Products 1995 to 2003

Objectives The objective of this study was to review and analyze the use of health-related quality of life (HRQL) and other patient-reported outcome (PRO) evaluations for the approval of new pharmaceutical products by the European Medicines Agency (EMEA). Methods All published EMEA guidance documents and regulatory information for products authorized at the EMEA and appearing in the European Public Assessment Report (EPAR) database between 1995 and 2003 were examined for reference to HRQL and other PROs. Results More than half of the guidance documents for clinical investigation of pharmaceutical products in specific disease areas included reference to HRQL or other PROs. Guidance notes for 10 conditions indicated PROs can serve as primary endpoints in clinical trials, among which three included HRQL outcomes. The review of EPAR documentation uncovered HRQL and other PRO data for 34% of the drugs registered during the period of the review, with cancer-related treatments most frequently including PRO data. There was a trend toward increasing HRQL and other PRO claims in regulatory documents of pharmaceutical products in recent years, with the proportion exceeding 30% from 1999 to 2003. Conclusions There is further scope for health outcomes researchers and regulatory decision-makers to contribute to the more efficient utilization of PROs and HRQL outcomes. Health researchers need to better justify the inclusion of these outcomes in clinical trials and highlight the added value of PRO data; while the regulators should develop harmonized procedures and capacities to adequately appraise the submitted information.

The Regulation of Patient-Reported Outcome Claims: Need for a Flexible Standard

We review the FDA's policies for the regulation of patient-reported outcome (PRO) claims such as quality of life, productivity, satisfaction and symptom reports and suggest alternative standards for substantiation. We base our review on FDA regulatory activities and public statements in the field of advertising substantiation. We compare these activities to the FDA's label substantiation policies and policies for health-economic (HE) claim substantiation. There is an overt inconsistency between the FDA's policies for substantiation of PRO claims in product labels and substantiation for such claims in advertising materials. This results in a higher standard for PRO claims in promotional vehicles than in product labels. Rather than relying on a “substantial evidence” standard, the FDA should consider a more flexible standard, such as the one currently applied to information included in the Clinical Trials section of product labels, or adopting a “competent and reliable scientific evidence” standard as set forth in Section 114 of the Food and Drug Administration Modernization Act (FDAMA) for HE data. We conclude that there needs to be greater consistency for substantiation in product labels and promotional materials. Furthermore, reconceptualizing most PRO claims as benefit extrapolations as opposed to efficacy information suggests a less rigorous standard is necessary.