The Role of Patient-reported Outcomes and Medication Adherence Assessment in Patient-focused Drug Development for Solid Organ Transplantation.

Defining Endpoints and Biomarkers in Inflammatory Bowel Disease: Moving the Needle Through Clinical Trial Design

PHP154 - Patient-Reported Outcome Measures in the FDA Pilot Compendium: Meeting Today’s Standards for Patient Engagement in Development?

The Importance of Patient-Focused Drug Development in Pemphigus and Pemphigoid

e18202 Background: Patient-reported outcomes (PROs) are increasingly valued as a key tool in patient-focused treatment decisions. However, a lack of standardization leads to significant variability in PRO collection and reporting in ground-breaking clinical trials of novel agents. We sought to characterize the mechanisms of assessment and variability by which PROs are reported for newly approved anti-cancer therapies. Methods: We reviewed the U.S. Food and Drug Administration (FDA) approvals between 2011 and 2017 for anti-cancer new molecular entities (NMEs) and new biologic approvals (BLAs). For each therapy, the pivotal clinical trial leading to FDA approval was identified using the national clinical trial (NCT) number and assessed for inclusion of PROs. A separate PubMed search was conducted to evaluate for PRO publication distinct from the original trial based on national clinical trial registry number. Results: From 2011 to 2017, the FDA approved 66 NMEs/BLAs based on 74 clinical trials for cancer treatment. Of the 74 clinical trial publications, 21 (28%) of the trials published PRO data in their original clinical publication, 18 (24%) published a separate PRO analysis, and 35 (47%) did not publish PRO data in either format. Among the 32 clinical trials (43%) that listed PROs as pre-specified outcomes, 72% published PROs (23/32). The separate PRO analyses (N = 18) were published considerably later following FDA approval (mean 605 days) than the original clinical trials (mean 20 days, N = 74, P < 0.001). Conclusions: As cancer treatment options expand, therapy decisions become increasingly nuanced. PROs assist decision-making by providing detailed information on important aspects of quality of life and tolerability. Our research has identified a significant lag in the publication of companion studies of PRO data associated with pivotal clinical trials, representing a meaningful gap in information critical to patients and oncologists in the process of making informed decisions.

In 2009, members of the ophthalmic research community held a joint meeting with members of the Food and Drug Administration (FDA) and the National Eye Institute (NEI) to define and describe the types of patient-focused drug development (PFDD) tools used in ophthalmology. Since then numerous reports have been published which indicate that many of the questionnaires used for patient-reported outcomes (PROs) in ophthalmic clinical development lack rigor and reliability according to modern methods. In 2017, the FDA began development of a series of four methodological guidances for sponsors of clinical trials on the significance of PFDD. The new guidances delineate the FDA's thinking and commitments under the Prescription Drug User Fee Act to implement a more structured approach to the assessment of risks and benefits in clinical trials. In these guidances, the FDA provides steps that drug and device manufacturers should follow, not only to obtain, but also to develop reliable and validated tools that measure patients' experience in clinical trials. Subsequent efforts have resulted in the development and validation of PROs specifically for ophthalmology. The purpose of this paper is to assesses the PROs currently used in ophthalmology and to provide practical strategies for incorporating them into clinical trials.

Many clinical trials use patient-reported outcome (PRO) measures, which can influence treatment decision-making, drug approval and label claims. Given that many PRO measure options exist, and there are conceptual and contextual complexities with PRO measurement, we aimed to evaluate how and why specific PRO measures have been selected for pivotal multiple sclerosis (MS) clinical trials. Specifically, we aimed to identify the reasons documented for PRO measure selection in contemporary phase III MS disease-modifying treatment (DMT) clinical trials. We searched for phase III clinical trials of MS DMTs published between 2015 and 2021 and evaluated trial protocols, or primary publications where available, for PRO measure selection information. Specifically, we examined study documents for their clarification of clinical concepts measured, definitions of concepts measured, explanations of which PRO measures were considered, why specific PRO measures were chosen, and trade-offs in PRO measure selection. We identified 1705 abstracts containing 61 unique phase III MS DMT clinical trials. We obtained and examined 27/61 trial protocols. Six protocols were excluded: four contained no mention of PRO measures and two contained redacted sections preventing adequate assessment, leaving 21 protocols for assessment. For the remaining 34 trials (61-27), we retrieved 31 primary publications; 15 primary publications mentioned the use of a PRO measure. None of the 36 clinical trials that mentioned the use of PRO measures (21 protocols and 15 primary publications) documented clear PRO or clinical outcome assessment (COA) measurement strategies, provided clear justifications for PRO selection, or reasons why specific PRO measures were selected when alternatives existed. PRO measure selection for clinical trials is not evidence-based or underpinned by structured systematic approaches. This represents a critical area for study design improvement as PRO measure results directly affect patient care, PRO measurement has conceptual and contextual complexities, and there is a wide range of options when selecting a PRO measure. We recommend trial designers use formal approaches for PRO measure selection to ensure PRO measurement-based decisions are optimised. We provide a simple, logical, five-stage approach for PRO measure selection in clinical trials.

Patient-reported outcome (PRO) measures validated in primary sclerosing cholangitis (PSC) are needed for clinical trials. This review describes the recent US Food & Drug Administration (FDA) Patient-Focused Drug Development (PFDD) guidelines, existing PRO measures used in PSC studies, and the design of PSC-specific symptom measures adherent with the guidelines. FDA released updated guidance reflecting best practices for the design and evaluation of clinical outcome assessments (including PROs) and the design of trial endpoints. Two recent systematic reviews (2018, 2020) identified multiple PRO measures used in PSC studies, with two additional measures published since. Of these, four were developed in samples inclusive of PSC patients and six have been psychometrically evaluated in PSC. Published evidence to sufficiently support alignment with the recent guidance is sparse. We review the design of three symptom measures for PSC to illustrate alignment with FDA guidance, including qualitative and quantitative studies to provide evidence for their validity for use in adult PSC trials. Investigators planning to use PRO measures as study endpoints for PSC need to be adherent with the recent FDA guidelines and build the evidence base to support the measure as fit-for-purpose as an endpoint for clinical trials.

Patient-Reported Outcome Measures in the Food and Drug Administration Pilot Compendium: Meeting Today’s Standards for Patient Engagement in Development?

Aicardi-Goutières Syndrome (AGS) is a genetic type 1 interferonopathy that causes white matter abnormalities and intracranial calcifications, resulting in varying degrees of neurologic impairment and systemic manifestations. Novel disease-modifying therapies for AGS are forthcoming. The 2022 Food and Drug Administration guidance, "Patient-Focused Drug Development" (PFDD), emphasizes the importance of including patients' voices early in the design of clinical trials. This represents an urgent unmet need in rare disease research. In this study, we propose and pilot a new methodology to identify patient-centered Concepts of Interest (COIs) and suitable Clinical Outcome Assessments (COAs) for clinical trials. The study was performed under the Myelin Disease Biorepository Project within the Global Leukodystrophy Initiative Clinical Trial Network. A sequential multicomponent approach, piloted in AGS, was designed to (i) identify COIs, (ii) select COAs capable of measuring the COIs through expert consensus, and (iii) assess the feasibility of COA application. Experts were identified based on relevant scientific publications and expertise in AGS (disease experts for COI) and/or their application of relevant COAs (outcome experts for COA). Expert consensus was achieved using the modified eDelphi approach for COIs, expertise-specific multi-panel focus group discussions, and pre-and post-surveys for COA selection. Consensus was defined as ≥70% agreement among the experts. This was followed by a virtual stakeholder discussion with patients and/or patient representatives to assess the feasibility of the COA application in the context of a clinical trial. Based on the health priorities identified by patient caregivers, the proposed approach revealed a set of fit-for-purpose COIs across the motor, adaptive behavior, and neurologic functional domains. All experts acknowledged the significance of each caregiver-identified priority but expressed differing opinions on the likelihood of observing changes in the functional domain within a 6- to 12-month timeframe. Following this, a consensus-building approach for COA selection for each identified COI resulted in a paired COI-COA panel applicable to future AGS clinical trials. Finally, the discussion on the feasibility of application of the selected COAs with the patients and/or patient representatives elicited critical information to design a patient-centered prospective COA protocol, applicable to clinical trials and natural history studies. The proposed approach marks the first step toward a patient-centered clinical trial design for rare diseases. It establishes a paired COI-COA panel, as well as informs the design of a patient-centered prospective COA protocol for upcoming AGS clinical trials and natural history studies. Additionally, the identified COA panel facilitates the creation of a multicomponent endpoint for clinical trials, which is especially crucial in phenotypically diverse disorders like AGS. This approach is widely applicable across leukodystrophies and rare diseases.

BackgroundClinical trials for obesity have traditionally focused on weight loss and resolution of comorbidities as primary outcomes. However, secondary outcomes, such as the impact of weight reduction on patient experience, like health-related quality of life (HRQoL), have increasingly been recognized as important. Therefore, a review was conducted to determine the Clinical Outcome Assessments (COAs) and Digital Health Technologies (DHTs) used in clinical trials for obesity to assess the patient experience.MethodsTwo clinical trial databases (United States & European Union) were reviewed to identify Phase 2–4 clinical trials for obesity (2018–2023). A targeted literature review was also conducted using the OVID database to identify clinical trial for obesity publications which included COAs/DHTs (2010–2023).ResultTrials from the databases (n = 53) and publications (n = 42) were included in data extraction (N = 73). This resulted in identification of 108 COAs, the majority being patient-reported outcome (PRO) measures (n = 83), but also 24 performance outcomes (PerfO) measures, and 1 composite PRO-clinician-reported outcomes (ClinRO) measure, as well as 2 DHTs. The most frequently identified PRO measures were the Short Form 36 and the Impact of Weight on Quality of Life Lite Clinical Trials. Twenty-four PerfO measures were also identified, with the 6-minute walk test being most common. These measures were most often used to construct secondary endpoints, with physical function (PF) being the most frequently specified domain. PRO measures assessing eating-related thoughts/behaviours, physical activity, and disordered eating were also frequently included, although individual measures varied widely across trials.ConclusionReview of COAs and DHTs in registered clinical trials and publications for obesity found that PRO measures were the most common type of COA used to develop endpoints with current use of DHTs limited. Specifically, the physical function domain of multidimensional patient-reported outcome measures assessing health-related quality of life were often used to construct secondary endpoints. Further work is warranted to assess how the COAs and DHT data collected in clinical trials are viewed by regulators and payers.

Rationale: Patient-reported outcome (PRO) measures offer valuable insights into the patient experience in asthma clinical trials. The US FDA's patient-focused drug development (PFDD) initiative prioritizes the patient perspective in evaluating treatment benefit. However, these data are often underutilized, and traditional high-ranking asthma trial endpoints do not capture the patient's day-to-day experience. There is a growing need for trial endpoints that incorporate meaningful patient-reported experiences to align with PFDD principles. This study aimed to understand how asthma exacerbations, control, and remission are conceptualized and measured across qualitative and quantitative literature, randomized controlled trials, and published guidelines. Methods: We conducted a targeted literature review using electronic databases, ClinicalTrials.gov, and hand-searching of relevant regulatory websites and reference lists. Qualitative data from patient and clinician perspectives were analyzed using content analysis methods. Definitions and measurement approaches for asthma exacerbations, control, and remission were extracted from identified sources and analyzed quantitatively, focusing on PROs and their alignment with PFDD principles. Results: The review revealed that the concepts of control, remission and exacerbations are interrelated, both in their definitions and measurement. There are variations in terminology and perceptions of asthma exacerbations between patients and clinicians. While clinicians favor the term “exacerbation”, patients primarily use the term “attack” – although it is unclear to what extent these are conceptually equivalent. Asthma control, though lacking a universally accepted definition, was consistently characterized based on medication use, lung function, healthcare utilization, and patient-reported outcomes (PROs) including symptoms. However, patient interpretations of asthma control went beyond clinical guideline criteria, for example some patients considered their ability to live a “normal” life. Limited evidence was found regarding patient perspectives on asthma remission. Clinical guidelines considered symptom absence, improved lung function, and control as crucial components of remission. The Asthma Control Questionnaire and Asthma Control Test were often used to measure elements of control, remission and exacerbation in trial endpoints, but patient-reported daily diaries were rarely used. Where consensus-based definitions for concepts were identified, patients were rarely involved in their development. Conclusions: This review highlights the need for greater alignment between clinical trial endpoints and the patient-reported experience of asthma, following PFDD principles. While PRO measures are increasingly used, gaps remain in capturing treatment benefits from the patient perspective, particularly for exacerbations and remission. Further research, including qualitative and quantitative data-driven analysis, is needed to develop patient-centric endpoints in clinical trials.

Background Symptoms of ulcerative colitis (UC) negatively affect patients’ health-related quality of life (HRQoL). The aim of this study was to identify symptoms and impacts experienced by patients with UC, develop a conceptual model (CM) and evaluate available patient-reported outcome (PRO) measures for appropriateness for inclusion in UC clinical studies. Methods We conducted a landscape assessment that included: targeted literature reviews (TLRs) to identify concepts of interest and frequently used PRO measures among patients with UC; label claims searches for US and European regulatory and health technology assessment (HTA) submissions; and US and European clinical trial database searches to identify PRO measures used as primary and secondary endpoints in ongoing clinical trials. Results from the TLR informed a CM of UC. Concepts from the CM were mapped to selected PRO measures. Appropriateness of selected PRO measures for UC populations was evaluated via a gap analysis. Results Fifty-two symptoms and 72 impacts of UC were identified from the TLR. The most frequently reported symptoms were diarrhoea, incontinence/leaking/lack of bowel control, urgency, rectal bleeding, frequent bowel movements and fatigue. The most frequently reported impacts were anxiety, depression, inability to conduct daily activities, embarrassment and affected relationships with others. The CM grouped the 52 symptom concepts into eight dimensions, the 29 impacts proximal to UC into two dimensions and the 43 impacts distal to UC into five dimensions (Figure 1). Of the 69 PRO measures identified, eight were selected for conceptual analysis based on being disease-specific and having evidence of use in regulatory label claims, HTA submissions, as UC clinical trial endpoints and/or having US Food and Drug Administration (FDA) qualification status. The five PRO measures that covered the most concepts when mapped against the CM and included in the gap analysis were: the Inflammatory Bowel Disease Questionnaire (IBDQ); Symptoms and Impacts Questionnaire for UC (SIQ-UC); UC-PRO symptoms modules (UC-PRO-Signs and Symptoms [UC-PRO/SS] and UC-PRO-Systemic Symptoms); UC-PRO impact modules (UC-PRO-Daily Coping [UC-PRO-DC], UC-PRO-Daily Life Impact [UC-PRO-DLI] and UC-PRO-Emotional Impact [UC-PRO-EI]); and Crohn’s and Ulcerative Colitis Questionnaire (CUCQ) (Table 1). All five PRO measures had good or excellent support for content validity; the UC-PRO/SS fully met FDA PRO guidance for content validity and most psychometric properties. Conclusion Based on the CM and PRO measures review, the IBDQ plus UC-PRO/SS are recommended to capture UC symptoms and IBDQ plus UC-PRO impact modules to capture proximal impacts. All PRO measures reviewed require further psychometric evaluation.

Patient-Reported Outcomes in Clinical Trials of CKD-Related Therapies: Report of a Symposium Sponsored by the National Kidney Foundation and the US Food and Drug Administration

<p>The US food and drug administration (FDA) has long called for clinical outcomes assessments (COA), such as patient-reported outcomes (PRO), to be ‘fit-for-purpose’ meaning the COA has been validated to support the context of use. The FDA’s recent patient-focused drug development guidance series has renewed the importance of ensuring that COA is ‘fit-for-purpose’ and valid. In addition, the FDA has recommended that COA be collected electronically and that the electronic (eCOA) system and devices also be validated. Advancing technology requires eCOA systems and devices to evolve; eCOA devices may change over time. As bring your own device (BYOD) models gain popularity and acceptance, devices may also be mixed within trials. Changes in eCOA devices or mixing devices may require equivalence testing to prove validity across platforms. The aim of this article is to provide an overview of the different types of validation at both the assessment level and the eCOA system (device) level to help clinical trial sponsors determine the appropriate level of validation or equivalence testing required for COA used in their clinical trials. </p>

<h3>Background</h3> The importance in measurement and analysis of patient-reported outcomes (PROs) in early oncology development as toxicity and efficacy endpoints— particularly with the emergence of targeted therapies and immunotherapies, has been recognized among researchers.^1-6 Recently, more attention has been directed towards considerations for applying PROs to early oncology development by the FDA in public workshops.^7,8 Despite their recognized value, methods for collecting, analyzing, and interpreting early phase PRO data are complex, leading to infrequent use in early oncology trials. The aim of this abstract is to conduct a scoping review of PRO usage in early oncology trials and highlight the novelty of a Sanofi-developed PRO measure, Patient Qualitative Assessment of Treatment version 2 (PQATv2). <h3>Methods</h3> To validate our approach to PQATv2 implementation, we sought to identify early phase industry-sponsored oncology trials reporting PRO endpoints registered with ClinicalTrials.gov between January 1, 2009, to July 20, 2022—a start date to coincide with the publication of the 2009 FDA PRO Guidance for Industry. The PQATv2 is a 6-item, generic PRO measure. The PQATv2 includes: two 11-point numeric rating scales assessing participant-perceived treatment benefits and disadvantages (0 = not at all beneficial/disadvantageous to 10 = extremely beneficial/disadvantageous); an item assessing participants’ willingness to continue treatment after the trial (yes/no); a 7-point Likert-type item assessing participants’ overall benefit/risk ratio perceptions (-3 = ‘disadvantages of the drug I received significantly outweighs the benefits’ to 3 = ‘the benefits of the drug I received significantly outweigh the disadvantages’); and three free-text items assessing participant-perceived treatment benefits, disadvantages, and reasons why the participant would be willing or unwilling to continue the treatment after the trial. <h3>Results</h3> Of the 78 early phase studies reporting PRO endpoints and registered with ClinicalTrials.gov, Phase 1 oncology trials accounted for 33.3% (n=26) and Phase 1|2 at 66.7% (n=52). The PQATv2 is being included in several of our early oncology studies. Recognizing the need to enrich traditional efficacy and safety endpoints, Sanofi believes the PQATv2 is a novel and important approach to identifying salient and important concepts that guide the identification of future PRO measures in later phases. <h3>Conclusions</h3> The PQATv2 is a novel exploratory measure aimed at generating additional hypotheses to guide selection of fit-for-purpose PROs in later phases. Further analysis of the utility of PROs in early phase oncology, and their impact in guiding preparation of PROs for later stage studies will be conducted as we gain more experience. <h3>References</h3> Henon C, Lissa D, Paoletti X, Thibault C, Le Tourneau C, Lanoy E, Hollebecque A, Massard C, Soria JC, Postel-Vinay S. Patient-reported tolerability of adverse events in phase 1 trials. <i>ESMO Open</i>. 2017;<b>2</b>(2). Minasian L, Rosen O, Auclair D, Rahman A, Pazdur R, Schilsky RL. Optimizing dosing of oncology drugs. <i>Clin Pharmacol Ther</i> 2014; <b>96</b>(5): 572–579. Anota A, Boulin M, Dabakuyo-Yonli S, Hillon P, Cercueil JP, Minello A, Jouve JL, Paoletti X, Bedenne L, Guiu B, Bonnetain F. An explorative study to assess the association between health-related quality of life and the recommended phase II dose in a phase I trial: idarubicin-loaded beads for chemoembolisation of hepatocellular carcinoma. <i>BMJ Open</i> 2016;<b>6</b>(6). Mendoza TR. Understanding the Toxicity of Cancer Immunotherapies: Use of Patient-Reported Outcomes. <i>Journal of Immunotherapy and Precision Oncology</i> 2018; <b>1</b>(1):38–45 Bossi P, Botta L, Bironzo P, Sonetto C, Musettini G, Sbrana A, Di Giannantonio V, Locati LD, Di Maio M, Antonuzzo A. Systematic review of adverse events reporting in clinical trials leading to approval of targeted therapy and immunotherapy. <i>Future Oncology</i>. 2019;<b>15</b>(21):2543–53. Safa H, Tamil M, Spiess PE, Manley B, Pow-Sang J, Gilbert SM, Safa F, Gonzalez BD, Oswald LB, Semaan A, Diab A, Chahoud J. Patient-Reported Outcomes in Clinical Trials Leading to Cancer Immunotherapy Drug Approvals From 2011 to 2018: A Systematic Review. <i>J Natl Cancer Inst</i> 2021;<b>113</b>(5):532–542. US Food and Drug Administration (FDA) Clinical Outcome Assessment in Cancer Clinical Trials (COA-CCT). Workshop: 7th Annual Clinical Outcome Assessment in Cancer Clinical Trials Workshop. Virtual June 29th 2022. US Food and Drug Administration (FDA) American Society of Clinical Oncology (ASCO). Getting the Dose Right: Optimizing Dose Selection Strategies in Oncology. Virtual Workshop May 3-5th 2022.