Recommendations on the Selection, Development, and Modification of Performance Outcome Assessments: A Good Practices Report of an ISPOR Task Force.

In evaluating the clinical benefit of new therapeutic interventions, it is critical that the treatment outcomes assessed reflect aspects of health that are clinically important and meaningful to patients. Performance outcome (PerfO) assessments are measurements based on standardized tasks actively undertaken by a patient that reflect physical, cognitive, sensory, and other functional skills that bring meaning to people's lives. PerfO assessments can have substantial value as drug development tools when the concepts of interest being measured best suit task performance and in cases where patients may be limited in their capacity for self-report. In their development, selection, and modification, including the evaluation and documentation of validity, reliability, usability, and interpretability, the good practice recommendations established for other clinical outcome assessment types should continue to be followed, with concept elicitation as a critical foundation. In addition, the importance of standardization, and the need to ensure feasibility and safety, as well as their utility in patient groups, such as pediatric populations, or those with cognitive and psychiatric challenges, may enhance the need for structured pilot evaluations, additional cognitive interviewing, and evaluation of quantitative data, such as that which would support concept confirmation or provide ecological evidence and other forms of construct evidence within a unitary approach to validity. The opportunity for PerfO assessments to inform key areas of clinical benefit is substantial and establishing good practices in their selection or development, validation, and implementation, as well as how they reflect meaningful aspects of health is critical to ensuring high standards and in furthering patient-focused drug development.

Public-private partnerships in transplant drug development.

The Transplant Therapeutics Consortium (TTC), a public-private partnership (PPP) led by the Critical Path Institute (C-Path), recently published a whitepaper titled "The Importance of Drug Safety and Tolerability in the Development of New Immunosuppressive Therapy for Transplant Recipients" by Stegall et al in the American Journal of Transplantation. As staff members of the Food and Drug Administration's (FDA), Center for Drug Evaluation and Research (CDER), Office of New Drugs and Office of Translational Science, and the Oncology Center of Excellence, we would like to provide our perspective on the TTCs efforts and the whitepaper.

Why Reinvent the Wheel? Use or Modification of Existing Clinical Outcome Assessment Tools in Medical Product Development.

Assessment of clinical benefit in treatment trials can be made through report by a clinician, a patient, or a nonclinician observer (eg, caregiver) or through a performance-based assessment. The US Food and Drug Administration (FDA) published a final guidance for industry for one type of clinical outcome assessment (COA)-patient-reported outcome (PRO) measures-in 2009 that described how FDA reviews PRO measures for their adequacy to support medical product-labeling claims. Many of the principles described in the PRO Guidance could be applicable to the other types of COAs, including instruments completed by clinicians (ie, clinician-reported outcome assessments) and nonclinician observers (ie, observer-reported outcome assessments). FDA guidance describing the regulatory expectations for all COA types including performance outcome assessments, which are based on the patient's performance of a defined task or activity, is in progress to meet requirements described within the 21st Century Cures Act and PDUFA VI. This communication highlights potential ways in which existing instruments might be modified or used "as is" to conform to good measurement principles. An industry and a regulatory perspective are described.

Can we use social media to support content validity of patient-reported outcome instruments in medical product development?

We report a panel designed to open a dialog between pharmaceutical sponsors, regulatory reviewers, and other stakeholders regarding the use of social media to collect data to support the content validity of patient-reported outcome instruments in the context of medical product labeling. Multiple stakeholder perspectives were brought together to better understand the issues encountered in pursuing social media as a form of data collection to support content validity. Presenters represented a pharmaceutical sponsor of clinical trials, a regulatory reviewer from the Food and Drug Administration, and an online data platform provider. Each presenter shared its perspective on the advantages and disadvantages of using social media to collect this type of information. There was consensus that there is great potential for using social media for this purpose. There remain, however, unanswered questions that need to be addressed such as identifying which type of social media is most appropriate for data collection and ensuring that participants are representative of the target population while maintaining the advantages of anonymity provided by online platforms. The use of social media to collect evidence of content validity holds much promise. Clarification of issues that need to be addressed and accumulation of empirical evidence to address these questions are essential to moving forward.

Well-defined and reliable clinical outcome assessments for pediatric Crohn disease: a critical need for drug development.

OBJECTIVES: The aim of the present study was to identify areas for further development of clinical outcome assessment (COA) in pediatric Crohn disease (CD). METHODS: The study analyzed the measurement properties of all existing COA tools for pediatric CD in literature and published registration trials of approved drugs for pediatric CD based on criteria described in Food and Drug Administration guidance for patient-reported outcome (PRO) development. RESULTS: The Pediatric Crohn's Disease Activity Index (PCDAI) and its derivatives (abbreviated, short, modified, and weighted PCDAIs) were reviewed. The Crohn's Disease Activity Index (CDAI) and Harvey-Bradshaw index (HBI), designed for adult patients, have been adapted for use in a few pediatric CD studies. The use of PCDAI as an endpoint in Remicade and Humira trials led to the Food and Drug Administration-approved indication in pediatric CD. Common issues in measurement properties of COA tools included the absence of direct patient or caregivers' input to generate the items measuring signs and symptoms; absence of evidence demonstrating correlation with clinically relevant inflammation observed with endoscopic measures; lack of standardization in measurement, age-appropriate interviewer script, and response rating criteria for the physician interviewer. CONCLUSIONS: Available evidence indicates that CDAI, HBI, and 5 versions of the PCDAI lack adequate measurement properties for use as a primary endpoint for phase 3 trials intended to support approval of products intended to treat pediatric CD. In order to facilitate pediatric drug development, a well-defined, reliable, sensitive, and globally recognized PRO that measures signs and symptoms in children with CD and that can be used in conjunction with endoscopy-based endpoints and/or biomarkers is sorely needed.

Pain palliation measurement in cancer clinical trials: the US Food and Drug Administration perspective.

BACKGROUND: Pain palliation resulting from antitumor therapy provides direct evidence of treatment benefit when combined with evidence of antitumor activity. The US Food and Drug Administration (FDA) previously issued guidance regarding the use of patient-reported outcome (PRO) measures to support labeling claims. The purpose of this article is to identify common challenges and key design strategies when measuring pain palliation in antitumor therapy clinical trials that are consistent with PRO Guidance principles. METHODS: Antitumor clinical protocols submitted to the FDA between 1995 and 2012 that included pain palliation as a primary or secondary endpoint were reviewed. Challenges in critical trial design components were identified. Design strategies consistent with PRO Guidance principles are proposed. RESULTS: The challenges identified were measurement of pain intensity and analgesic use, enrollment eligibility criteria, data collection methods, responder definitions, missing data, and blinding. Strategies included the use of well-defined, reliable, PRO assessments of pain intensity and analgesics; ensuring that enrollment criteria define patients with clinically significant pain attributable to cancer on an optimal analgesic regimen; defining responders using both pain and analgesic use criteria; incorporating an analysis of tumor response to support evidence of pain response; and minimizing missing data and inadvertent unblinding. CONCLUSIONS: Improvement in cancer-related pain resulting from antitumor therapy is an important treatment benefit that can support drug approval and labeling claims when adequately measured if study results demonstrate statistically and clinically significant findings. Sponsors are encouraged to discuss pain palliation assessment methods with the FDA early in and throughout product development.

Alternate endpoints and clinical outcome assessments in pediatric ulcerative colitis registration trials.

OBJECTIVES: Presently, there is no consensus on endpoint measures to assess clinical outcomes for pediatric ulcerative colitis (UC). This study reviewed the endpoints used in the registration trials of approved drugs for pediatric UC. METHODS: The primary efficacy endpoints of all registration trials completed from 1950 to 2008 that led to Food and Drug Administration approval for indications in pediatric and adult UC were reviewed. RESULTS: Colazal and Remicade have been approved for pediatric UC indication, and clinical response was used as a primary endpoint in these registration trials. The clinical response in the adult Colazal trials was defined as a reduction of rectal bleeding and improvement in at least one of the other assessed symptoms (stool frequency, patient functional assessment, abdominal pain, sigmoidoscopic grade, and physician's global assessment) assessed by the Sutherland UC Activity Index. The pediatric Colazal trial defined clinical response using the Modified Sutherland UC Activity Index, which excluded abdominal pain and functional assessment. Both adult and pediatric Remicade trials used clinical response defined by the Mayo score as the primary endpoint. The Pediatric Ulcerative Colitis Activity Index was used to measure various secondary endpoints in the pediatric Remicade trial. CONCLUSIONS: Pediatric-specific endpoints were used, but outcome measures and definition of clinical response were not consistent in pediatric UC trials. Consensus on the definition of successful treatment outcome (clinical response and/or remission) and collaboration in the development of well-defined and reliable measures of signs and symptoms for use in conjunction with endoscopic parameters of mucosal healing will facilitate pediatric drug development.

Steps toward harmonization for clinical development of medicines in pediatric ulcerative colitis-a global scientific discussion, part 1: efficacy endpoints and disease outcome assessments.

OBJECTIVES: There is a pressing need for drug development in pediatric ulcerative colitis (UC). Lack of scientific consensus on efficacy endpoints and disease outcome assessments presents a hurdle for global drug development in pediatric UC. Scientists from 4 regulatory agencies convened an International Inflammatory Bowel Disease Working Group (i-IBD Working Group) to harmonize present thinking about various aspects of drug development in pediatric UC globally. METHODS: The i-IBD Working Group was convened in 2012 by scientists from the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan. The members of this group considered reasons for differences in their acceptance of efficacy endpoints and disease activity indices used in pediatric UC, reviewed the available literature, and developed consensus opinions regarding approaches for evaluating outcomes in pediatric UC trials. RESULTS: There is lack of harmonization in using efficacy endpoint and outcome assessments including disease activity indices to assess clinical benefit in pediatric UC trials. Many disease activity indices have been developed, but their biometric properties, such as responsiveness, reliability, and validity, have not been properly validated. Biomarkers, such as fecal calprotectin and lactoferrin, are being investigated for their potential as noninvasive surrogate endpoints in UC. CONCLUSIONS: Consensus on the efficacy endpoints, disease activity indices, and outcome assessments is needed for globalization of pediatric UC trials. The i-IBD Working Group offers several perspectives to facilitate harmonization across regions. The development of noninvasive biomarkers as reliable surrogate endpoints needs to be explored further.

Leveraging sensor-based functional outcomes to enhance understanding of the patient experience: challenges and opportunities.

INTRODUCTION: Sensor-based digital health technology (DHT) has emerged as a promising means to assess patient functioning within and outside clinical trials. Sensor-based functional outcomes (SBFOs) provide valuable insights that complement other measures of how a patient feels or functions to enhance understanding of the patient experience to inform medical product development. AREAS COVERED: This perspective paper provides recommendations for defining SBFOs, discusses the core evidence required to support SBFOs to inform decision-making, and considers future directions for the field. EXPERT COMMENTARY: The clinical outcome assessment (COA) development process provides an important starting point for developing patient-centered SBFOs; however, given the infancy of the field, SBFO development may benefit from a hybrid approach to evidence generation by merging exploratory data analysis with patient engagement in measure development. Effective SBFO development requires combining unique expertise in patient engagement, measurement and regulatory science, and digital health and analytics. Challenges specific to SBFO development include identifying concepts of interest, ensuring measurement of meaningful aspects of health, and identifying thresholds for meaningful change. SBFOs are complementary to other COAs and, as part of an integrated evidence strategy, offer great promise in fostering a holistic understanding of patient experience and treatment benefits, particularly in real-world settings.

Measuring What Matters to Patients in Dermatology Drug Development: A Regulatory Perspective.

Incorporating the patient voice into drug development and regulatory review process allows for the science of drug development to be more patient-centered. Dermatology is one therapeutic area where patients have the potential to provide valuable perspectives on symptoms, functional impacts, and aesthetic outcomes. Patient-reported and observer-reported outcomes play an important role in capturing concerns related to the disease or condition and its treatment. Patient experience data from well-designed trials are critical for regulatory decision-making and ultimately enable prescribers and patients to make better informed treatment decisions at the point of care.

Acute pain pathways: protocol for a prospective cohort study.

INTRODUCTION: Opioid analgesics are often used to treat moderate-to-severe acute non-cancer pain; however, there is little high-quality evidence to guide clinician prescribing. An essential element to developing evidence-based guidelines is a better understanding of pain management and pain control among individuals experiencing acute pain for various common diagnoses. METHODS AND ANALYSIS: This multicentre prospective observational study will recruit 1550 opioid-naïve participants with acute pain seen in diverse clinical settings including primary/urgent care, emergency departments and dental clinics. Participants will be followed for 6 months with the aid of a patient-centred health data aggregating platform that consolidates data from study questionnaires, electronic health record data on healthcare services received, prescription fill data from pharmacies, and activity and sleep data from a Fitbit activity tracker. Participants will be enrolled to represent diverse races and ethnicities and pain conditions, as well as geographical diversity. Data analysis will focus on assessing patients' patterns of pain and opioid analgesic use, along with other pain treatments; associations between patient and condition characteristics and patient-centred outcomes including resolution of pain, satisfaction with care and long-term use of opioid analgesics; and descriptive analyses of patient management of leftover opioids. ETHICS AND DISSEMINATION: This study has received approval from IRBs at each site. Results will be made available to participants, funders, the research community and the public. TRIAL REGISTRATION NUMBER: NCT04509115.

Considerations in the Assessment of Clinical Benefit with a Focus on Pain: a Regulatory Perspective.

In the USA, the regulatory standard for demonstration of efficacy of a drug is evidence of clinical benefit from adequate and well-controlled clinical trials. Understanding the natural history of disease and how treatment is expected to alter its course, and gathering input from relevant stakeholders, such as patients, caregivers, and clinicians, is essential to understand the best way to measure clinical benefit in a clinical trial. Though pain intensity has been the primary outcome measure in clinical trials for pain, an array of measures assessing clinical outcomes from multiple perspectives can allow for more comprehensive interpretation of how a treatment affects patients' lives. Careful consideration should be given to how pain affects the feeling and functioning of each distinct patient population and which outcome assessment, or combination of outcome assessments, may be necessary to provide a more comprehensive view of the patient experience. The early stages of medical product development are an important opportunity to engage with regulatory agencies to discuss potential approaches to clinical trial design and outcome measurement strategies.

Advancing Therapeutic Development for Pulmonary Morbidities Associated with Preterm Birth.

Chronic pulmonary and respiratory conditions associated with preterm birth are incompletely characterized, complicating long-term treatment and development of more effective therapies. Stakeholders face challenges in the development of validated, clinically meaningful endpoints that adequately measure morbidities and predict or represent health outcomes for preterm neonates. We propose in this paper a research agenda, informed by the input of experts from a 2018 workshop we convened on this topic, to advance endpoint and treatment development. We discuss the necessity of further evaluation of existing endpoints and the improved characterization of disease endotypes. We also discuss key steps to the development of optimized short- and long-term endpoints that can be linked to meaningful health outcomes. Finally, we discuss the importance of limiting variability in data collection and the application of new clinical trial endpoints as well as the critical nature of multi-stakeholder collaboration to advancing therapeutic development for this vulnerable patient population.

Developing and Implementing Performance Outcome Assessments: Evidentiary, Methodologic, and Operational Considerations.

The use of performance outcome (PerfO) assessments to measure cognitive or physical function in drug trials presents several challenges for both sponsors and regulators, owing in part to a relative lack of scientific guidance on their development, implementation, and interpretation. In December 2016, the Duke-Margolis Center for Health Policy convened a 2-day workshop to explore the evidentiary, methodologic, and operational challenges associated with PerfO measures, and to identify potential paths to addressing these challenges. This paper presents both a summary of the discussion as well as additional input from a working group of experts from FDA, industry, academia, and public-private consortia. It is intended to advance the discussion around the development and use of PerfO measures to assess patient functioning in clinical trials intended to support registration of new treatments, and to highlight the key gaps in knowledge where additional research, collaboration, and discussion are needed.

Use of PRO Measures to Inform Tolerability in Oncology Trials: Implications for Clinical Review, IND Safety Reporting, and Clinical Site Inspections.

Cancer therapeutics frequently lead to symptomatic adverse events (AE) that can affect treatment tolerability. The NCI has developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to assess symptomatic AEs by direct patient self-report. Although longitudinal assessment of patient-reported symptomatic AEs holds promise to better inform treatment tolerability, using patient-reported outcome (PRO) measures to assess symptomatic AEs has raised several regulatory and good clinical practice issues among those who conduct cancer clinical trials. These include concerns regarding trial monitoring, clinical review of PRO results by investigators and delegated clinical staff, whether PRO data on symptomatic AEs require investigational new drug (IND) safety reporting, and how the trial conduct and resultant PRO data will be assessed during clinical investigator site inspections. This article addresses current thinking regarding these issues in cancer clinical trials from the FDA, the NCI, and the Office for Human Research Protections. PRO measures, such as PRO-CTCAE, that assess symptomatic AEs in cancer trials are considered similar to other PRO assessments of symptoms, function, and health-related quality of life and can generate complementary data that may inform tolerability. Clarity on operational concerns related to incorporating PRO measures to inform tolerability is critical to continue the advancement of rigorous PRO assessment in cancer clinical trials. Clin Cancer Res; 24(8); 1780-4. ©2017 AACRSee related commentary by Nipp and Temel, p. 1777.

Use of Mobile Devices to Measure Outcomes in Clinical Research, 2010-2016: A Systematic Literature Review.

BACKGROUND: The use of mobile devices in clinical research has advanced substantially in recent years due to the rapid pace of technology development. With an overall aim of informing the future use of mobile devices in interventional clinical research to measure primary outcomes, we conducted a systematic review of the use of and clinical outcomes measured by mobile devices (mobile outcomes) in observational and interventional clinical research. METHOD: We conducted a PubMed search using a range of search terms to retrieve peer-reviewed articles on clinical research published between January 2010 and May 2016 in which mobile devices were used to measure study outcomes. We screened each publication for specific inclusion and exclusion criteria. We then identified and qualitatively summarized the use of mobile outcome assessments in clinical research, including the type and design of the study, therapeutic focus, type of mobile device(s) used, and specific mobile outcomes reported. RESULTS: The search retrieved 2,530 potential articles of interest. After screening, 88 publications remained. Twenty-five percent of the publications (n = 22) described mobile outcomes used in interventional research, and the rest (n = 66) described observational clinical research. Thirteen therapeutic areas were represented. Five categories of mobile devices were identified: (1) inertial sensors, (2) biosensors, (3) pressure sensors and walkways, (4) medication adherence monitors, and (5) location monitors; inertial sensors/accelerometers were most common (reported in 86% of the publications). Among the variety of mobile outcomes, various assessments of physical activity were most common (reported in 74% of the publications). Other mobile outcomes included assessments of sleep, mobility, and pill adherence, as well as biomarkers assessed using a mobile device, including cardiac measures, glucose, gastric reflux, respiratory measures, and intensity of head-related injury. CONCLUSION: Mobile devices are being widely used in clinical research to assess outcomes, although their use in interventional research to assess therapeutic effectiveness is limited. For mobile devices to be used more frequently in pivotal interventional research - such as trials informing regulatory decision-making - more focus should be placed on: (1) consolidating the evidence supporting the clinical meaningfulness of specific mobile outcomes, and (2) standardizing the use of mobile devices in clinical research to measure specific mobile outcomes (e.g., data capture frequencies, placement of device). To that aim, this manuscript offers a broad overview of the various mobile outcome assessments currently used in observational and interventional research, and categorizes and consolidates this information for researchers interested in using mobile devices to assess outcomes in interventional research.

Development of a harmonized patient-reported outcome questionnaire to assess myelofibrosis symptoms in clinical trials.

Along with reducing spleen size, relieving symptom severity is a key objective of the treatment of myelofibrosis (MF). Several questionnaires have been developed for patient self-report of MF symptoms in clinical trials and each includes unique instructions, items, and/or response scales. This variability in questionnaire content increases uncertainty; it is unclear which questionnaire is the most appropriate for assessing MF symptoms and it makes comparisons across trials difficult. The Patient-Reported Outcome (PRO) Consortium's MF Working Group (WG) was established to review existing MF symptom questionnaires and to develop a harmonized, consensus-based PRO questionnaire for use in future MF trials. The WG focused on the seven core symptoms of MF: fatigue, night sweats, pruritus, abdominal discomfort, pain under the ribs on the left side, early satiety, and bone pain. The resulting Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) asks respondents to report symptom severity at its worst for each of the seven items on a 0 (Absent) to 10 (Worst Imaginable) numeric rating scale. The MFSAF v4.0, for which there are 24-h and 7-day recall formats, will be maintained and licensed by the Critical Path Institute and made publicly available for use in future clinical trials.