Search

The FDA conducts independent reviews of scientific data obtained with investigational drug products to ensure that they are safe and effective. As a result of this process, FDA-approved product labeling is generated that is considered one of the most trusted sources of information for use of an approved drug. But FDA approval is only the beginning of the life cycle of a new drug; the first oncology drugs now have more than 7 decades of clinical experience in the postmarketing setting. Due, in part, to lack of incentives, some companies may not seek inclusion of new data, other than new safety information, in FDA-approved product labeling. Ensuring that product labeling provides adequate directions for use is important for all drugs, including older therapies that may form the backbone of many standard combination regimens for pediatric and adult cancers. Project Renewal is an FDA Oncology Center of Excellence pilot program that leverages expertise from the clinical and scientific oncology communities to review published literature and generate a drug-specific product report summarizing data that may support updates to FDA-approved product labeling. This article provides a broad overview of Project Renewal's collaborative pilot process for identifying and assessing literature supporting potential labeling updates, while engaging the oncology community to increase awareness of FDA's evidentiary standards and deliberative processes used when considering the addition of new indications and dosing regimens to product labeling.

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry.

Distal symmetrical axonal polyneuropathy (DSP) is due to injury to peripheral sensory, motor, and autonomic nerve fibers, resulting in distal predominant sensory loss, pain, and gait instability. DSP occurs as a complication of multiple medical conditions including diabetes or HIV, or following exposure to various toxins such as chemotherapy. It affects at least 10% of the United States population. Few treatments for DSP are approved by regulatory agencies. Reliable and responsive outcome measures are integral to developing new DSP treatments. Multiple clinician-rated measures that incorporate neuropathy signs exist, however, it is not clear which of these measures performs best for various DSP phenotypes. This systematic review summarizes the content of 18 published measures of DSP identified using PubMed and from personal archives of the authors. The relative percentage of scoring dedicated to motor, reflex, large and small fiber sensory, and autonomic domains varied considerably among measures. The most common neurologic examination items included in the scales were (1) vibration perception (n = 18, 100%), (2) reflexes (n = 16, 89%), (3) pinprick perception (n = 14, 78%), (4) muscle strength (n = 11, 61%), (5) touch–pressure perception (n = 9, 50%), and (6) joint position perception (n = 8, 44%). This review can be used to inform decisions regarding which of the available clinician-rated sign outcome measures would be most appropriate for use in a particular DSP population, based on the domains most affected by that neuropathy or on the domains most likely to be affected by a particular experimental therapy.

Objective A novel Oral Lichen Planus Symptom Severity Measure was developed as a clinical outcome assessment of the daily symptom experience of patients with oral lichen planus. Methods A literature review and expert input were followed by open-ended concept elicitation interviews with 17 adults with oral lichen planus in the United States and Ireland. Item content was generated, and the interviews continued until input saturation was reached. The final electronic version of the measure was cognitively debriefed in 6 US patients and subsequently translated and linguistically validated in Germany and Denmark. Results Concept elicitation interviews demonstrated content validity and saturation in identifying symptoms and daily activities that generate symptoms in patients with oral lichen planus. The content and electronic daily diary format demonstrated content validity during cognitive debriefing interviews. Linguistic validation of the 7-item Oral Lichen Planus Symptom Severity Measure in Germany and Denmark confirmed the content validity of the German and Danish versions. Conclusions Qualitative research methods generated evidence that the 7-item Oral Lichen Planus Symptom Severity Measure version 1.0 is a well-defined assessment tool to characterize the severity, specificity and variations of symptoms in patients with oral lichen planus.

Copyright © 2020 International Association for the Study of Pain., Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.

Background Multiple Sclerosis (MS) clinical trials increasingly focus on progressive and advanced MS, with upper limb function (ULF) as a key outcome. Within clinical trials, Patient Reported Outcomes (PROs) quantify clinical variables and establish meaningfulness of changes. Scientific standards and regulatory criteria (from Food and Drug Administration [FDA]) require PROs be “fit-for-purpose”: well-defined and reliable measures of specific concepts in defined contexts. Objective To identify, from literature, existing PROs measuring ULF and determine which satisfy scientific and regulatory clinical trials requirements. Method We screened PubMed/Web of Science using multiple relevant terms. Abstracts and full texts were screened using suitability criteria. PRO development papers were evaluated using recently expanded Consensus Standards for Measurement Instruments (COSMIN) criteria for content development. Results We identified 3619 articles; 485 used 24 different ULF PROs. No PRO satisfied scientific and regulatory requirements as a well-defined measure of a clearly defined construct in a specific clinical context. Conclusions Existing ULF PROs don't meet fit-for-purpose criteria. MS clinical trials require new measures with greater emphasis on patient engagement to derive theoretical frameworks, concepts of interest, and contexts of use followed by systematic literature searches, expert input, and qualitative research to support item generation. Until then, trials will miss aspects of meaningful within-patient change and thereby misrepresent (likely underestimating) treatment effects., Highlights • With MS clinical trials increasingly focusing on progressive and advanced MS, we searched for and assessed existing Upper Limb Function (ULF) Patient Reported Outcome (PRO) for MS clinical trials • We established that existing PROs for ULF in MS do not meet regulatory and scientific criteria for content validity. • In fact, we established that the content development of existing PROs is worrisome – often falling short of guidelines around conceptual development, qualitative involvement of patients, use of representative samples and well-documented literature searches. • These results reiterate the work of other authors, where poor historical PRO content development has been established in various clinical contexts. • New measures are required.

Integrating information on physical function and pain intensity into a composite measure may provide a useful method for assessing treatment efficacy in clinical trials of chronic pain. Accordingly, we evaluated composite outcomes in trials of duloxetine, gabapentin, and pregabalin. Data on 2287 patients in 9 trials for painful diabetic peripheral neuropathy (DPN) and 1513 patients in 6 trials for postherpetic neuralgia (PHN) were analyzed. All trials assessed pain intensity on a 0 to 10 numeric rating scale and physical function with the 10-item subscale of the Short Form-36, ranging 0 to 100 with higher scores indicating better function. Correlation between change in pain intensity from baseline to posttreatment and change in physical function was small in DPN (ρ = -0.22; P < 0.001) and nonsignificant in PHN (ρ = -0.05; P = 0.08). Assay sensitivities of 10 composite outcomes were examined in a random subsample of patients enrolled in pregabalin trials for DPN and PHN. Of these, a responder outcome of ≥50% improvement in pain intensity, or a ≥20% improvement in pain intensity and ≥30% improvement in physical function was not only significantly associated with pregabalin vs placebo in the development cohorts for both pain conditions but also in the validation cohorts. Furthermore, this composite outcome was cross-validated in trials of gabapentin for PHN and duloxetine for DPN, and had slightly lower number needed to treat than a standard responder outcome of ≥50% reduction in pain intensity. In summary, this study identified a composite outcome of pain intensity and physical function that may improve the assay sensitivity of future neuropathic pain trials.

Background Rare diseases (RDs) affect a small number of people within a population. About 5000 to 8000 distinct RDs have been identified, with an estimated 6% to 8% of people worldwide suffering from an RD. Approximately 75% of RDs affect children. Frequently, these conditions are heterogeneous; many are progressive. Regulatory incentives have increased orphan drug designations and approvals. Objective To develop emerging good practices for RD outcomes research addressing the challenges inherent in identifying, selecting, developing, adapting, and implementing patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments for use in RD clinical trials. Good Practices for Outcomes Research This report outlines the challenges and potential solutions in determining clinical outcomes for RD trials. It follows the US Food and Drug Administration Roadmap to Patient-Focused Outcome Measurement in Clinical Trials. The Roadmap consists of three columns: 1) Understanding the Disease or Condition, 2) Conceptualizing Treatment Benefit, and 3) Selecting/Developing the Outcome Measure. Challenges in column 1 include factors such as incomplete natural history data and heterogeneity of disease presentation and patient experience. Solutions include using several information sources, for example, clinical experts and patient advocacy groups, to construct the condition’s natural history and understand treatment patterns. Challenges in column 2 include understanding and measuring treatment benefit from the patient’s perspective, especially given challenges in defining the context of use such as variations in age or disease severity/progression. Solutions include focusing on common symptoms across patient subgroups, identifying short-term outcomes, and using multiple types of COA instruments to measure the same constructs. Challenges in column 3 center around the small patient population and heterogeneity of the condition or study sample. Few disease-specific instruments for RDs exist. Strategies include adapting existing instruments developed for a similar condition or that contain symptoms of importance to the RD patient population, or using a generic instrument validated for the context of use. Conclusions This report provides state-of-the-art solutions to patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments challenges in clinical trials of patients with RDs. These recommended solutions are both pragmatic and creative and posed with clear recognition of the global regulatory context used in RD clinical development programs.

Introduction: No treatments for axonal peripheral neuropathy are approved by the United States Food and Drug Administration (FDA). Although patient- and clinician-reported outcomes are central to evaluating neuropathy symptoms, they can be difficult to assess accurately. The inability to identify efficacious treatments for peripheral neuropathies could be due to invalid or inadequate outcome measures. Methods: This systematic review examined the content validity of symptom-based measures of diabetic peripheral neuropathy, HIV neuropathy, and chemotherapy-induced peripheral neuropathy. Results: Use of all FDA-recommended methods to establish content validity was only reported for 2 of 18 measures. Multiple sensory and motor symptoms were included in measures for all 3 conditions; these included numbness, tingling, pain, allodynia, difficulty walking, and cramping. Autonomic symptoms were less frequently included. Conclusions: Given significant overlap in symptoms between neuropathy etiologies, a measure with content validity for multiple neuropathies with supplemental disease-specific modules could be of great value in the development of disease-modifying treatments for peripheral neuropathies. Muscle Nerve 55: 366–372, 2017

The Food and Drug Administration Modernization Act (FDAMA) of 1997 included Section 114 as a regulatory safe harbor with the goal of increasing the dissemination of health care economic information (HCEI) to those responsible for formulary decision making. HCEI is typically not included within FDA-approved labeling. Although it has been nearly 20 years since passage and enactment of Section 114, proactive distribution of HCEI has been underutilized by biopharmaceutical companies partly because of (a) vague wording in the statute and (b) the absence of FDA-implementing regulations. Consequently, companies and health care decisions makers have had to speculate about the scope of the provisions. As a result, the biopharmaceutical industry has significant concerns about stepping over the line when using the safe harbor. Also, payers and other "payer-like" decision makers (e.g., self-funded corporate insurers) who are trying to make appropriate coverage and utilization decisions are demanding this information but are not receiving it because of the uncertainties in the statute. Considering this renewed interest by multiple stakeholders regarding the need for revisions and/or guidance pertaining to Section 114, the Academy of Managed Care Pharmacy held a partnership forum on March 1-2, 2016, with a diverse group of health care stakeholders to provide the FDA with considerations for disseminating a guidance document on current thinking for the sharing of HCEI with health care decision makers. Forum participants represented the managed care industry, biopharmaceutical industry, health care providers, pharmacoeconomic experts, policy experts, and patient advocacy groups with specific expertise in the development, use, and dissemination of HCEI. The multistakeholder group represented the key professionals and entities affected by the provisions of Section 114 and present the collective credibility necessary for Congress and the FDA to modernize and operationalize the safe harbor by using the consensus recommendations developed during the forum. Speakers, panelists, and attendees focused on 4 terms in Section 114 that remain open to interpretation by companies and enforcement bodies: (1) the scope of HCEI, (2) the scope of "formulary committee or similar entity," (3) the definition of "competent and reliable scientific evidence (CRSE)," and (4) the parameters of how information "directly relates to an approved indication." Based on the forum results, it was recommended that the safe harbor for companies' proactive dissemination of information under Section 114 should include health care decision makers beyond health plan formulary committees, including organizations, or individuals in their role in an organization, who make health care decisions for patient populations. Recommendations also suggested expansion to organizations that evaluate HCEI or develop value frameworks and compendia and individuals in such organizations. Forum participants also recommended that HCEI be truthful, and not misleading, and be based on the expertise of professionals in the relevant area. HCEI must also be developed and disclosed in a transparent, reproducible, and accurate manner. Forum participants also discussed and agreed on the types of information, format, and processes by which managed care pharmacy and other health care decision makers seek to receive HCEI from biopharmaceutical companies. Finally, participants encouraged the FDA, Congress, and other stakeholders to find ways to ensure that patients or their representative organizations have appropriate access to a full range of information about their medications and that information related to the medication pipeline is communicated to appropriate stakeholders in a timely manner.The AMCP Partnership Forum on FDAMA Section 114-Improving the Exchange of Pharmacoeconomic Data and the development of this proceedings document were supported by AbbVie, Amgen, Boehringer Ingelheim Pharmaceuticals, MerckCo., National Pharmaceutical Council, Pharmaceutical Research and Manufacturers of America, Precision for Value, Pfizer, Takeda Pharmaceuticals, U.S.A., and Xcenda. All sponsors participated in the forum and participated in revising and approving the manuscript.

Established in 2008, the Patient-Reported Outcome (PRO) Consortium is a collaboration among the US Food and Drug Administration's Center for Drug Evaluation and Research, the Critical Path Institute, the pharmaceutical/biotechnology industry, and other stakeholders. The purpose of the consortium is to qualify PRO instruments through the Center for Drug Evaluation and Research's drug development tool qualification process for use as clinical trial endpoints to support drug approval and product labeling claims. The PRO Consortium has made notable progress toward collaborative development of PRO instruments in the following areas: asthma, mild cognitive impairment, depression, functional dyspepsia, irritable bowel syndrome, non-small cell lung cancer, and rheumatoid arthritis. This progress has come with considerable challenges, including navigating a new and evolving regulatory initiative, gaining consensus on key issues, and maintaining communication and engagement in a precompetitive environment. The purpose of this paper is to describe some of the challenges and lessons learned since the creation of the PRO Consortium in hopes that this information may provide direction and insight for similar collaborations.

For many patients with sickle cell disease (SCD), jaundice is a significant clinical disease manifestation that impacts on patient well-being. We report a case of a patient with SCD and chronic jaundice treated with voxelotor (GBT440), a novel small molecule hemoglobin oxygen affinity modulator and potential disease-modifying therapy for SCD. The case patient is a 27- year-old Black male with a long history of SCD with clinical jaundice and scleral icterus. After starting voxelotor, the patient reported that his jaundice cleared within one week, and that he felt much better with more energy, and was relieved after his eyes cleared. Voxelotor reduced bilirubin and unconjugated bilirubin (by up to 76%), and hemoglobin improved from 9.9 g/dL at baseline to 11.1 g/dL at 90 days. Jaundice impacts many adults with SCD, significantly impacting self-image. Voxelotor treatment reduced bilirubin levels and improved jaundice, resulting in an improved sense of well-being in our case patient.

This article summarizes the results of a meeting convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) on key considerations and best practices governing the design of acute pain clinical trials. We discuss the role of early phase clinical trials, including pharmacokinetic-pharmacodynamic (PK-PD) trials, and the value of including both placebo and active standards of comparison in acute pain trials. This article focuses on single-dose and short-duration trials with emphasis on the perioperative and study design factors that influence assay sensitivity. Recommendations are presented on assessment measures, study designs, and operational factors. Although most of the methodological advances have come from studies of postoperative pain after dental impaction, bunionectomy, and other surgeries, the design considerations discussed are applicable to many other acute pain studies conducted in different settings.

Objectives: To determine whether patients with neurogenic claudication associated with lumbar spinal stenosis would prefer a treatment that makes it possible for them to walk farther or walk with less pain; to examine associations between this treatment preference and patient-reported and in-clinic treadmill testing measures of walking ability and walking-associated pain. Methods: In this cross-sectional study, 269 patients with neurogenic claudication were asked to report their pain intensity when walking, complete the Swiss Spinal Stenosis Questionnaire, rank their outcome preferences for treatment, and undergo standardized treadmill testing, including measures of final pain rating and time to first pain of moderate intensity (T first ). Descriptive statistics were used to characterize patient preferences for treatment outcome. Associations between self-report questionnaires and standardized treadmill testing outcomes were evaluated using Spearman correlations. Results: Seventy-nine percent of patients expressed a preference for treatment that allowed them to walk with less pain. Preference for reduced pain was associated with higher pain during daily walking, along with a shorter T first and higher final pain severity on treadmill testing. In contrast, patient preference for treatment outcome was not associated with self-reported measures of daily walking capacity or walking distance on the treadmill. Conclusions: A majority of patients with neurogenic claudication prioritized walking with reduced pain over walking farther. Reduction in pain while walking may therefore constitute a sufficient patient-focused treatment outcome for the majority of these patients. These results have implications for clinical trial design and assessment of treatment efficacy in neurogenic claudication.

Patient-Focused Drug Development (PFDD) is a new initiative from the Food and Drug Administration (FDA) intended to bring patient perspectives into an earlier stage of product development. The goal is that patients will be able to provide context for benefit-risk assessments and input to review divisions, and also aid in the development of new assessment tools, study endpoints, and risk communications. This paper provides a summary on what is known to date about FDA's PFDD initiative and describes implications for patients, researchers, payers, and the biopharmaceutical industry. It also provides a roadmap for stakeholders to consider in defining their role in and in shaping PFDD's direction, and for expanding PFDD principles to conditions beyond the current 20 under FDA consideration.A search was conducted of the peer-reviewed and gray literature using PubMed and Google. This included laws, FDA guidance documents, the peer-reviewed literature, and FDA presentations for content relevant to the search term "patient-focused drug development."Currently, FDA activities within PFDD are limited to gaining patient insights through 20 disease-specific meetings. However, many stakeholders see the initiative much more generally as representing a broad shift toward patient centeredness in biopharmaceutical product development.Depending upon the trajectory taken and whether or not all PFDD aims are eventually addressed, the initiative has the potential to change product development in fundamental ways. Further research should explore how patient input on disease manifestation and treatment options is best ascertained from patients and documented before initiating and during drug development.

Identifying methods to improve assay sensitivity in randomized clinical trials (RCTs) may facilitate the discovery of efficacious pain treatments. RCTs evaluating pain treatments typically use average pain intensity (API) or worst pain intensity (WPI) as the primary efficacy outcome. However, little evidence is available comparing the assay sensitivity of these 2 measures. In this systematic review and meta-analysis, we comprehensively reviewed all low back pain, osteoarthritis pain, fibromyalgia, diabetic peripheral neuropathy pain, and postherpetic neuralgia RCTs that used a parallel group design. Eligibility required: 1) primary RCT report published between 1980 and 2016, 2) comparing 1 or more active, efficacious pharmacologic pain treatment(s) with placebo, and 3) providing data on the standardized effect size (SES) for API as well as WPI for all treatment arms. Twenty-seven active versus placebo comparisons were identified in 23 eligible articles. Using a random-effects meta-analysis, API SES and WPI SES did not differ significantly (difference = −.021, 95% confidence interval = −.047 to .004, P = .12). The findings indicate that, depending on the objectives of the study, either API or WPI could be used as a primary outcome measure in clinical trials for the chronic pain conditions included in this analysis. Perspective Understanding the comparative assay sensitivity of API and WPI may advance pain treatment research. A meta-analysis of trials of efficacious pharmacologic treatments in 5 pain conditions did not show a statistically significant difference between the assay sensitivity of API and WPI.

Accurate assessment of inappropriate medication use events (ie, misuse, abuse, and related events) occurring in clinical trials is an important component in evaluating a medication's abuse potential. A meeting was convened to review all instruments measuring such events in clinical trials according to previously published standardized terminology and definitions. Only 2 approaches have been reported that are specifically designed to identify and classify misuse, abuse, and related events occurring in clinical trials, rather than to measure an individual's risk of using a medication inappropriately: the Self-Reported Misuse, Abuse, and Diversion (SR-MAD) instrument and the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS). The conceptual basis, strengths, and limitations of these methods are discussed. To our knowledge, MADDERS is the only system available to comprehensively evaluate inappropriate medication use events prospectively to determine the underlying intent. MADDERS can also be applied retrospectively to completed trial data. SR-MAD can be used prospectively; additional development may be required to standardize its implementation and fully appraise the intent of inappropriate use events. Additional research is needed to further demonstrate the validity and utility of MADDERS as well as SR-MAD. Perspective Identifying a medication's abuse potential requires assessing inappropriate medication use events in clinical trials on the basis of a standardized event classification system. The strengths and limitations of the 2 published methods designed to evaluate inappropriate medication use events are reviewed, with recommended considerations for further development and current implementation.

Performing multiple analyses in clinical trials can inflate the probability of a type I error, or the chance of falsely concluding a significant effect of the treatment. Strategies to minimize type I error probability include prespecification of primary analyses and statistical adjustment for multiple comparisons, when applicable. The objective of this study was to assess the quality of primary analysis reporting and frequency of multiplicity adjustment in 3 major pain journals (ie, European Journal of Pain, Journal of Pain, and PAIN®). A total of 161 randomized controlled trials investigating noninvasive pharmacological treatments or interventional treatments for pain, published between 2006 and 2012, were included. Only 52% of trials identified a primary analysis, and only 10% of trials reported prespecification of that analysis. Among the 33 articles that identified a primary analysis with multiple testing, 15 (45%) adjusted for multiplicity; of those 15, only 2 (13%) reported prespecification of the adjustment methodology. Trials in clinical pain conditions and industry-sponsored trials identified a primary analysis more often than trials in experimental pain models and non-industry-sponsored trials, respectively. The results of this systematic review demonstrate deficiencies in the reporting and possibly the execution of primary analyses in published analgesic trials. These deficiencies can be rectified by changes in, or better enforcement of, journal policies pertaining to requirements for the reporting of analyses of clinical trial data.

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. Cancer 2014;120:761–767. © 2013 American Cancer Society.

The National Institutes of Health released the trial registry ClinicalTrials.gov in 2000 to increase public reporting and clinical trial transparency. This systematic review examined whether registered primary outcome specifications (POS; ie, definitions, timing, and analytic plans) in analgesic treatment trials correspond with published POS. Trials with accompanying publications (n = 87) were selected from the Repository of Registered Analgesic Clinical Trials (RReACT) database of all postherpetic neuralgia, diabetic peripheral neuropathy, and fibromyalgia clinical trials registered at ClinicalTrials.gov as of December 1, 2011. POS never matched precisely; discrepancies occurred in 79% of the registry–publication pairs (21% failed to register or publish primary outcomes [PO]). These percentages did not differ significantly between industry and non-industry-sponsored trials. Thirty percent of the trials contained unambiguous POS discrepancies (eg, omitting a registered PO from the publication, “demoting” a registered PO to a published secondary outcome), with a statistically significantly higher percentage of non-industry-sponsored than industry-sponsored trials containing unambiguous POS discrepancies. POS discrepancies due to ambiguous reporting included vaguely worded PO registration; or failing to report the timing of PO assessment, statistical analysis used for the PO, or method to address missing PO data. At best, POS discrepancies may be attributable to insufficient registry requirements, carelessness (eg, failing to report PO assessment timing), or difficulty uploading registry information. At worst, discrepancies could indicate investigator impropriety (eg, registering imprecise PO [“pain”], then publishing whichever pain assessment produced statistically significant results). Improvements in PO registration, as well as journal policies requiring consistency between registered and published PO descriptions, are needed.

Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials.

A clinician-reported outcome (ClinRO) assessment is a type of clinical outcome assessment (COA). ClinRO assessments, like all COAs (patient-reported, observer-reported, or performance outcome assessments), are used to 1) measure patients' health status and 2) define end points that can be interpreted as treatment benefits of medical interventions on how patients feel, function, or survive in clinical trials. Like other COAs, ClinRO assessments can be influenced by human choices, judgment, or motivation. A ClinRO assessment is conducted and reported by a trained health care professional and requires specialized professional training to evaluate the patient's health status. This is the second of two reports by the ISPOR Clinical Outcomes Assessment-Emerging Good Practices for Outcomes Research Task Force. The first report provided an overview of COAs including definitions important for an understanding of COA measurement practices. This report focuses specifically on issues related to ClinRO assessments. In this report, we define three types of ClinRO assessments (readings, ratings, and clinician global assessments) and describe emerging good measurement practices in their development and evaluation. The good measurement practices include 1) defining the context of use; 2) identifying the concept of interest measured; 3) defining the intended treatment benefit on how patients feel, function, or survive reflected by the ClinRO assessment and evaluating the relationship between that intended treatment benefit and the concept of interest; 4) documenting content validity; 5) evaluating other measurement properties once content validity is established (including intra- and inter-rater reliability); 6) defining study objectives and end point(s) objectives, and defining study end points and placing study end points within the hierarchy of end points; 7) establishing interpretability in trial results; and 8) evaluating operational considerations for the implementation of ClinRO assessments used as end points in clinical trials. Applying good measurement practices to ClinRO assessment development and evaluation will lead to more efficient and accurate measurement of treatment effects. This is important beyond regulatory approval in that it provides evidence for the uptake of new interventions into clinical practice and provides justification to payers for reimbursement on the basis of the clearly demonstrated added value of the new intervention.

Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.

Clinical trial participants often require additional instruction to prevent idiosyncratic interpretations regarding completion of patient-reported outcomes. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership developed a training system with specific, standardized guidance regarding daily average pain intensity ratings. A 3-week exploratory study among participants with low-back pain, osteoarthritis of the knee or hip, and painful diabetic peripheral neuropathy was conducted, randomly assigning participants to 1 of 3 groups: training with human pain assessment (T+); training with automated pain assessment (T); or no training with automated pain assessment (C). Although most measures of validity and reliability did not reveal significant differences between groups, some benefit was observed in discriminant validity, amount of missing data, and ranking order of least, worst, and average pain intensity ratings for participants in Group T+ compared with the other groups. Prediction of greater reliability in average pain intensity ratings in Group T+ compared with the other groups was not supported, which might indicate that training produces ratings that reflect the reality of temporal pain fluctuations. Results of this novel study suggest the need to test the training system in a prospective analgesic treatment trial.

The importance of content validity in developing patient reported outcomes (PRO) instruments is stressed by both the US Food and Drug Administration and the European Medicines Agency. Content validity is the extent to which an instrument measures the important aspects of concepts that developers or users purport it to assess. A PRO instrument measures the concepts most significant and relevant to a patient's condition and its treatment. For PRO instruments, items and domains as reflected in the scores of an instrument should be important to the target population and comprehensive with respect to patient concerns. Documentation of target population input in item generation, as well as evaluation of patient understanding through cognitive interviewing, can provide the evidence for content validity. Developing content for, and assessing respondent understanding of, newly developed PRO instruments for medical product evaluation will be discussed in this two-part ISPOR PRO Good Research Practices Task Force Report. Topics include the methods for generating items, documenting item development, coding of qualitative data from item generation, cognitive interviewing, and tracking item development through the various stages of research and preparing this tracking for submission to regulatory agencies. Part 1 covers elicitation of key concepts using qualitative focus groups and/or interviews to inform content and structure of a new PRO instrument. Part 2 covers the instrument development process, the assessment of patient understanding of the draft instrument using cognitive interviews and steps for instrument revision. The two parts are meant to be read together. They are intended to offer suggestions for good practices in planning, executing, and documenting qualitative studies that are used to support the content validity of PRO instruments to be used in medical product evaluation.

The importance of content validity in developing patient reported outcomes (PRO) instruments is stressed by both the US Food and Drug Administration and the European Medicines Agency. Content validity is the extent to which an instrument measures the important aspects of concepts developers or users purport it to assess. A PRO instrument measures the concepts most relevant and important to a patient's condition and its treatment. For PRO instruments, items and domains as reflected in the scores of an instrument should be important to the target population and comprehensive with respect to patient concerns. Documentation of target population input in item generation, as well as evaluation of patient understanding through cognitive interviewing, can provide the evidence for content validity. Part 1 of this task force report covers elicitation of key concepts using qualitative focus groups and/or interviews to inform content and structure of a new PRO instrument. Building on qualitative interviews and focus groups used to elicit concepts, cognitive interviews help developers craft items that can be understood by respondents in the target population and can ultimately confirm that the final instrument is appropriate, comprehensive, and understandable in the target population. Part 2 details: 1) the methods for conducting cognitive interviews that address patient understanding of items, instructions, and response options; and 2) the methods for tracking item development through the various stages of research and preparing this tracking for submission to regulatory agencies. The task force report's two parts are meant to be read together. They are intended to offer suggestions for good practice in planning, executing, and documenting qualitative studies that are used to support the content validity of PRO instruments to be used in medical product evaluation.

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. Clinical Pharmacology & Therapeutics (2011); 90 5, 743–748. doi:10.1038/clpt.2011.203

The National Cancer Institute (NCI) is developing a patient-reported version of its Common Terminology Criteria for Adverse Events, called the "PRO-CTCAE." The PRO-CTCAE consists of a library of patient-reported items which can be administered in clinical trials to directly capture the patient experience of adverse events during cancer treatment, as well as a software platform for administering these items via computer or telephone. In order to better understand the impressions of stakeholders involved in cancer clinical research about the potential value of the PRO-CTCAE approach to capturing adverse event information in clinical research, as well as their perspectives about barriers and strategies for implementing the PRO-CTCAE in NCI-sponsored cancer trials, a survey was conducted. A survey including structured and open-ended questions was developed to elicit perceptions about the use of patient-reported outcomes (PROs) for adverse event reporting, and to explore logistical considerations for implementing the PRO-CTCAE in cancer trials. The survey was distributed electronically and by paper to a convenience sample of leadership and committee members in the NCI's cooperative group network, including principal investigators, clinical investigators, research nurses, data managers, patient advocates, and representatives of the NCI and Food and Drug Administration. Between October, 2008 through February, 2009, 727 surveys were collected. Most respondents (93%) agreed that patient reporting of adverse symptoms would be useful for improving understanding of the patient experience with treatment in cancer trials, and 88%, 80%, and 76%, respectively, endorsed that administration of PRO-CTCAE items in clinical trials would improve the completeness, accuracy, and efficiency of symptom data collection. More than three fourths believed that patient reports would be useful for informing treatment dose modifications and towards FDA regulatory evaluation of drugs. Eighty-eight percent felt that patients in clinical trials would be willing to self-report adverse symptoms at clinic visits via computer, and 68% felt patients would self-report weekly from home via the internet or an automated telephone system. Lack of computers and limited space and personnel were seen as potential barriers to in-clinic self-reporting, but these were judged to be surmountable with adequate funding. The PRO-CTCAE items and software are viewed by a majority of survey respondents as a means to improve adverse event data quality and comprehensiveness, enhance clinical decision-making, and foster patient-clinician communication. Research is ongoing to assess the measurement properties and feasibility of implementing this measure in cancer clinical trials.

There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain.

Irritable bowel syndrome (IBS) involves a broad range of physiological and psychological alterations that may affect brain-gut dysregulation, gut function, visceral perception, and mucosal integrity and function. Despite advances in our understanding of basic neuroenteric mechanisms and the role of effectors and transmitters in the brain-gut axis, a reliable biologic marker of IBS has yet to be identified. IBS diagnosis and status depend entirely on an assessment of IBS signs and symptoms. This has made development of optimal end points and study design for evaluation of efficacy of IBS drugs a challenge. This article addresses three main topics: the evolution of primary end points for IBS clinical trials; a potential path forward for IBS end points in new clinical trials; and recommendations for the future development of patient-reported outcome (PRO) instruments for use in IBS clinical trials.

Background: Patient-reported outcome (PRO) instruments are used to evaluate the effect of medical products on how patients feel or function. This article presents the results of an ISPOR task force convened to address good clinical research practices for the use of existing or modified PRO instruments to support medical product labeling claims. The focus of the article is on content validity, with specific reference to existing or modified PRO instruments, because of the importance of content validity in selecting or modifying an existing PRO instrument and the lack of consensus in the research community regarding best practices for establishing and documenting this measurement property. Methods: Topics addressed in the article include: definition and general description of content validity; PRO concept identification as the important first step in establishing content validity; instrument identification and the initial review process; key issues in qualitative methodology; and potential threats to content validity, with three case examples used to illustrate types of threats and how they might be resolved. A table of steps used to identify and evaluate an existing PRO instrument is provided, and figures are used to illustrate the meaning of content validity in relationship to instrument development and evaluation. Results & Recommendations: Four important threats to content validity are identified: unclear conceptual match between the PRO instrument and the intended claim, lack of direct patient input into PRO item content from the target population in which the claim is desired, no evidence that the most relevant and important item content is contained in the instrument, and lack of documentation to support modifications to the PRO instrument. In some cases, careful review of the threats to content validity in a specific application may be reduced through additional well documented qualitative studies that specifically address the issue of concern. Conclusion: Published evidence of the content validity of a PRO instrument for an intended application is often limited. Such evidence is, however, important to evaluating the adequacy of a PRO instrument for the intended application. This article provides an overview of key issues involved in assessing and documenting content validity as it relates to using existing instruments in the drug approval process.

The objective of the present research was to develop a single measure of the major symptoms of both neuropathic and non-neuropathic pain that can be used in studies of epidemiology, natural history, pathophysiologic mechanisms, and treatment response. We expanded and revised the Short-form McGill Pain Questionnaire (SF-MPQ) pain descriptors by adding symptoms relevant to neuropathic pain and by modifying the response format to a 0-10 numerical rating scale to provide increased responsiveness in longitudinal studies and clinical trials. The reliability, validity, and subscale structure of the revised SF-MPQ (SF-MPQ-2) were examined in responses from 882 individuals with diverse chronic pain syndromes and in 226 patients with painful diabetic peripheral neuropathy who participated in a randomized clinical trial. The data suggest that the SF-MPQ-2 has excellent reliability and validity, and the results of both exploratory and confirmatory factor analyses provided support for four readily interpretable subscales-continuous pain, intermittent pain, predominantly neuropathic pain, and affective descriptors. These results provide a basis for use of the SF-MPQ-2 in future clinical research, including clinical trials of treatments for neuropathic and non-neuropathic pain conditions.

The increasing complexity of randomized clinical trials and the practice of obtaining a wide variety of measurements from study participants have made the consideration of multiple endpoints a critically important issue in the design, analysis, and interpretation of clinical trials. Failure to consider important outcomes can limit the validity and utility of clinical trials; specifying multiple endpoints for the evaluation of treatment efficacy, however, can increase the rate of false positive conclusions about the efficacy of a treatment. We describe the use of multiple endpoints in the design, analysis, and interpretation of pain clinical trials, and review available strategies and methods for addressing multiplicity. To decrease the probability of a Type I error (i.e., the likelihood of obtaining statistically significant results by chance) in pain clinical trials, the use of gatekeeping procedures and other methods that correct for multiple analyses is recommended when a single primary endpoint does not adequately reflect the overall benefits of treatment. We emphasize the importance of specifying in advance the outcomes and clinical decision rule that will serve as the basis for determining that a treatment is efficacious and the methods that will be used to control the overall Type I error rate.

This two-phase study was conducted to identify relevant domains of patient-reported outcomes from the perspective of people who experience chronic pain. In Phase 1, focus groups were conducted to generate a pool of patient outcome-related domains and their components. The results of the focus groups identified 19 aspects of their lives that were significantly impacted by the presence of their symptoms and for which improvements were important criteria they would use in evaluating the effectiveness of any treatment. Phase 2 was conducted to examine the importance and relevance of domains identified from a much larger and diverse sample of people with chronic pain. A survey was developed and posted on the American Chronic Pain Association website. Participants were asked to rate the importance of each item or domain identified by the focus groups on a scale of 0 to10 (i.e., 0="not at all important" and 10="extremely important"). The survey was completed by 959 individuals. The results indicate that all 19 aspects of daily life derived from the focus groups were considered important with a majority of respondents indicating a score of 8 or greater. In addition to pain reduction, the most important aspects were enjoyment of life, emotional well-being, fatigue, weakness, and sleep-related problems. Chronic pain clearly impacts health-related quality of life. The results of the two phases of the study indicate that people with chronic pain consider functioning and well-being as important areas affected by the presence of symptoms and as appropriate targets of treatment. These multiple outcomes should be considered when evaluating the efficacy and effectiveness of chronic pain treatments.

In 2006, the US Food and Drug Administration (FDA) published draft guidance to provide recommendations for development, validation, implementation, and interpretation of patient-reported outcome (PRO) measures that can support treatment benefit claims in product labeling. Here, we summarize and discuss FDA approvals of anticancer products in the context of the draft guidance. We identified anticancer product approvals having efficacy claim(s) based at least in part on a PRO. In addition, we collated limitations of PRO instruments commonly submitted for regulatory review over the period from October 1, 2004 to September 30, 2006. From 1995 onward, nine indications were approved for seven anticancer products based at least in part on a PRO. In eight of nine approvals, PRO data supplemented other evidence of clinical benefit. In seven approvals, the PRO measured a single symptom or functional domain that was directly attributable to the treatment benefit observed in the disease. The FDA's draft PRO guidance describes principles that have been used in anticancer product approvals for more than a decade. PRO end points typically support treatment benefit claims that refer to a patient's symptoms or ability to function. Single-item PROs may be acceptable. PRO data should be both internally consistent and aligned with other evidence of clinical benefit. The FDA encourages sponsors to consult with the FDA early in the process of PRO development.

Objective The unique characteristics of cancer, particularly issues involving the use of surrogate endpoints in clinical trials, present special challenges in the development of cancer drugs. In response, the U.S. Food and Drug Administration (FDA) has partnered with the American Society of Clinical Oncology, the American Association for Cancer Research, and the American Society of Hematology to conduct public workshops evaluating potential endpoints for drug approvals for the most common tumor types. Methods A workshop evaluating potential endpoints in ovarian cancer drug research was held in Bethesda, Maryland, in April 2006. Invited experts presented research findings and discussed endpoints in trials of drugs for treatment of Stage III and IV ovarian cancer. Results The panel responded to specific questions from FDA, discussing use of progression-free survival as a surrogate for overall survival and use of CA-125 levels as an indicator of response. Panel members also addressed endpoints in first-line therapy, second-line and subsequent therapy, and maintenance therapy. Conclusion Expert commentary provided by panel members will inform FDA's draft guidance on clinical endpoints for cancer drug approvals and will be discussed at meetings of the FDA's Oncologic Drugs Advisory Committee. FDA intends to develop a set of principles that can be used to define efficacy standards for drugs used to treat ovarian and other cancers.

The U.S. Food and Drug Administration (FDA) approves labeling claims of drug efficacy based on substantial evidence of clinical benefit demonstrated in adequate and well-controlled investigations. Patient-reported outcomes (PROs) may support marketing claims of clinical benefit, either alone or with other study endpoints. Health-related quality of life (HRQL) is a PRO that comprehensively measures patients' reported health status. We present an overview of why HRQL-based efficacy claims have not to date been accepted by the FDA for inclusion in anticancer product labels. Persistent challenges to allowance of such claims include shortcomings in randomization and blinding of clinical trials, missing data, statistical multiplicity, and unclear intrinsic meaning of selected HRQL findings.

Many of the Institutes, Agencies and Centers that make up the US Department of Health and Human Services (DHHS) have recognized the need for better instrumentation in health outcomes research, and provide support, both internally and externally, for research utilizing advances in measurement theory and computer technology (informatics). In this paper, representatives from several DHHS agencies and institutes will discuss their need for better instruments within their discipline and describe current or future initiatives for exploring the benefits of these technologies. Together, the perspectives underscore the importance of developing valid, precise, and efficient measures to capture the full burden of disease and treatment on patients. Initiatives, like the Patient-Reported Outcomes Measurement Information System (PROMIS) to create health-related quality of life item banks, represent a trans-DHHS effort to develop a standard set of measures for informing decision making in clinical research, practice, and health policy.

Objective.Systematic reviews often struggle with how to combine information when more than 1 instrument is used across studies being synthesized. Different techniques have been suggested based on frequency of use in the literature, or on consensus. We explore an approach blending 2 initiatives: OMERACT (Outcome Measurement in Rheumatology) and COSMIN (Consensus On Selection of Measurement Instruments), and investigate the effects of an evidence-based measurement approach on selection of outcomes.Methods.Readings were circulated to attendees registered for a preconference workshop on pain measurement. Three instruments were considered and exercises conducted to engage people in the content and measurement performance of these tools. Consensus was sought that an evidence-based approach could be created for selection of instruments for summary of findings (SoF) tables.Results.The blending of COSMIN and OMERACT approaches led to an evidence-based approach that depended both on a clear definition of target concept and a review of measurement performance of the instrument. Participants emphasized that conceptual clarity and practical considerations should come before measurement property results.Conclusion.Evidence-based approaches can be adopted for selection of instruments for SoF tables. A research agenda was formulated.

An outcome assessment, the patient assessment used in an endpoint, is the measuring instrument that provides a rating or score (categorical or continuous) that is intended to represent some aspect of the patient’s health status. Outcome assessments are used to define efficacy endpoints when developing a therapy for a disease or condition. Most efficacy endpoints are based on specified clinical assessments of patients. When clinical assessments are used as clinical trial outcomes, they are called clinical outcome assessments (COAs). COAs include any assessment that may be influenced by human choices, judgment, or motivation. COAs must be well-defined and possess adequate measurement properties to demonstrate (directly or indirectly) the benefits of a treatment. In contrast, a biomarker assessment is one that is subject to little, if any, patient motivational or rater judgmental influence. This is the first of two reports by the ISPOR Clinical Outcomes Assessment – Emerging Good Practices for Outcomes Research Task Force. This report provides foundational definitions important for an understanding of COA measurement principles. The foundation provided in this report includes what it means to demonstrate a beneficial effect, how assessments of patients relate to the objective of showing a treatment’s benefit, and how these assessments are used in clinical trial endpoints. In addition, this report describes intrinsic attributes of patient assessments and clinical trial factors that can affect the properties of the measurements. These factors should be considered when developing or refining assessments. These considerations will aid investigators designing trials in their choice of using an existing assessment or developing a new outcome assessment. Although the focus of this report is on the development of a new COA to define endpoints in a clinical trial, these principles may be applied more generally. A critical element in appraising or developing a COA is to describe the treatment’s intended benefit as an effect on a clearly identified aspect of how a patient feels or functions. This aspect must have importance to the patient and be part of the patient’s typical life. This meaningful health aspect can be measured directly or measured indirectly when it is impractical to evaluate it directly or when it is difficult to measure. For indirect measurement, a concept of interest (COI) can be identified. The COI must be related to how a patient feels or functions. Procedures are then developed to measure the COI. The relationship of these measurements with how a patient feels or functions in the intended setting and manner of use of the COA (the context of use) could then be defined. A COA has identifiable attributes or characteristics that affect the measurement properties of the COA when used in endpoints. One of these features is whether judgment can influence the measurement, and if so, whose judgment. This attribute defines four categories of COAs: patient reported outcomes, clinician reported outcomes, observer reported outcomes, and performance outcomes. A full description as well as explanation of other important COA features is included in this report. The information in this report should aid in the development, refinement, and standardization of COAs, and, ultimately, improve their measurement properties.