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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.

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.

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.

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.

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.

Context The term “patient-reported outcomes” (PROs) has evolved to include any endpoint derived from patient reports, whether collected in the clinic, in a diary, or by other means, including single-item outcome measures, event logs, symptom reports, formal instruments to measure health-related quality of life (HRQL), health status, adherence, and satisfaction with treatment. This term coincides with the explicit interest from drug development researchers and regulatory authorities in the appropriate utilization and reporting of treatment impact measures. Objective To determine the level and nature of use of PROs compared to other types of effectiveness endpoints in approved product labeling for new drugs recently approved in the United States. Design and sources Review and analysis of effectiveness endpoints as reported in clinical study descriptions in approved product labeling of new molecular entities (NMEs) approved in the United States from 1997 through 2002. Main outcome measures Effectiveness study endpoints reported in approved product labeling that fall into the following categories of measurement: PROs, clinician-reported outcomes (CROs), and laboratory test/device measurement endpoints. Results PROs were reported in 64 (30%) of the 215 product labels reviewed. Clinician-reported outcomes were reported most frequently (62%) followed by laboratory/device endpoints (50%). PROs were the only type of endpoint used in the FDA-approved label for 23 products. Formal multiitem PRO scales were cited 22 times. Use of PROs is most common in antiinflammatory, CNS, gastrointestinal, respiratory, allergic conjunctivitis, and urologic therapy areas. The frequency of reported PRO use over this period did not change. Conclusion PROs, although quite variable as a class of study endpoints, were found to have a significant role in the development and evaluation of new medicines. More formal guidance from the FDA about use of such measures along with continued collaboration by PRO researchers to develop and disseminate standards will enhance the appropriate use of PROs in future drug development and labeling.

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.