Improving Study Conduct and Data Quality in Clinical Trials of Chronic Pain Treatments: IMMPACT Recommendations.

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.

Montreal Accord on Patient-Reported Outcomes (PROs) use series - Paper 6: creating national initiatives to support development and use-the PROMIS example.

BACKGROUND: Patient-reported outcome (PRO) data are beneficial to a range of stakeholders including patients, clinicians, researchers, national funding and regulatory agencies, health system administrators, and policymakers. OBJECTIVE: Because stakeholders represent diverse groups and needs, it is challenging to reach consensus on how to advance PRO development and harmonize data across settings to enable use for multiple secondary purposes. Collaborative national networks can facilitate the sharing of expertise, resources, and necessary infrastructure; create development, use, and reporting standards; optimize formats to efficiently store and transfer data; and disseminate tools and information for widespread uptake. DISCUSSION: In the United States, the National Institutes of Health's Patient-Reported Outcomes Measurement Information System offers an example of how collaborators can work across distances to form essential partnerships, create a common vision, and leverage technology to accelerate the development and testing of universal PROs that are broadly applicable across health conditions and settings.

Montreal Accord on Patient-Reported Outcomes (PROs) use series - Paper 8: patient-reported outcomes in electronic health records can inform clinical and policy decisions.

BACKGROUND: Given that the goal of health care systems is to improve and maintain the health of the populations they serve, the indicators of performance must include outcomes that are meaningful to patients. The growth of health technologies provides an unprecedented opportunity to integrate the patient voice into clinical care by linking electronic health records (EHRs) to patient-reported outcome (PRO) data collection. However, PRO data must be relevant, meaningful, and actionable for those who will have to invest the time and effort to collect it. OBJECTIVE: In this study, we highlight opportunities to integrate PRO data collection into EHRs. We consider how stakeholder perspectives should influence the selection of PROs and ways to enhance engagement in and commitment to PRO implementation. We propose a research and policy agenda to address unanswered questions and facilitate the widespread adoption of PRO data collection into EHRs. DISCUSSION: Building a learning health care system that gathers PRO data in ways that can inform individual patient care, quality improvement, and comparative effectiveness research has the potential to accelerate the application of new evidence and knowledge to patient care.

The Potential Role of Sensory Testing, Skin Biopsy, and Functional Brain Imaging as Biomarkers in Chronic Pain Clinical Trials: IMMPACT Considerations.

Valid and reliable biomarkers can play an important role in clinical trials as indicators of biological or pathogenic processes or as a signal of treatment response. Currently, there are no biomarkers for pain qualified by the U.S. Food and Drug Administration or the European Medicines Agency for use in clinical trials. This article summarizes an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting in which 3 potential biomarkers were discussed for use in the development of analgesic treatments: 1) sensory testing, 2) skin punch biopsy, and 3) brain imaging. The empirical evidence supporting the use of these tests is described within the context of the 4 categories of biomarkers: 1) diagnostic, 2) prognostic, 3) predictive, and 4) pharmacodynamic. Although sensory testing, skin punch biopsy, and brain imaging are promising tools for pain in clinical trials, additional evidence is needed to further support and standardize these tests for use as biomarkers in pain clinical trials. PERSPECTIVE: The applicability of sensory testing, skin biopsy, and brain imaging as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers for use in analgesic treatment trials is considered. Evidence in support of their use and outlining problems is presented, as well as a call for further standardization and demonstrations of validity and reliability.

The Promise of Patient-Reported Outcomes Measurement Information System-Turning Theory into Reality: A Uniform Approach to Patient-Reported Outcomes Across Rheumatic Diseases.

PROMIS, the Patient-Reported Outcomes Measurement Information System, is opening new possibilities to explore and learn how patient (or proxy) self-report of core symptoms and health-related quality of life can meaningfully advance clinical research and patient care. PROMIS leverages Item Response Theory to agnostically assess, across diseases and conditions or clinical settings, numerous universally applicable core "domains" of health (symptoms and functioning) from the patient perspective. Importantly, PROMIS is enabling the testing and adoption of computerized adaptive testing, which holds great potential to minimize patient burden while maximizing accuracy.

Assessment of physical function and participation in chronic pain clinical trials: IMMPACT/OMERACT recommendations.

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.

Item response theory, computerized adaptive testing, and PROMIS: assessment of physical function.

OBJECTIVE: Patient-reported outcome (PRO) questionnaires record health information directly from research participants because observers may not accurately represent the patient perspective. Patient-reported Outcomes Measurement Information System (PROMIS) is a US National Institutes of Health cooperative group charged with bringing PRO to a new level of precision and standardization across diseases by item development and use of item response theory (IRT). METHODS: With IRT methods, improved items are calibrated on an underlying concept to form an item bank for a "domain" such as physical function (PF). The most informative items can be combined to construct efficient "instruments" such as 10-item or 20-item PF static forms. Each item is calibrated on the basis of the probability that a given person will respond at a given level, and the ability of the item to discriminate people from one another. Tailored forms may cover any desired level of the domain being measured. Computerized adaptive testing (CAT) selects the best items to sharpen the estimate of a person's functional ability, based on prior responses to earlier questions. PROMIS item banks have been improved with experience from several thousand items, and are calibrated on over 21,000 respondents. RESULTS: In areas tested to date, PROMIS PF instruments are superior or equal to Health Assessment Questionnaire and Medical Outcome Study Short Form-36 Survey legacy instruments in clarity, translatability, patient importance, reliability, and sensitivity to change. CONCLUSION: Precise measures, such as PROMIS, efficiently incorporate patient self-report of health into research, potentially reducing research cost by lowering sample size requirements. The advent of routine IRT applications has the potential to transform PRO measurement.

Personalized medicine and opioid analgesic prescribing for chronic pain: opportunities and challenges.

UNLABELLED: Use of opioid analgesics for pain management has increased dramatically over the past decade, with corresponding increases in negative sequelae including overdose and death. There is currently no well-validated objective means of accurately identifying patients likely to experience good analgesia with low side effects and abuse risk prior to initiating opioid therapy. This paper discusses the concept of data-based personalized prescribing of opioid analgesics as a means to achieve this goal. Strengths, weaknesses, and potential synergism of traditional randomized placebo-controlled trial (RCT) and practice-based evidence (PBE) methodologies as means to acquire the clinical data necessary to develop validated personalized analgesic-prescribing algorithms are overviewed. Several predictive factors that might be incorporated into such algorithms are briefly discussed, including genetic factors, differences in brain structure and function, differences in neurotransmitter pathways, and patient phenotypic variables such as negative affect, sex, and pain sensitivity. Currently available research is insufficient to inform development of quantitative analgesic-prescribing algorithms. However, responder subtype analyses made practical by the large numbers of chronic pain patients in proposed collaborative PBE pain registries, in conjunction with follow-up validation RCTs, may eventually permit development of clinically useful analgesic-prescribing algorithms. PERSPECTIVE: Current research is insufficient to base opioid analgesic prescribing on patient characteristics. Collaborative PBE studies in large, diverse pain patient samples in conjunction with follow-up RCTs may permit development of quantitative analgesic-prescribing algorithms that could optimize opioid analgesic effectiveness and mitigate risks of opioid-related abuse and mortality.

The prevalence of inflammatory back pain: population-based estimates from the US National Health and Nutrition Examination Survey, 2009-10.

OBJECTIVE: To estimate the current US inflammatory back pain (IBP) prevalence using four published case definitions. METHODS: Analysis of an IBP data collection instrument specifically designed for the 2009-10 National Health and Nutrition Examination Survey. Subjects were 5103 US adults ages 20-69 with complete data. IBP prevalence as determined by Calin et al criteria, European Spondylarthropathy Study Group (ESSG) criteria, and Berlin criteria 8a and 7b. RESULTS: Age-adjusted US prevalence of IBP by Calin criteria was 5.0% (95% CI 4.2% to 5.8%). Prevalence of IBP was 5.6% (95% CI 4.7% to 6.5%) by ESSG criteria, and 5.8% (95% CI 5.2% to 6.4%) and 6.0% (95% CI 4.9% to 7.1%) by Berlin Criteria 8a and 7b, respectively. IBP prevalence did not differ significantly by age groups or between men and women. IBP prevalence was significantly lower among non-Hispanic black persons compared with non-Hispanic white persons for the Calin and ESSG IBP criteria. For the ESSG and Berlin 7b criteria, non-Hispanic white persons had significantly higher IBP prevalences compared with Mexican Americans. CONCLUSIONS: IBP is associated with spondyloarthritis. Awareness of the prevalence of IBP may be useful for planning future epidemiological studies as well as development and validation of diagnostic and classification criteria for specific clinically defined diseases.

Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations.

A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo ("assay sensitivity"). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence-based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety.

Prevalence of axial spondylarthritis in the United States: estimates from a cross-sectional survey.

OBJECTIVE: The US national prevalence of spondylarthritis (SpA) was estimated for 2 published sets of classification criteria: the Amor criteria and the European Spondylarthropathy Study Group (ESSG) criteria. These 2 SpA criteria sets have been the most widely utilized in previous population-based studies of SpA. METHODS: The US SpA prevalence estimates were based on a representative sample of 5,013 US adults ages 20-69 years who were examined in the US National Health and Nutrition Examination Survey (NHANES) 2009-2010. RESULTS: The overall age-adjusted prevalence of definite and probable SpA by the Amor criteria was 0.9% (95% confidence interval [95% CI] 0.7-1.1%), corresponding to an estimated 1.7 million persons (95% CI 1.4-2.1 million persons). The age-adjusted prevalence of SpA by the ESSG criteria was 1.4% (95% CI 1.0-1.9%), corresponding to an estimated 2.7 million persons (95% CI 1.9-3.7 million persons). There were no statistically significant sex differences in SpA prevalence. The SpA prevalence among non-Hispanic white persons was 1.0% (95% CI 0.7-1.5%) by the Amor criteria and 1.5% (95% CI 1.0-2.3%) by the ESSG criteria. SpA prevalence could not be reliably estimated in other race/ethnicity subgroups due to sample size imitations. CONCLUSION: The SpA prevalence estimates are in the range of SpA prevalence estimates reported elsewhere in population-based surveys and it is likely that SpA may affect up to 1% of US adults, a prevalence similar to that reported for rheumatoid arthritis. The current US SpA prevalence estimates may be lower than the true value because the NHANES 2009-2010 data collection did not capture a complete set of the elements specified in the 2 SpA criteria sets.

Improving the pharmacologic management of pain in older adults: identifying the research gaps and methods to address them.

OBJECTIVE: There has been a growing recognition of the need for better pharmacologic management of chronic pain among older adults. To address this need, the National Institutes of Health Pain Consortium sponsored an "Expert Panel Discussion on the Pharmacological Management of Chronic Pain in Older Adults" conference in September 2010 to identify research gaps and strategies to address them. Specific emphasis was placed on ascertaining gaps regarding use of opioid and nonsteroidal anti-inflammatory medications because of continued uncertainties regarding their risks and benefits. DESIGN: Eighteen panel members provided oral presentations; each was followed by a multidisciplinary panel discussion. Meeting transcripts and panelists' slide presentations were reviewed to identify the gaps and the types of studies and research methods panelists suggested could best address them. RESULTS: Fifteen gaps were identified in the areas of treatment (e.g., uncertainty regarding the long-term safety and efficacy of commonly prescribed analgesics), epidemiology (e.g., lack of knowledge regarding the course of common pain syndromes), and implementation (e.g., limited understanding of optimal strategies to translate evidence-based pain treatments into practice). Analyses of data from electronic health care databases, observational cohort studies, and ongoing cohort studies (augmented with pain and other relevant outcomes measures) were felt to be practical methods for building an age-appropriate evidence base to improve the pharmacologic management of pain in later life. CONCLUSION: Addressing the gaps presented in the current report was judged by the panel to have substantial potential to improve the health and well-being of older adults with chronic pain.

Domains selection for patient-reported outcomes: current activities and options for future methods.

INTRODUCTION: Over the years, Outcome Measures in Rheumatology Clinical Trials (OMERACT) has worked toward consensus on core sets for outcome measurement in specific rheumatologic diseases. OMERACT core sets refer to the minimum number of domains and instruments essential to address the desired outcomes in trials. "Domains" are the attributes of an activity or function. This article discusses the need for an open process for selecting domains, existing frameworks for choosing domains, and the importance of describing the methods for selecting domains. METHODS: We reviewed the domains selection process of 3 OMERACT groups working on patient-reported outcomes (PRO). We categorized these methods in a hierarchy of comprehensiveness and examined the extent to which they address related issues. RESULTS: There was agreement that a gold standard for domain selection would include 3 important aspects: following a framework, remaining true to the clinical question, and including the clinically relevant outcomes for both benefits and harms. DISCUSSION: OMERACT participants agreed that a guide for the options for developing domains that meet the OMERACT Filter would be useful. More discussion and explanation is needed to outline outcomes related to the patient perspective that are not covered by the current version of the International Classification of Functioning, Disability and Health (ICF) and to explain the usefulness of the population/intervention/comparison/outcome (PICO) structure in domain selection. Future OMERACT work includes addressing these issues and developing a framework based on the ICF to support comprehensive outcome measurements.

Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations.

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.

Developing a standardized definition for disease "flare" in rheumatoid arthritis (OMERACT 9 Special Interest Group).

OBJECTIVE: Traditional outcome measures in randomized controlled trials (RCT) include well-established response criteria as well as ACR EULAR responses using Disease Activity Score 44 (DAS44)/DAS28 to assess improvement; however, a measure to assess worsening of disease has yet to be developed. This special interest group (SIG) was established to develop an evidence-based, consensus-driven standard definition of "flare" in rheumatoid arthritis (RA). METHODS: At OMERACT 8, the need for a standardized definition of RA flare was recognized; interested individuals developed a proposal to form a SIG. A literature review was performed to identify publications and abstracts with flare definitions applied in RA, JIA, and lupus RCT as well as concerning patient perspectives on disease worsening. A SIG was held at OMERACT 9 with breakout sessions for patients and investigators. RESULTS: The RA flare SIG was attended by about 120 participants, including 11 patients. Patients and investigators held separate breakout sessions to discuss various aspects of disease worsening. The following consensus was obtained at OMERACT 9: a working definition of flare should indicate worsening of disease activity (88%), persistence, and duration as critical elements (77%), and consideration of change or increase in therapy (74%). CONCLUSION: A working definition of RA flare was developed based on these votes: flare is any worsening of disease activity that would, if persistent, in most cases lead to initiation or change of therapy; and a flare represents a cluster of symptoms of sufficient duration and intensity to require initiation, change, or increase in therapy. Using this working definition, evaluation of candidate domains will be conducted via Delphi exercise and further informed by patient focus groups. Validation of candidate definitions in appropriate RCT will be required.

Analyzing multiple endpoints in clinical trials of pain treatments: IMMPACT recommendations. Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials.

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.

Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations.

UNLABELLED: A consensus meeting was convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to provide recommendations for interpreting clinical importance of treatment outcomes in clinical trials of the efficacy and effectiveness of chronic pain treatments. A group of 40 participants from universities, governmental agencies, a patient self-help organization, and the pharmaceutical industry considered methodologic issues and research results relevant to determining the clinical importance of changes in the specific outcome measures previously recommended by IMMPACT for 4 core chronic pain outcome domains: (1) Pain intensity, assessed by a 0 to 10 numerical rating scale; (2) physical functioning, assessed by the Multidimensional Pain Inventory and Brief Pain Inventory interference scales; (3) emotional functioning, assessed by the Beck Depression Inventory and Profile of Mood States; and (4) participant ratings of overall improvement, assessed by the Patient Global Impression of Change scale. It is recommended that 2 or more different methods be used to evaluate the clinical importance of improvement or worsening for chronic pain clinical trial outcome measures. Provisional benchmarks for identifying clinically important changes in specific outcome measures that can be used for outcome studies of treatments for chronic pain are proposed. PERSPECTIVE: Systematically collecting and reporting the recommended information needed to evaluate the clinical importance of treatment outcomes of chronic pain clinical trials will allow additional validation of proposed benchmarks and provide more meaningful comparisons of chronic pain treatments.

Stimulating the development of mechanism-based, individualized pain therapies.

Biomedical science has greatly improved our understanding of pain in recent decades, but few novel molecular entities that address fundamentally new pain mechanisms have entered the clinic, despite dramatically increased pharmaceutical investment. Indeed, virtually all new analgesics approved over the past 25 years are derivatives or reformulations of opioids or aspirin-like drugs, existing drugs given for a new indication or older drugs given by a different route of administration. Here, we discuss factors contributing to this lack of innovation in therapies for pain and advocate public-private partnerships (PPPs) to translate new knowledge into more efficacious and safer treatments.