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

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

A Survey of Patient Experience in CML: American and Canadian Perspectives.

Purpose: With treatment, chronic myeloid leukemia (CML) has a favorable prognosis, however, individuals with CML experience impairment to their quality of life (QoL). The aim of this study was to examine the perspectives and experiences of individuals with CML and to understand their challenges communicating with their CML physician. Patients and Methods: An online survey in adults with CML (n=100) in the US and Canada assessed QoL, patient-provider relationships, treatment satisfaction, and understanding of CML and treatment goals via the MD Anderson Symptom Inventory, the Cancer Therapy Satisfaction Questionnaire and de novo survey questions. Participants were recruited via an external patient recruiter and CML Patient Groups. Results: Many participants reported hardships due to CML and its treatment. The main impacts were on the ability to work (21%), engage in personal activities (e.g., hobbies, 28%), and to enjoy sexual relations (median=2.00, IQR=8.50). A substantial proportion (21-39%) wished to discuss additional topics with their providers (e.g., management of CML and/or its impacts). While participants reported satisfaction with therapy overall (median=85.71, IQR=17.86), they indicated low to moderate treatment satisfaction with specific components, including concerns regarding side effects (median=43.75, IQR=43.75). Participants generally had a good understanding of CML (97%) and its treatment goals (92%). Conclusion: These findings advance our understanding of issues that need improvement to support QoL for individuals living with CML. Future work is needed to improve patient-provider relationships, address treatment-related side effects, and provide clinical information that is easier for patients to understand.

Experiences of children and adolescents living with achondroplasia and their caregivers.

BACKGROUND: Achondroplasia, caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene (FGFR3), leads to significant multisystem complications across the lifespan that may affect the health-related quality of life (HRQoL) of individuals and families living with the condition. METHODS: The objective of this qualitative study was to describe the HRQoL of children and adolescents with achondroplasia and their caregivers. Thirty-four caregivers and 12 adolescents from the United States and Spain participated in one of eight focus groups or completed an individual interview, which was audio-recorded and transcribed. Thematic analysis of qualitative data was performed to identify commonly occurring themes pertaining to HRQoL. RESULTS: Caregivers and adolescents described challenges with physical functioning and medical complications due to achondroplasia. Key challenges included difficulties performing activities of daily living, issues of accessibility, bullying, or unwanted attention in public, and negative effects on self-esteem. Caregivers were concerned about accessing appropriate medical care for their child, and also reported experiencing financial, relational, and emotional challenges in their families. Achondroplasia also affected individuals and their families in positive ways, including increasing empathy, receiving positive attention, and feeling supported by the achondroplasia community. CONCLUSIONS: These findings underscore the importance of regular assessments of HRQoL and the provision of psychosocial support to affected children and families.

The Challenges of Living with and Caring for a Child or Children Affected by Neuronal Ceroid Lipofuscinosis Type 2 Disease: In-Depth Family Surveys in the United Kingdom and Germany

Abstract Limited research has investigated the challenges faced by families caring for children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease. Face-to-face, mixed-method, in-depth surveys were conducted with 19 families (23 children) in the UK (n=9) and Germany (n=10) to assess the impact of caring for children with CLN2 disease, using national wellbeing and quality of life (QoL) measures. Primary (n=19) and secondary (n=10) caregivers, adult siblings (n=2), and child siblings (n=2) were included. Caregivers reported reduced health-related QoL compared with age and gender-matched controls (mean utility scores 0.08 and 0.11 lower in Germany and the UK, respectively). Hours of caregiving were significantly higher relative to that provided to a child of normal health, with stress, back pain, and reductions in sleep being recorded. Lower life satisfaction and happiness with partners were also reported, along with significant financial burden. Those caring for children in the late stage of disease were more greatly impacted than those with children in the rapidly progressive stage, or who were bereaved. The results of this study make clear the importance of emotional and practical support for caregivers and siblings coping with CLN2 disease.

Measurement of Utilities Associated with Parenteral Support Requirement in Patients with Short Bowel Syndrome and Intestinal Failure.

PURPOSE: Short bowel syndrome (SBS) is the main cause of intestinal failure. Intravenous supplementation (parenteral support [PS]) helps patients regain health but can affect patients' health-related quality of life (HRQoL). The value of health states associated with the number of days on PS per week is unknown in the United Kingdom. The objectives of the present study were to develop health state vignettes for SBS and PS, and to estimate health state utilities by using the time trade-off (TTO) technique. METHODS: Vignettes were developed and reviewed through various processes. Eight states described the impact of 0 days (weaned off PS) through to 7 days on PS; each state comprised the conditions, symptoms, treatments, and impacts related to EuroQol-5 dimensions. A sample of the UK general public viewed each state in interviews; they provided ratings using a visual analog scale and utility scores using the TTO. Participants completed background questionnaires. FINDINGS: One hundred participants rated and valued each health state. Visual analog scale and utility scores showed a steady decline for the health states associated with increasing numbers of days on PS. With "full health" equivalent to a utility score of 1, the most burdensome state was "7 days on PS" (mean [SD] utility score, 0.36 [0.35]), whereas weaned off ("0 days on PS") showed the least burden (0.82 [0.22]). IMPLICATIONS: More days of PS are perceived by members of the public to have an increasing negative impact on HRQoL. Therapies aimed at reducing the number of days on PS may be beneficial for improving patients' HRQoL.

Evaluation of the Measurement Properties of Four Performance Outcome Measures in Patients with Elective Hip Replacements, Elective Knee Replacements, or Hip Fractures.

OBJECTIVES: To evaluate the measurement properties of four performance outcome (PerfO) measures (timed up and go, four-step stair climb, long stair climb, and repeated chair stand) in three patient populations(elective total hip replacement [eTHR], elective total knee replacement [eTKR], and hip fracture [HF]). METHODS: A cross-sectional and longitudinal design was used to assess the PerfO measurement properties using the US Food and Drug Administration guidance for industry around patient-reported outcome measures to support labeling claims. Patient-reported outcome measures and patient- and clinician-reported global concept items were completed along with four PerfO measures at visit 1 and two follow-up visits. Measurement properties assessed included reliability, construct validity, ability to detect change, and estimates of meaningful change. RESULTS: A total of 280 patients (100 eTHR, 105 eTKR, and 75 HF) were recruited, with most (n = 276) providing data at visit 1. Most of the patients were female (64%) and retired (64%), and had at least one comorbidity (91%). Inter-rater and test-retest reliability ranged from good to excellent (0.73 ≤ intraclass correlation coefficient ≤ 0.95) for each PerfO measure. Known-groups validity was demonstrated for all PerfO measures, with those reporting less pain better physical functioning and those who did not use an assistive device having quicker mean completion times. Construct validity and ability to detect change were demonstrated and estimates of meaningful change derived. CONCLUSIONS: This study found the measurement properties of four PerfO measures in samples of patients with eTHR, eTKR, and HF to be supported for consideration of future use, and provided estimates for interpretation of change.

Evaluating the Content Validity of Four Performance Outcome Measures in Patients with Elective Hip Replacements and Hip Fractures.

OBJECTIVES: To assess the content validity of performance outcome (PerfO) measures for use with patients undergoing hip fracture (HF) surgery and elective total hip replacement (eTHR). METHODS: This study was a substudy of a broader evaluation of measurement properties of PerfO measures. The PerfO measures assessed were timed up and go (TUG), four-step stair climb (4SC), long stair climb (LSC), and repeated chair stand (RCS). For this substudy, HF and eTHR participants were interviewed to evaluate the relevance and difficulty of each PerfO measure. Qualitative analysis was conducted on interview transcripts, and summaries of coded data were produced to assess saturation. RESULTS: All 18 HF participants related the PerfO measures (TUG, 4SC, and RSC) to activities they completed in daily life, with slight variations in some specific aspects. For the eight eTHR participants, the correspondence between the PerfO measures (TUG, 4SC, and LSC) and activities in daily life varied: all participants saw similarity in the movements for the TUG; most undertook short stair climbs in daily life, but most did not regularly undertake LSC in daily life. Nevertheless, all HF and eTHR participants reported that the PerfO measures were relevant and had a level of difficulty similar to daily activities. CONCLUSIONS: This study contributes novel methods that adapt US regulatory guidance for patient-reported outcome measures to the evaluation of PerfO measures. A structured approach was used to explore specific details of each measure and correspondence to everyday life. This study demonstrates how content validity of PerfO measures can be meaningfully assessed.

Selection of and Evidentiary Considerations for Wearable Devices and Their Measurements for Use in Regulatory Decision Making: Recommendations from the ePRO Consortium.

BACKGROUND: Wearable devices offer huge potential to collect rich sources of data to provide insights into the effects of treatment interventions. Despite this, at the time of writing this report, limited regulatory guidance on the use of wearables in clinical trial programs has been published. OBJECTIVES: To present recommendations from the Critical Path Institute's Electronic Patient-Reported Outcome Consortium regarding the selection and evaluation of wearable devices and their measurements for use in regulatory trials and to support labeling claims. METHODS: The evaluation group was composed of Critical Path Institute's clinical outcome assessment (COA) scientists and COA specialists from pharmaceutical trial eCOA solution providers, including COA development and validation specialists. The resulting recommendations were drawn from a broad range of backgrounds, perspectives, and expertise that enriched the development of this report. Recommendations were developed through analysis of existing regulatory guidance relating to COA development and use in clinical trials, medical device certification/clearance regulations, literature-reported best practice, and practical experience of wearable technology application in clinical trials. RESULTS: We identify the essential properties of fit-for-purpose wearables and propose evidence needed to support their use. In addition, we overview the activities required to establish clinical endpoints derived from wearables data. CONCLUSIONS: Using this framework, we believe there is enough current understanding to promote the appropriate use of wearables in study protocols. We hope this will provide a basis for discussion among clinical trial stakeholders and catalyze the development of more robust regulatory guidance.

Managing neurogenic bowel dysfunction: what do patients prefer? A discrete choice experiment of patient preferences for transanal irrigation and standard bowel management.

BACKGROUND: Most patients with bowel dysfunction secondary to neurological illness are managed by a range of nonsurgical methods, including dietary changes, laxatives, and suppository use to transanal irrigation (TAI). The aim of the present study was to explore individuals' preferences regarding TAI devices and furthermore investigate willingness to pay (WTP) for attributes in devices in the UK. METHODS: A discrete choice experiment survey was conducted to evaluate the patients' perceived value of TAI devices. Attributes were selected based upon a literature review and input from clinicians. Interviews were conducted with three clinicians and the survey was developed and finalized with the input from both patients and professionals. The final attributes were "risk of urinary tract infections" (UTIs), "risk of fecal incontinence" (FI), "frequency of use", "time spent on toilet", "ease of use", "level of control/independence", and "cost". Participants were recruited by a patient panel of TAI device users in the UK. Data were analyzed using the conditional logit model whereby the coefficients obtained from the model provided an estimate of the (log) odds ratios (ORs) of preference for attributes. WTP was also estimated for each attribute. RESULTS: A total of 129 participants were included in the final analyses. Sixty two percent of the participants had suffered from three UTIs in the preceding year and 58% of patients reported currently experiencing FI using their current device. All attributes were significant predictors of choice. The most important attributes for participants were the "risk of FI", "frequency of use", and "risk of UTIs". CONCLUSION: Participants with bowel dysfunction regarded "risk of FI", "frequency of use", and "avoiding UTIs" as the most important features of a TAI device. These preferences are valuable in informing decision makers and clinicians regarding different bowel management solutions as well as for development of future devices.

Adjuvant chemotherapy in elderly women with breast cancer: patients' perspectives on information giving and decision making.

BACKGROUND: Decisions about adjuvant chemotherapy in older women with early stage breast cancer (EBC) are often challenging. Uncertainty about benefits due to limited data about treatment efficacy and outcomes complicates decision making. This qualitative study explored older patients' experiences and preferences towards information giving and ultimate decisions about adjuvant chemotherapy. METHODS: Clinicians from 24 UK breast cancer teams reported on adjuvant chemotherapy decisions for women aged ≥70 years with EBC from April 2010 to December 2011. Women who were offered chemotherapy were invited to participate in structured interviews. Self-reported quality of life (QoL) and functional ability were assessed. Qualitative methods were used to identify themes associated with information giving and decision making. RESULTS: A total of 58/95 eligible women (61%) participated. Median age was 73 years (range 70-83). Mean total scores for QoL and functional ability were average. The majority of women preferred to make their treatment decisions collaboratively with a clinician (59%) or on their own (19%). The main reasons influencing decisions to accept chemotherapy were categorised as prevention of recurrence and clinician recommendation. Side effects, length of treatment, impact on QoL, low survival benefits and clinician recommendation influenced decisions to decline chemotherapy. The majority (80%) were satisfied with information provision, the communication with their clinician and explanation of treatment. CONCLUSIONS: Older women with EBC preferred to be involved in clinical decision making. Clinician recommendation plays a significant role in either accepting or declining chemotherapy. Well-informed decision making and effective communication between clinicians, older women and their family members are therefore important.

Patient attitudes towards undergoing additional breast biopsy for research.

BACKGROUND: Acquisition of additional breast tissue has become integral to breast oncology research. This questionnaire study examines patient willingness to undergo research-dedicated breast biopsies either at time of diagnostic biopsy (T1) or after carcinoma diagnosis has been confirmed and eligibility for a specific study established (T2), and influencing factors thereof. METHODS: Prior to consultation, patients attending breast clinics were recruited to complete a questionnaire examining willingness to undergo an extra fine needle aspirate (FNA) and/or core needle biopsy (CNB) for research either at T1 or T2. Descriptions of FNA and CNB procedures were supplied to those with no prior experience. Patient perspectives towards donating surplus tissue remaining from a diagnostic procedure and/or surgery for future research were also explored. FINDINGS: A total of 100 patients were recruited, 42% with prior history of breast carcinoma (BC), 22% with family history of BC (FHBC) and 65%/42% with previous experience of CNB/FNA respectively. Overall, 57% were willing to undergo additional biopsy at one or both time points. Willingness to undergo additional biopsy was greater for T1 than T2, but equivalent for CNB and FNA (willingness CNB T1, 50% vs T2, 26%, willingness FNA T1 50% vs T2 29%). A statistically significant increase in willingness to undergo CNB and/or FNA at T1 and/or T2 was seen in association with prior diagnosis of BC, FHBC, previous visit to breast clinic and prior experience of breast biopsy. 83% of patients expressed a willingness to allow surplus tissue to be stored in a biobank for future research. INTERPRETATION: Where possible patients should be approached to undergo baseline research biopsies at time of diagnostic process rather than subsequently. Patients do not find FNA more acceptable than core biopsy. Prior exposure to the biopsy procedure increases willingness to undergo research-dedicated biopsies.

Science, politics, and health in the brave new world of pharmaceutical carcinogenic risk assessment: technical progress or cycle of regulatory capture?

The carcinogenicity (cancer-inducing potential) of pharmaceuticals is an important risk factor for health when considering whether thousands of patients on drug trials or millions/billions of consumers in the marketplace should be exposed to a new drug. Drawing on fieldwork involving over 50 interviews and documentary research spanning 2002-2010 in Europe and the US, and on regulatory capture theory, this article investigates how the techno-regulatory standards for carcinogenicity testing of pharmaceuticals have altered since 1998. It focuses on the replacement of long-term carcinogenicity tests in rodents (especially mice) with shorter-term tests involving genetically-engineered mice (GEM). Based on evidence regarding financial/organizational control, methodological design, and interpretation of the validation and application of these new GEM tests, it is argued that regulatory agencies permitted the drug industry to shape such validation and application in ways that prioritized commercial interests over the need to protect public health. Boundary-work enabling industry scientists to define some standards of public-health policy facilitated such capture. However, as the scientific credibility of GEM tests as tools to protect public health by screening out carcinogens became inescapably problematic, a regulatory resurgence, impelled by reputational concerns, exercised more control over industry's construction and use of the tests, The extensive problems with GEM tests as public-health protective regulatory science raises the spectre that alterations to pharmaceutical carcinogenicity-testing standards since the 1990s may have been boundary-work in which the political project of decreasing the chance that companies' products are defined as carcinogenic has masqueraded as techno-science.

Specialist breast care and research nurses' attitudes to adjuvant chemotherapy in older women with breast cancer.

PURPOSE: Breast cancer largely affects older women (≥ 70 y) who have historically been excluded from clinical trials; consequently, treatment is often not evidence-based. Older women may not be offered adjuvant chemotherapy due to assumptions that they would not benefit, cannot tolerate it or do not wish to have it. Specialist breast care nurses (BCN) and research nurses (RN) play an important role influencing decisions. We report the roles, attitudes and involvement of such nurses regarding adjuvant chemotherapy in older women. METHOD: A questionnaire examined 259 UK BCN and RN's views about efficacy and desirability of chemotherapy in older women, participation in decision-making in MDTs, and roles when chemotherapy was discussed with patients. RESULTS: 72% of BCN and 48% of RN agreed that age should not be a factor influencing who is offered chemotherapy. BCNs indicated involvement in decision-making with older breast cancer patients, discussing chemotherapy with patients at different points following diagnosis and during treatment, and proposing chemotherapy in MDT meetings. RNs were involved to a lesser extent. 69% of all nurses had not received specific training in the area and 70% thought training would be beneficial. Nurses disagreed that older patients would not tolerate or did not want chemotherapy but 1/3 agreed or were uncertain that burdens of chemotherapy outweighed benefits. A third felt that older women had less control over treatment decisions than younger women. CONCLUSIONS: This study suggests a need to develop the role of specialist nurses to facilitate treatment decision-making relating to chemotherapy in older women.

Power, expertise and the limits of representative democracy: genetics as scientific progress or political legitimation in carcinogenic risk assessment of pharmaceuticals?

In modern 'representative' democratic states, the legitimacy of governments' actions rests on their publicly declared commitment to protect the interests of their citizens. Regarding the pharmaceutical sector in most democracies, new drug products are developed and marketed by a capitalist industry, whose member firms, via shareholders, have commercial interests in expanding product sales. In those democracies, states have established government agencies to regulate the pharmaceutical industry on behalf of citizens. State legislatures, such as the US Congress and European Parliaments, have charged government drug regulatory agencies with the legal responsibility to protect public health. Yet, this paper argues that government drug regulatory agencies in the EU, Japan, and USA have permitted the pharmaceutical industry to reshape the regulatory guidance for carcinogenic risk assessment of pharmaceuticals in ways that are not techno-scientifically defensible as bases for improved, or even equivalent, protection of public health, compared with the previous techno-regulatory standards. By adopting the industry's agenda of streamlining carcinogenicity testing in order to accelerate drug development and regulatory review, it is contended that these regulatory agencies have allowed the techno-regulatory standards for carcinogenic risk assessment to be loosened in ways that are presented as scientific progress resulting from new genetics, but for which there is little evidence of progress in public health protection.

Patients' decision-making in a UK specialist centre with high mastectomy rates.

A national audit identified one breast cancer unit as having the highest mastectomy rate in the UK: 50% compared to a national average of 14% for cancers <15mm in diameter. This anomaly needed investigation. A questionnaire was sent within 2 years of their surgery to 189 breast cancer patients probing perceived surgical choice, factors in decision-making and usefulness of information. One hundred thirty-one (69%) replied, of these 97 (74%) felt they had choice of surgery. Of these, the most important factor was minimising worry about recurrence. However, only 16% knew that recurrence rates were different between types of surgery. Sixty-one percent felt their healthcare professionals had surgical preferences for them, believed that clinical issues determined these preferences, but still knew the choice was theirs. The extent to which surgical choice is offered and patients are made aware that it is their choice, may account for the high mastectomy rate in this unit.