Appraisal of patient-reported outcome measures in analogous diseases and recommendations for use in phase II and III clinical trials of pyruvate kinase deficiency

Purpose: Pyruvate kinase deficiency (PKD) is a rare disease and understanding of its epidemiology and associated burden remains limited. With no current curative therapy, clinical manifestations can be life threatening, clinically managed by maintaining adequate hemoglobin levels through transfusion and subsequent support, but with frequent complications. Treatment goals are to maintain/improve the patient’s quality of life. With new therapies, reliable, valid, and relevant patient-reported outcome (PRO) tools are required for use in clinical trials. Methods: Systematic literature search identified no current PRO tools for capturing/measuring the impact of PKD and treatments in clinical trials. Therefore, the search strategy was revised to consider conditions analogous to PKD in terms of symptoms and impacts that might serve as parallels to the experience in PKD; this included sickle cell anemia, thalassemia, and hemolytic anemia. Psychometric properties, strengths, and weakness of selected appropriate PRO instruments were compared, and recommendations made for choice of PRO tools. Results: In adult populations, EORTC QLQ C30 and SF-36v2 are recommended, the former being a basic minimum, covering generic HRQoL, and core symptoms such as fatigue. In pediatric populations, PedsQL Generic Core Scale to measure HRQoL and PedsQL MFS scale to measure fatigue are recommended. Conclusions: Some symptoms/life impacts may be unique to PKD and not observable in analogous conditions. A ‘Physico-Psychosocial Model’ derived from the ‘Medical Model’ is proposed to form the basis for a hypothesized conceptual framework to address the development of PKD-specific PRO instruments.Peer reviewedFinal Published versio

The South African Medicines Control Council: Comparison of Its Registration Process With Australia, Canada, Singapore, and Switzerland

© 2019 Keyter, Salek, Banoo and Walker.Introduction: Comparisons between regulatory authorities of similar size and regulatory characteristics facilitate value-added benchmarking and provide insight into regulatory performance. Such comparisons highlight areas for improvement as authorities move toward achieving their regulatory goals and stakeholders’ demands. The aims of this study were to compare the registration process and the regulatory review model of the South African Medicines Control Council (MCC) to that of four other similar-sized regulatory authorities and to identify areas for improvement that may inform recommendations to the South African Health Products Regulatory Authority (SAHPRA) as it looks to re-engineer and enhance the registration process in South Africa. Methods: A questionnaire describing the organisational structure, the registration process, good review and decision-making practices of the MCC was completed by the author (AK) for the purpose of this study and validated by the Registrar of the MCC. Similar questionnaires were also completed and validated by Australia’s Therapeutic Goods Administration (TGA), Canada’s Health Canada, Singapore’s Health Science Authority (HSA) and Switzerland’s Swissmedic. Results: A comparison of the MCC regulatory process with the four comparative agencies indicated that they all have similar requirements and employ a full-review model although the timelines for the MCC were considerably longer. However, similar quality measures were implemented by all authorities as part of their good review practices (GRevP) including prioritising transparency, communication, continuous improvement initiatives and training. Conclusion: Comparisons made through this study provided insight into the areas of the MCC registration process that may be improved and have informed recommendations to SAHPRA including the implementation of facilitated regulatory pathways, definition of targets for key milestones in regulatory review and formal implementation and monitoring of GRevP. In order to build quality into the review process the application of a standardised template for the clinical assessment of medicines such as the Universal Methodology for Benefit-Risk Assessment (UMBRA) could be considered as well as enhancing transparency and communication through the application of an electronic management system and the development of publicly available summaries for the basis of approval.Peer reviewedFinal Published versio

Correlating the Dermatology Life Quality Index with psychiatric measures: A systematic review.

© 2018 Published by Elsevier Inc. All rights reserved.Skin conditions may have a major impact on the psychologic well-being of patients, ranging from depression to anxiety. The Dermatology Life Quality Index (DLQI) is the most commonly used quality of life tool in dermatology, though it has yet to be correlated with psychiatric measures used in clinical therapeutic trials. We conducted a systematic review to determine whether there is any correlation between the DLQI and psychiatric measure scores, potentially allowing the DLQI to be used as a surrogate measure for depression or psychiatric screening. Six databases were searched using the following keywords: "DLQI," "Dermatology Life Quality Index," "Psych*," "depression," "anxiety," "stress," and "trial*." All randomized trials where full DLQI and psychiatric scores were provided were included. PRISMA guidelines were followed. In all, 462 records were screened, but only seven met inclusion criteria. Hospital Anxiety and Depression Scale (HADS) was the most commonly used psychiatric measure; the "depression" component score changes correlated strongly with the DLQI (r = 0.715). There needs to be guidance on psychiatric measurement and reporting in clinical trials. Although the DLQI correlated well with the "depression" domain of the HADS scale, interviews and screening for depression are still vital for full assessment of patient psychologic well-being.Peer reviewe

Paper and electronic versions of HM-PRO, a novel patient-reported outcome measure for hematology: an equivalence study.

© 2019 Goswami, Oliva, Ionova et al.Aim:To determine measurement equivalence of paper and electronic application of the hematologi-cal malignancy-patient-reported outcome (HM-PRO), a specific measure for the evaluation of patient-reported outcomes in HMs.Patients & methods:Following International Society of Pharmacoeconomicsand Outcomes Research ePRO Good Research Practice Task Force guidelines, a total of 193 adult patientswith different HMs were recruited into a multicenter prospective study. The paper and the electronic ver-sion of the instrument were completed in the outpatient clinics in a randomized crossover design with a30-min time interval to minimize the learning effect. Those who completed the paper version first, com-pleted the electronic version after 30 min and vice versa. Instrument version and order effects were testedon total score of the two parts of the HM-PRO (Part A: quality of life and Part B: signs & symptoms) in atwo-way ANOVA with patients as random effects. Intraclass correlation coefficients (95% CI) and Spear-man’s rank correlation coefficients were used to evaluate test–retest reliability and reproducibility. Theeffects of instrument version and order were tested on total score of the two parts of HM-PRO.Results:The questionnaire version and administration order effects were not significant at the 5% level. Therewere no interactions found between these two factors for HM-PRO (Part A [quality of life]; p=0.95); and(part B [signs and symptoms]; p=0.72]. Spearman’s rank correlation coefficients were greater than 0.9, andintraclass correlation coefficients ranged from 0.94 to 0.98; furthermore, the scores were not statisticallydifferent between the two versions, showing acceptable reliability indexes. Noteworthy, the differencebetween the completion time for both paper (mean=6:38 min) and electronic version (mean=7:29 min)was not statistically significant (n=100; p=0.11). Patients did not report any difficulty in completing theelectronic version during cognitive interviews and were able to understand and respond spontaneously.Conclusion:Measurement equivalence has been demonstrated for the paper and electronic applicationof the HM-PRO.Peer reviewe

Presenting signs and patient co-variables in Gaucher disease : outcome of the Gaucher Earlier Diagnosis Consensus (GED-C) Delphi initiative

© 2018 The Authors. Internal Medicine Journal by Wiley Publishing Asia Pty Ltd on behalf of Royal Australasian College of Physicians.Background: Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognise the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities. Aim: The Gaucher Earlier Diagnosis Consensus (GED-C) initiative aimed to identify signs and co-variables considered most indicative of early type 1 and type 3 GD, to help non-specialists identify ‘at-risk’ patients who may benefit from diagnostic testing. Methods: An anonymous, three-round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5-point Likert scales and scoring thresholds defined a priori. Results: For type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone-related manifestations, anaemia, hyperferritinaemia, hepatomegaly and gammopathy) and two major co-variables (family history of GD and Ashkenazi-Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances and kyphosis) and one major co-variable (family history of GD) were identified. Lack of disease awareness, overlooking mild early signs and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis. Conclusion: The signs and co-variables identified in the GED-C initiative as potentially indicative of early GD will help to guide non-specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD.Peer reviewedFinal Published versio

Patient-centered research and practice in the era of genomics: a novel approach

Non peer reviewedFinal Published versio

Validation of the electronic Psoriasis Area and Severity Index application : Establishing measurement equivalence

© 2019 by the American Academy of Dermatology, Inc. This manuscript is made available under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND 4.0). For further details please see: https://creativecommons.org/licenses/by-nc-nd/4.0/To the Editor: Despite its many shortcomings, the Psoriasis Area and Severity Index (PASI) remains the standard method worldwide for psoriasis assessment.1 Several studies have implemented electronic versions without evidence of formal validation, raising the possibility of lack of equivalence with the paper counterpart.2 This study compared the conventional paper-based and a novel electronic application version of the PASI (Fig 1). International Society for Pharmacoeconomics and Outcomes Research (ISPOR) guidelines3 were followed to assess rater preference and consistency of scores.Peer reviewedFinal Accepted Versio

The Role of Therapy in Impairing Quality of Life in Dermatological Patients: A Multinational Study

Skin disease and its therapy affect health-related quality of life (HRQoL). The aim of this study was to measure the burden caused by dermatological therapy in 3,846 patients from 13 European countries. Adult outpatients completed questionnaires, including the Dermatology Life Quality Index (DLQI), which has a therapy impact question. Therapy issues were reported by a majority of patients with atopic dermatitis (63.4%), psoriasis (60.7%), prurigo (54.4%), hidradenitis suppurativa (54.3%) and blistering conditions (53%). The largest reduction in HRQoL attributable to therapy, as a percentage of total DLQI, adjusted for confounders, was seen in blistering conditions (10.7%), allergic/drug reactions (10.2%), psoriasis (9.9%), vasculitis/immunological ulcers (8.8%), atopic dermatitis (8.7%), and venous leg ulcers (8.5%). In skin cancer, although it had less impact on HRQoL, the reduction due to therapy was 6.8%. Treatment for skin disease contributes considerably to reducing HRQoL: the burden of dermatological treatment should be considered when planning therapy and designing new dermatological therapies.Peer reviewe

Occurrence, Chronicity and Intensity of Itch in a Clinical Consecutive Sample of Patients with Skin Diseases: a Multi-centre Study in 13 European Countries

Itch is an unpleasant symptom, affecting many dermatological patients. Studies investigating the occurrence and intensity of itch in dermatological patients often focus on a single skin disease and omit a control group with healthy skin. The aim of this multi-centre study was to assess the occurrence, chronicity and intensity (visual analogue scale 0-10) of itch in patients with different skin diseases and healthy-skin controls. Out of 3,530 dermatological patients, 54.3% reported itch (mean ± standard deviation itch intensity 5.5 ± 2.5), while out of 1,094 healthy-skin controls 8% had itch (3.6 ± 2.3). Chronic itch was reported by 36.9% of the patients and 4.7% of the healthy-skin controls. Itch was most frequent (occurrence rates higher than 80%) in patients with unclassified pruritus, prurigo and related conditions, atopic dermatitis and hand eczema. However, many patients with psychodermatological conditions and naevi also reported itch (occurrence rates higher than 19%).Peer reviewe