Psychometric validation of the Pyruvate Kinase Deficiency Diary and Pyruvate Kinase Deficiency Impact Assessment in adults in the phase 3 ACTIVATE trial.

BACKGROUND: Pyruvate kinase (PK) deficiency is a rare hereditary disorder characterized by chronic hemolytic anemia and serious sequalae which negatively affect patient quality of life. This study aimed to psychometrically validate the first disease-specific patient-reported outcome (PRO) instruments: the 7-item PK Deficiency Diary (PKDD) and 12-item PK Deficiency Impact Assessment (PKDIA), designed to assess signs, symptoms, and impacts of PK deficiency in patients enrolled in the ACTIVATE global phase 3 study of mitapivat versus placebo (NCT03548220). METHODS: All validation analyses for the PKDD and PKDIA were performed on blinded data, with analyses on item integrity, scoring, reliability, and validity conducted on data from screening and baseline. Completion rates and baseline response distributions were characterized using descriptive statistics. Item response modelling was used to inform a weighted scoring system. Reliability was assessed by internal consistency and test-retest reliability; and validity by convergent and known-groups analyses. RESULTS: Of the 80 adults enrolled, baseline data were available for 77 (96.3%) and 78 (97.5%) patients for the PKDD and PKDIA, respectively. Item responses skewed right, indicating that mean values exceeded median values, especially for items utilizing a 0-10 numeric scale, which were subsequently recoded to a 0-4 scale; 4 items were removed from the PKDIA due to redundancy or low relevance to the trial population. Both the PKDD and PKDIA demonstrated high internal consistency (McDonald's coefficient ω = 0.86 and 0.90, respectively), test-retest reliability (intra-class coefficients of 0.94 and 0.87, respectively), and convergent validity with other PROs (linear correlation coefficients [|r|] between 0.30-0.73 and 0.50-0.82, respectively). CONCLUSIONS: The findings provide evidence of validity and reliability for the PKDD and PKDIA, the first disease-specific PRO measures for PK deficiency, and can therefore increase understanding of, and more accurately capture, the wider impact of PK deficiency on health-related quality of life. Trial registration ClinicalTrials.gov, NCT03548220. Registered June 07, 2018; https://www. CLINICALTRIALS: gov/ct2/show/NCT03548220 .

Pyruvate kinase (PK) deficiency is a rare genetic blood disorder with a wide range of signs and symptoms that may have a negative impact on patients' quality of life. Patient-reported outcome (PRO) instruments are tools that assess how a disease affects a patient from the patient's perspective. These instruments must go through a validation process to make sure they truly capture the patient's experience with their condition or its treatment. This study aimed to validate two new PRO instruments in adult patients enrolled in the ACTIVATE clinical trial (NCT03548220), where patients with PK deficiency received the drug mitapivat or a placebo. These two new PRO instruments are the first to be developed specifically for PK deficiency: the PK Deficiency Diary (PKDD), a daily diary that asks 7 questions to measure the core signs and symptoms of PK deficiency, and the PK Deficiency Impact Assessment (PKDIA), a weekly questionnaire with 12 questions to assess the impact of PK deficiency on a patient's life. The results of this study showed that the PKDD and PKDIA properly and reliably measured the signs, symptoms, and impacts of PK deficiency that they aimed to capture. These findings indicate that the PKDD and PKDIA are the first validated PROs specifically for PK deficiency and can help improve the understanding of the impact of PK deficiency on patients' quality of life.

Assessment of the effectiveness and efficiency of the economic community of West African States Medicines Regulatory Harmonization initiative by the pharmaceutical industry.

Background: Following the establishment of Economic Community of West African States Medicines Regulatory Harmonization (ECOWAS-MRH) initiative in 2017, it was considered timely to carry out an evaluation of the current status of the initiative's operating model by the pharmaceutical industry users. This study examined the challenges being encountered and identified strategies that would strengthen the ECOWAS-MRH initiative moving forward. Methods: The Process Effectiveness and Efficiency Rating (PEER) questionnaire was used to collect data from manufacturers who have submitted applications to the joint assessment procedure and had identified recommendations for improving the performance of the ECOWAS-MRH initiative. Results: Ten pharmaceutical manufacturer participants (innovator, generic foreign, generic local) all reported that harmonisation of registration requirements was a major benefit, allowing submission of the same dossier to multiple countries, reducing the application burden and saving time and resources. Additionally, receipt of the same list of questions from several countries enables the compilation of a single response package, resulting in shorter timelines for approvals compared to the individualised country responses. Another benefit of a harmonised registration process was the simultaneous accessibility of medicines in various markets. Key challenges included a lack of centralised submission and tracking, differences in regulatory performance of the national medical regulatory authorities, a lack of detailed information for applicants and a low motivation to use the ECOWAS-MRH route with a preference for other regulatory pathways in the ECOWAS member states. Conclusion: This study identified several approaches to increase the effectiveness of this initiative: the implementation of risk-based approaches such as use of reliance pathways; establishment of a robust information technology systems, building assessor capacity to facilitate processing and monitoring applications; and priority review of ECOWAS-MRH products.

Regulatory performance of the East African Community joint assessment procedure: The way forward for regulatory systems strengthening.

BACKGROUND: Seven national medicines regulatory authorities in the East African Community (EAC) have embraced regulatory reliance, harmonization and work sharing through the EAC Medicines Regulatory Harmonization programme. Measuring the performance of regulatory systems provides key baseline information to build on regulatory system-strengthening strategies. Therefore, the aim of the study was to evaluate the regulatory performance of the EAC joint scientific assessment of applications approved between 2018 and 2021. METHODS: Utilising a data metrics tool, information was collected reflecting timelines for various milestones including submission to screening, scientific assessment and communication of regional recommendations for biologicals and pharmaceuticals that received a positive regional recommendation for product registration from 2018 to 2021. RESULTS: Several challenges as well as possible solutions were identified, including median overall approval times exceeding the EAC 465-day target and median times to issue marketing authorisation following EAC joint assessment recommendation that far exceeded the 116-day target. Recommendations included establishment of an integrated information management system and automation of the capture of regulatory timelines through the EAC metric tool. CONCLUSIONS: Despite initiative progress, work is required to improve the EAC joint regulatory procedure to achieve regulatory systems-strengthening and ensure patients' timely access to safe, efficacious and quality medicines.

A cross-sectional study of the prevalence and clinical management of atherosclerotic cardiovascular diseases in patients with type 2 diabetes across the Middle East and Africa (PACT-MEA): Study design and rationale.

AIM: To investigate the epidemiology and clinical management of patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (eASCVD) or high/very high ASCVD risk, defined by the 2021 European Society of Cardiology Guidelines, in seven countries in the Middle East and Africa (PACT-MEA; NCT05317845), and to assess physicians' attitudes and the basis for their decision-making in the management of these patients. MATERIALS AND METHODS: PACT-MEA is a cross-sectional, observational study undertaken in Bahrain, Egypt, Jordan, Kuwait, Qatar, South Africa and the United Arab Emirates based on a medical chart review of approximately 3700 patients with T2D in primary and secondary care settings, and a survey of approximately 400 physicians treating patients with T2D. RESULTS: The primary and secondary objectives are to determine the prevalence of eASCVD and high/very high ASCVD risk in patients with T2D. Current treatment with cardioprotective antidiabetic medication, the proportion of patients meeting the treatment criteria for reimbursement in the study countries where there is an applicable reimbursement guideline, and physician-reported factors in clinical decision-making in T2D management, will also be assessed. CONCLUSIONS: This large cross-sectional study will establish the estimated prevalence and management of eASCVD and high/very high ASCVD risk in patients with type 2 diabetes across the Middle East and Africa.

Evaluation of the Food and Drugs Authority, Ghana Regulatory Review Process: Challenges and Opportunities.

PURPOSE: This study aimed to assess the current regulatory review process of the food and drugs authority (FDA) Ghana by identifying key milestones, target timelines, good review practices and quality decision-making practices and evaluating the overall regulatory performance from 2019 to 2021, as well as the challenges and opportunities for improvement. METHODS: The FDA Ghana representatives completed the optimising efficiencies in regulatory agencies (OpERA) questionnaire, including data identifying the milestones and overall approval times for all products registered by the FDA Ghana from 2019 to 2021. RESULTS: Of the new active substances approved from 2019 to 2021, 91% were biologicals processed by full or abridged reviews pathways. Timelines for these reviews were within authority targets but were longer compared with generics. Of generics approved from 2019 to 2021, 97% were pharmaceuticals processed by the full review pathway, with timelines within authority targets and shorter compared with new active substances. Regardless of the review model used, approval times for new active substances increased from 84 to 355 calendar days 2019-2021 due to the impact of the pandemic. Guidelines, standard operating procedures and review templates were in place and the majority of indicators for good review practices were implemented. Several quality decision-making practices were implemented, although currently there is not a systematic structured approach. CONCLUSION: The FDA Ghana monitors regulatory performance and currently meets its target timelines. To achieve World Health Organization Maturity Level 4 status, an electronic tracking system, benefit-risk assessment framework and template and the publication of assessment reports are recommended.

Assessment of the effectiveness and efficiency of the West Africa medicines regulatory harmonization initiative by the member countries.

Background: The West Africa Health Organization launched the West Africa Medicines Regulatory Harmonization Project (WA-MRH) in 2017 with the overarching objective to improve the availability of high-quality, safe and effective medicines and vaccines by the 15 countries in the Economic Community of West African States region. Although this project has made significant progress towards the realisation of its goals, challenges still remain. The aims of this study were to evaluate the effectiveness and efficiency of the WA-MRH, examine what challenges are being encountered and identify strategies that would strengthen the process for realising the initiative's goals. Methods: The Process Effectiveness and Efficiency Rating (PEER) questionnaire was used to collect data from assessors representing the seven active NMRAs in the joint assessment procedure that identified the benefits, challenges and recommendations for improving the performance of the WA-MRH project. Results: The benefits of the joint assessment procedure include time savings to manufacturers resulting from submitting one dossier and the same response package to multiple countries resulting in access to the multiple African markets within the same timeframe. Additionally, some of the NMRAs have been able to strengthen their technical capacity as a result of this initiative. Key challenges to the project include the lack of a robust information technology system that would enable dossier tracking and constraints in human resources needed to support dossier submissions and the assessment process. Conclusion: This study identified the strengths of the WA-MRH initiative as well as strategies for improvement and achievement of its objectives. The centralised submission of a dossier and its tracking is key to the regulatory assessment process. This research has demonstrated that amongst other considerations, a robust information technology system, coupled with the necessary human resource capacity would greatly enhance the effectiveness and efficiency of the WA-MRH initiative.

Evaluation of the effectiveness and efficiency of the East African community joint assessment procedure by pharmaceutical companies: Opportunities for improvement.

Background: A 2021 study to determine the viewpoints among the seven member countries regarding the effectiveness (i.e., achieving the intended outcomes) and efficiency (i.e., achieving the intended outcomes in timely manner with the resources available) of the East African Community Medicine Regulatory Harmonisation (EAC-MRH) Joint Assessment Procedure recommended the conduct of a similar study among pharmaceutical company applicants. The aim of this study then was to evaluate the effectiveness and efficiency of the current EAC-MRH operating model from the applicants' perspective, including the challenges and opportunities for improvement. Methods: Using the Process Effectiveness and Efficiency Rating for Industry questionnaire developed by the authors, data were collected from company representatives responsible for EAC joint procedure submissions. Results: Responses from 14 study participants underlined the support of pharmaceutical companies for the EAC-MRH initiative, which has facilitated the harmonisation of registration requirements across the EAC region leading to one registration for all countries and a reduction of the workload for both applicants and assessors. In addition, it is expected that shorter timelines for approval will lead to improved access to quality-assured essential medicines in the region. Access to various markets at the same time was also noted as an important benefit to pharmaceutical companies. Noted challenges include a lack of process information, a lack of centralised submission and tracking process and a lack of mandated central registration. A key strategy proposed by participants is the establishment of a regional administrative body to centrally receive and track EAC applications and the eventual establishment of a Regional EAC Medicines Authority. Conclusion: This is the first study evaluating the performance of the EAC work-sharing initiative from the point of view of the applicants. In general, the applicants believe that the system performs efficiently and fulfils its promise. However, some participants indicated that in some countries an EAC positive recommendation does not directly result in an individual country approvals. Following the recommendations listed in this report may mitigate identified areas for improvement and facilitate the overall goal of the EAC-MRH initiative to expedite the availability of needed quality-assured medicines to patients in the region.

Evaluation of the Effectiveness and Efficiency of the East African Community Joint Assessment Procedure by Member Countries: The Way Forward.

Background: For almost a decade, the East African Community has implemented the Medicines Regulatory Harmonization (EAC-MRH) programme among its member states to harmonise technical requirements and standards for medical products regulation, jointly conduct scientific review of medical product dossiers to assess safety, efficacy and quality, inspect pharmaceutical manufacturing sites and streamline decision-making processes. This initiative enables the cost-effective use of limited resources and efficient and effective delivery of regulatory services to be determined, thus instilling transparency and accountability in all stakeholders, optimising the pharmaceutical market and economic development and improving access to safe, high-quality, effective medicines in the region. The aim of this study was to evaluate the effectiveness and efficiency of the current operating model of the EAC-MRH initiative, including challenges faced and to identify opportunities for improvement. Methods: The Process Effectiveness and Efficiency Rating (PEER) questionnaire, which was used to identify the benefits, challenges, and suggestions for improving performance of EAC-MRH initiative, was completed by assessors representing seven EAC authorities in the joint assessment procedure. Semi-structured interviews were also carried out to validate the responses. Results: This initiative has been of considerable value as it moves toward achieving its main objectives of shorter timelines for approval of medicines, information sharing among regulators and capacity building for assessments, resulting in quicker access and increased availability of medicines for patients in the region. However, the key challenges identified that have hindered effectiveness and efficiency were the lack of a centralised submission and tracking system; inadequate human resources, manufacturers' failure to submit the exact same dossier to all countries of interest; lack of an integrated information management system; lack of information on national medical regulatory authority or EAC websites; and challenges in monitoring and tracking assessment reports. Conclusion: The use of a robust information technology system for the central tracking of EAC products is essential to address the identified challenges and improve regulatory effectiveness and efficiency. One central point for payment is needed to expedite the process and to ensure transparency and the availability of information on decision making on national and regional websites. Other key strategies for enhancement include improving the capacity of assessors, work and information sharing and a coordination mechanism for the regional joint assessment, with the eventual establishment of a regional medicine agency.

A Process for Evaluating Quality Decision-Making Practices During the Development, Review and Reimbursement of Medicines.

BACKGROUND: The development of a medicine is not only underpinned by good science but also by Quality DecisionMaking Practices (QDMPs). Indeed, it is important to ensure that all organisations involved in the lifecycle of medicines are aligning their practices in decision-making to the QDMPs to ensure quality, transparent and consistent decisionmaking processes. METHODS: The aim of this study was to evaluate the practicality of QoDoS (Quality of Decision-Making Orientation Scheme) in assessing the incorporation of ten QDMPs during the development, review and reimbursement of medicines, illustrated by case studies with a pharmaceutical company, a regulatory authority and a health technology assessment (HTA) agency. Individuals from each organisation completed the 47-item QoDoS questionnaire. RESULTS: The results demonstrate the applicability of QoDoS in identifying favourable and unfavourable practices and in assessing the consistency and transparency of the QDMPs within each organisation, as well as across the different stakeholders. Furthermore, the study established the value of the methodology in raising awareness of the biases and best practices in decision-making, as well as having a basis for discussion for differences within and across stakeholders to promote consistency and alignment in decision-making. Finally, the QoDoS demonstrated the need for improvement across a number of decision-making practices for the 3 organisations such as the evaluation of alternatives and of the decision impact. CONCLUSION: The QoDoS can be used to benchmark organisations' decision-making practices to provide a basis for discussion to ultimately encourage a level of trust across and within organisations and helping to identify areas for improvement.

Challenges Faced by the Biopharmaceutical Industry in the Development and Marketing Authorization of Biosimilar Medicines in BRICS-TM Countries: An Exploratory Study.

BACKGROUND: Biosimilars are expected to emerge as a rapidly growing segment of the biopharmaceutical industry. However, the biosimilar industry faces multiple challenges and obstacles in developing and marketing these complex products. Divergent regulatory framework in emerging countries adds to repetitive trials and increased cost of biosimilar development, delaying the approval process. Due to such roadblocks, healthcare systems and patients are yet to realize the full benefits of biosimilars. OBJECTIVES: The aim of this exploratory study was to specifically identify the challenges faced by the industry in emerging countries including Brazil, Russia, India, China, South Africa, Turkey and Mexico (BRICS-TM), pertaining to biosimilar development and the regulatory approval process. In particular, this study aims to understand the perceptions of industry on the barriers faced by them in terms of complexity, costs for biosimilar development and time-to-market for biosimilar product. METHODS: A semi-quantitative questionnaire was designed based on secondary research. A total of 93 industry personnel and representatives from 14 trade associations from the BRICS-TM countries with 15-year minimum experience were identified and invited to take part in the study and participate in interviews, which were recorded verbatim. Data processing and analysis was carried out; descriptive statistics were used for quantitative data and content analysis was employed to generate themes for qualitative data. RESULTS: Of the 107 biopharmaceutical industry and trade association representatives invited to participate in the study, respondents from 33 biopharmaceutical companies agreed to take part and underwent the interviews. The industry personnel perceived biosimilar guidelines and approval processes as being protracted and in a state of evolution. The absence of an abridged approval pathway limited effectiveness of the regulatory process. The biggest hurdles in the development of biosimilar dossiers were the sourcing of the reference biological product and expectations around confirmatory clinical trials by the agencies. The non-comprehensive implementation of a stepwise approach resulting in unnecessary toxicity studies was also reported as a major challenge. The authors recommend further primary research with BRICS-TM regulatory agencies in order to propose a simplified pathway for development and approval. CONCLUSIONS: Lack of standardized biosimilar development criteria and regulatory convergence across BRICS-TM agencies has led to challenges in multi-country development programmes for these medicines, in turn impacting the ability of industry to launch newer and more affordable biosimilars.

Can Standardisation of the Public Assessment Report Improve Benefit-Risk Communication?

BACKGROUND: National regulatory authorities (NRAs) make the decision to register a medicine based on an assessment of its benefits and risks and publicly available assessment reports are used as a tool to communicate the basis for the decision. The Universal Methodology for Benefit-Risk Assessment (UMBRA) has also been used to effectively communicate the basis of regulatory decisions. Many NRAs in emerging markets place reliance on the public assessment reports (PARs) of reference agencies to inform about their own regulatory decisions. However, PAR users often criticise the redacted nature of PARs and may be challenged in identifying key benefits and risks, value judgements, and benefit-risk (BR) trade-offs. METHODS: PARs for ertugliflozin l-pyroglutamic acid, erenumab, and durvalumab published by regulatory bodies in Australia, Europe, Canada, and the United States were compared with the validated UMBRA Benefit-Risk Template to evaluate the BR decision documentation. Published validation of UMBRA included report of a consortium of four regulatory authorities in Australia, Canada, Switzerland, and Singapore indicating that their clinical assessment templates were modified to align with the UMBRA approach. A focus group discussed the use of PARs as potential knowledge management tools for stakeholder understanding of regulatory decision making. The South African Health Product Regulatory Authority (SAHPRA) approach to document and communicate the BR decisions was evaluated. RESULTS: Results indicate key elements to include in the PARs including regulatory history, an effects table and a record of the strengths and uncertainties for each benefit and risk. Focus group participants agreed that a harmonised PAR template would support improved regulatory decision-making transparency. SAHPRA communication of BR decisions could be improved through the use of the UMBRA BR Template as a guidance for BR assessment and the basis of the South Africa public assessment report format. CONCLUSION: SAHPRA's use of a structured template that supports transparent and quality decision making could have a major impact in ensuring consistency in the BR assessment of new medicines. The implementation of this effective approach for communicating BR decisions will advance agency goals of being a trusted, responsive, accountable regulatory body in which all healthcare stakeholders may rely on with confidence.

Evaluation of the Performance of the South Africa Regulatory Agency: Recommendations for Improved Patients' Access to Medicines.

BACKGROUND: Timely access to new medicines may be addressed through strengthening of registration efficiencies and timelines by establishing and refining value-added registration processes, resources, and systems. The aims of this study were to evaluate the timelines of the milestones of the South African review process and the overall approval process for new active substances (NASs) in 2015-2018 and to provide recommendations for improved patients' access to new medicines through timely registration. METHODS: Data identifying the milestones and overall approval times for NASs registered by the South African Agency during 2015-2018 were collected and analyzed. RESULTS: The most NASs (42) were approved in 2017 and the least (15) in 2018. The shortest median approval time (1218 calendar days) was achieved in 2015 and the longest (2124 days), in 2018. All applications were reviewed using the full review process, and 16/99 (16%) were assigned priority status and were reviewed and approved through the fast track review. CONCLUSIONS: While the extensive delays in NASs approvals in South Africa may be attributed to inefficient operational processes, resource constraints, and as an increased number of applications for registration, the newly established South African Heath Products Regulatory Agency has re-engineered and streamlined its regulatory review process, which has been piloted and will be enhanced prior to final implementation. Among recommendations for improvement, SAHPRA should consider measurement and monitoring of milestones, facilitated regulatory pathways, implementing a reliance strategy, and a quality management system.

Quality Decision Making in Health Technology Assessment: Issues Facing Companies and Agencies.

BACKGROUND: To evaluate the quality of the decision-making processes of pharmaceutical companies during medicines development for evidence generation to support reimbursement of new medicines and the appraisal recommendation decision-making process by health technology assessment (HTA) agencies. METHODS: Two questionnaires were developed and subsequently piloted for the purpose of content validation. These were sent to 24 pharmaceutical companies and 16 HTA agencies. RESULTS: Responses were obtained from 11 companies and 11 HTA agencies. Some similarities were identified between the decision-making processes of companies and agencies, such as the use of committees, having a primarily mixed (qualitative/quantitative) internal decisionmaking system, as well as the lack of systematic assessments of quality decision making and the relatively infrequent use of formal decision-making frameworks. Nevertheless, the results indicate differences as companies and agencies use diverse processes to arrive at the final decision either through consensus, majority vote, or an individual making the decision. The majority of companies and agencies believe that the quality of decision making can and should be measured. Moreover, organizations considered the occurrence of biases within their organization as pertinent. Finally, almost all the participants felt that there was room for improvement for their organization's quality of decision making. CONCLUSION: These findings are consistent with a published study on regulatory processes and support the need for more consistent and predictable decision-making processes during the life cycle of medicines. This could be achieved through capacity building, systematically evaluating the quality of decision making, and encouraging utilization of formal decision-making frameworks within companies and agencies.

Patients' Perspectives of the Pharmaceutical Regulatory and Reimbursement Systems in Istanbul, Turkey.

INTRODUCTION: The aim of this study was to explore patients' knowledge and perspectives in Istanbul, Turkey about the pharmaceutical regulatory review and reimbursement processes with respect to patients' access to new medicines. METHODS: For the purpose of this study a tailored made paper-based questionnaire, Patient Perspective Questionnaire (PPQ), was developed and subsequently piloted in the target population. A total of 350 patients were recruited consecutively into the study from hospital outpatient clinics, general practice, community pharmacies, patient organisations in 28 different districts of Istanbul receiving treatment for chronic conditions. In addition, 22 patients were randomly selected from the cohort for face-to-face interviews in order to obtain further insights about the relevance of the PPQ, and to help with formalising a set of recommendations for the involvement of patients in both processes. Data processing and analyses were carried out using SPSS version 23 statistical software. RESULTS: Overall 210 (60% response rate) completed the PPQ (51% males) with the mean age of 56, median of 54 and range of 18-75. Most patients in this study (84%) seemed to know that medicines had to be approved by the government. However, 81% of patients were not aware of the regulatory review process with 73% being unaware of approval timelines. Furthermore, 78 (37%) patients described the Turkish approval process to be of a lower standard compared to that of the US and EU. However, 147 (70%) of patients believed that there are novel alternative medicines for their disease available in other developed countries. Similarly, 126 (60%) patients thought that new medicines only become available in Turkey after their availability in the other developed countries. In contrast, patients in this cohort were more aware of the reimbursement system in Turkey where the majority expressed their satisfaction and 34% described access to new medicines to be adequate. In addition, the majority of patients (75%) recognised that the government is the main payer, even though insufficient information is provided about new medicines. Patients stated that they do not have any role in the decision-making process for the approval or reimbursement of new medicines and therefore most of them indicated that they wish to be more involved in reimbursement (60%) as well as in the approval process (58%). DISCUSSION: Faster access to medicines, improved health and pharmaceutical care as well as lower prices were considered by the study patients as the improvement priorities. Further, they were able to offer academic collaboration and active patient involvement in both processes as possible solutions.

Development of the pyruvate kinase deficiency diary and pyruvate kinase deficiency impact assessment: Disease-specific assessments.

INTRODUCTION: Currently recommended patient-reported outcome (PRO) measures for patients with pyruvate kinase (PK) deficiency are non-disease-specific. The PK Deficiency Diary (PKDD) and PK Deficiency Impact Assessment (PKDIA) were developed to be more targeted measures for capturing the symptoms and impacts of interest to this patient population. METHODS: The instruments were developed based on concept elicitation interviews with 21 adults and modified based on 20 cognitive interviews. The domain structure and item concepts of the PKDD and PKDIA were compared with currently recommended measures, the EORTC QLQ-C30 and the SF-36v2®. RESULTS: The PKDD is a seven-item measure of the core signs and symptoms of PK deficiency. The PKDIA is a 14-item measure of the impacts of PK deficiency on patients' health-related quality of life (HRQoL). Minimal similarities were found between the new measures and the EORTC QLQ-C30 (eg, 43% of concepts were similar to the PKDD; 42% were similar to the PKDIA) and SF-36v2® (57% of concepts were similar to the PKDD; 17% were similar to the PKDIA). CONCLUSIONS: The PKDD and PKDIA fill a gap in the existing outcomes measurement strategy for PK deficiency. Future work includes psychometric evaluation of these newly developed measures.

Itch and Mental Health in Dermatological Patients across Europe: A Cross-Sectional Study in 13 Countries.

Itch is a highly prevalent and multidimensional symptom. We aimed to analyze the association between itch and mental health in dermatological patients. This multicenter study is observational and cross-sectional and was conducted in dermatological clinics across 13 European countries. A total of 3,530 patients and 1,094 healthy controls were included. Patients were examined clinically. Outcome measures were itch (presence, chronicity, and intensity), the Hospital Anxiety and Depression Scale, EQ-5D visual analogue scale, sociodemographics, suicidal ideation, and stress (negative life events and economic difficulties). Ethical approval was obtained. Results showed significant association between the presence of itch in patients and clinical depression (odds ratio, 1.53; 95% confidence interval, 1.15-2.02), suicidal ideation (odds ratio, 1.27; 95% confidence interval, 1.01-1.60), and economic difficulties (odds ratio, 1.24; 95% confidence interval, 1.10-1.50). The mean score of reported generic health status assessed by the EQ-5D visual analogue scale was 65.9 (standard deviation = 20.1) in patients with itch, compared with 74.7 (standard deviation = 18.0) in patients without itch (P < 0.001) and 74.9 (standard deviation = 15.7) in controls with itch compared with 82.9 (standard deviation = 15.6) in controls without itch (P < 0.001). Itch contributes substantially to the psychological disease burden in dermatological patients, and the management of patients should include access to multidisciplinary care.

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

Aim: To determine measurement equivalence of paper and electronic application of the hematological malignancy-patient-reported outcome (HM-PRO), a specific measure for the evaluation of patient-reported outcomes in HMs. Patients & methods: Following International Society of Pharmacoeconomics and Outcomes Research ePRO Good Research Practice Task Force guidelines, a total of 193 adult patients with different HMs were recruited into a multicenter prospective study. The paper and the electronic version of the instrument were completed in the outpatient clinics in a randomized crossover design with a 30 min time interval to minimize the learning effect. Those who completed the paper version first, completed the electronic version after 30 min and vice versa. Instrument version and order effects were tested on total score of the two parts of the HM-PRO (Part A: quality of life and Part B: signs & symptoms) in a two-way ANOVA with patients as random effects. Intraclass correlation coefficients (95% CI) and Spearman's rank correlation coefficients were used to evaluate test-retest reliability and reproducibility. The effects 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. There were 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, and intraclass correlation coefficients ranged from 0.94 to 0.98; furthermore, the scores were not statistically different between the two versions, showing acceptable reliability indexes. Noteworthy, the difference between 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 the electronic version during cognitive interviews and were able to understand and respond spontaneously. Conclusion: Measurement equivalence has been demonstrated for the paper and electronic application of the HM-PRO.

Factors Influencing Delays in Patient Access to New Medicines in Canada: A Retrospective Study of Reimbursement Processes in Public Drug Plans.

Individuals who rely on public health payers to access new medicines can access fewer innovative medicines and must wait longer in Canada compared to major markets around the world. New medicines/indications approved by Health Canada and reviewed for eligibility for reimbursement by the Common Drug Review or the pan-Canadian Oncology Drug Review (CDR/pCODR) from the beginning of 2012 through to the end of December 2016 were analyzed, with data taken from the relevant bodies' websites and collected by IQVIA. This analysis investigated individual review segments - Notice of Compliance (NOC) to Health Technology Assessment (HTA) submission, HTA review time, pan-Canadian Pharmaceutical Alliance (pCPA) negotiation time, and public reimbursement decision time, and analyzed the trends of each over time and contributions to overall time to listing decisions. Average overall timelines for public reimbursement after NOC were long and most of this time is taken up by HTA and pCPA processes, at 236 and 273 days, respectively. This study confirms that Canadian public reimbursement delays from 2013-2014 to 2015-2016 lengthened from NOC to listing (Quebec + 53%, first provincial listing + 38%, and country-wide listing + 22%), reaching 499, 505, and 571 days, respectively. Over the same period, time from NOC to completion of HTA has increased by 33%, and time from post-HTA to first provincial listing by 44%. The pCPA process appears to be the main contributor to this increasing time trend, and although some provinces could be listing more quickly post-pCPA, they appear to be listing fewer products. Reasons for large delays in time to listing include the many-layered sequential process of reviews conducted before public drug plans decide whether to provide access to new innovative medicines. Although there has been some headway made in certain parts of the review processes (e.g., pre-NOC HTA), total time to listing continues to increase, seemingly due to the pCPA process and other additional review processes by drug plans. More clarity in the pCPA and provincial decision-making processes and better coordination between HTA, pCPA, and provincial decision-making processes is needed to increase predictability in the processes and reduce timelines for Canadian patients and manufacturers.

The Reliability and Relevance of a Quality of Decision Making Instrument, Quality of Decision-Making Orientation Scheme (QoDoS), for Use During the Lifecycle of Medicines.

Introduction: The Quality of Decision-Making Orientation Scheme (QoDoS) was developed to provide organisations involved in submission, approval and reimbursement of new medicines with a tool to improve the quality of their decision-making processes and is considered the most promising tool for such purpose. This study aimed to further establish the measurement properties of the QoDoS by evaluating its reliability (internal consistency and test-retest reliability) and relevance in the target population. Methods: The study participants consisted of 55 individuals recruited from pharmaceutical companies, regulatory and HTA agencies. It was designed as a longitudinal study with participants assessed on two different occasions, at baseline (test 1) and then 7 days later (test 2). Internal consistency reliability was assessed with Cronbach's alpha and the test-retest reliability was evaluated using the intraclass correlation coefficients (ICC) based on absolute agreement, 2 way mixed-effects model for the four QoDoS domains. The relevance of the QoDoS was evaluated by applying cognitive debriefing using five short feedback questions following test 1. Results: Test 1 was completed by 44 study participants (80% response rate) and test 2 was completed by 32 of the 44 individuals, resulting in a 73% response rate. Cronbach's alpha coefficient was greater than 0.7 across all the domains for test 1 and test 2, ranging from 0.71 to 0.79, indicating good consistency of responses. For the overall score across all 47 items, the Cronbach's alpha coefficient was 0.81 for test 1 and 0.86 for test 2, which is rated as very good. The four QoDoS domains showed moderate to strong reproducibility (ICC range: 0.63-0.86). The outcome of the cognitive debriefing from the 43 respondents (98% response rate) confirmed the relevance (95% agreement), language clarity (95%) and completeness of items (86%); the clarity of the scaling (91%) as well as spontaneity of responses (95%). Conclusion: These results provide strong support for the relevance and reliability of the QoDoS, which are key properties for future longitudinal and cross-sectional applications of the instrument when evaluating quality of decision making by those involved in the lifecycle of medicines.

The burden of disease in pyruvate kinase deficiency: Patients' perception of the impact on health-related quality of life.

OBJECTIVES: This study explored how signs and symptoms of pyruvate kinase (PK) deficiency, a rare hemolytic anemia caused by mutations in the PKLR gene, impacts patients' health-related quality of life (HRQoL). METHODS: Interviews with 21 adults with PK deficiency in the United States, Netherlands, and Germany were conducted. Participants were asked to describe signs, symptoms, and impacts of the disease on their daily lives. Interviews were transcribed and analyzed using qualitative analysis methods. RESULTS: The most common signs and symptoms reported were yellow eyes (n = 19), tiredness (n = 18), yellow skin (n = 17), fatigue (n = 15), low energy (n = 13), and shortness of breath (n = 13). Furthermore, signs and symptoms of PK deficiency negatively impact the ability to perform physical activities, appearance, social activities, emotional states, activities of daily living, leisure activities, work and/or school, sleep, and cognitive states of those living with PK deficiency. A conceptual model is presented that further demonstrates the profound impact that signs and symptoms of PK deficiency have on dimensions of patients' HRQoL. CONCLUSIONS: This is the first study that provides patient perspective on the burden of living with PK deficiency and lays the foundation for future studies to examine the effect of pharmacologic interventions on overall HRQoL for patients living with PK deficiency.