Evaluation of the Performance of the Gulf Cooperation Council Centralised Regulatory Review Process: Strategies to Improve Product Authorisation Efficiency and Quality.

BACKGROUND: The Gulf Centralised Committee for Drug Registration (GCC-DR), as part of the Gulf Health Council (GHC), enables the consolidated registration of pharmaceutical products throughout the member states of the Gulf Cooperation Council. OBJECTIVES: The objectives of this study were to provide an update of the performance of the GCC-DR centralised procedure; evaluate the review times for new products submitted to the GCC Centralised Registration between January 2015 and December 2020; assess the impact of applying facilitated regulatory pathways and implementing a reliance strategy; identify the strengths and weaknesses of the centralised review process; and propose strategies that could enhance the GCC regulatory review process leading to improved access to medicines for patients. METHODS: A standardised data collection template enabled the structured documentation of information collected by the Senior Regulatory Affairs and Regulatory Affairs Specialists from the Executive Board of the Health Ministers Council for GCC States to determine the GHC structure, resources, review models and milestones and timelines. The total number of applications approved was provided together with the average yearly timelines for new active substances and generics from January 2015 to December 2020 including both scientific assessment time from the agency as well as applicant response time to questions raised. Actual approval times for each product were calculated from the date of submission to the date of approval. RESULTS: The fewest (58) new products were approved in 2019 and the most (200) in 2020. The average review times for new medicines were the longest (838 calendar days) in 2015 and the shortest (321 calendar days) in 2019. Important changes recently implemented include an increase in the number of GCC-DR meetings, adoption of a standardised electronic common technical document and GCC regulatory review template, removal of authorisation dependence on pricing agreements and introduction of a reliance strategy. Additional recommendations include Executive Committee mandates for dossier review, target times for dossier validation, scientific review and Expert Committee recommendation and training for quality decision making. CONCLUSIONS: GCC procedures and decision-making processes have been positively influenced by a variety of expert reviewers, unified guidelines and the implementation of a reliance strategy. Certain barriers must still be overcome to enhance the quality of the review, and to shorten regulatory review times without compromising the scientific robustness of the review.

Occam's Razor and Managing Acute Thrombosis in the COVID-19 Era.

The COVID-19 pandemic has profoundly influenced the practice of medicine in Australia over the last 24 months. Recently, the development of several vaccines to COVID-19 has been accompanied by reports of an associated rare syndrome of thrombosis and thrombocytopaenia (VITTS). The possibility of this rare disorder confronts all clinicians who deal with acute thrombosis, particularly given the prevalence of patients who have recently been immunised. However, VITTS remains rare, and we believe unnecessary focus on its potential diagnosis may distract from other more common causes of acute thrombosis. We discuss this with reference to a recent case at our institution.

Weekend Carotid Endarterectomies are Not Associated with a Greater Risk of Stroke and/or Death in Australia and New Zealand.

BACKGROUND: Data from multiple surgical studies and settings have reported an increase in adverse events in patients admitted or treated on weekends. The aim of this study was to investigate short-term outcomes for patients undergoing carotid endarterectomy (CEA) in Australia and New Zealand based on the day of surgery. METHODS: This is a retrospective observational cohort study. Analysis of 7,857 CEAs recorded for more than 4 years in the Australasian Vascular Audit database was performed. Multivariate logistic regression was used to compare the following outcomes between CEAs performed during the week and on the weekend: (1) in-hospital stroke and/or death; (2) other postoperative complications; and (3) shorter (2 days or less) length of stay (LOS). RESULTS: A total of 7,857 CEAs were recorded, with significantly more procedures performed during the week (n = 7,333, P < 0.001). There was no statistically significant difference in the frequency of stroke and/or death or other complications between CEAs performed during the week or on the weekend (P = 0.294 and P = 0.806, respectively). However, there was a significant difference in LOS for procedures performed during the weekend, with more of these patients being discharged within 2 days compared with procedures performed during the week (56.8% vs. 51.5%; P = 0.003). Multivariable logistic regression found no effect of day of the week on the odds of postoperative stroke and/or death (P = 0.685). Day of surgery was also not associated with greater odds of other complications (P = 0.925). However, CEAs performed by nonconsultants had significantly lower adjusted odds of other complications (3.1% vs. 4.1%; P = 0.033). The adjusted odds of having a shorter LOS were significantly greater for operations taking place on the weekend (P = 0.003). CONCLUSIONS: In Australia and New Zealand, there appears to be no disadvantage to performing CEA on the weekend, in terms of stroke and/or death. Level of experience of the primary operator does not affect rates of stroke and/or death after CEA. Weekend CEA is associated with a shorter hospital LOS.

Quality Decision-Making Practices in Pharmaceutical Companies and Regulatory Authorities: Current and Proposed Approaches to Its Documentation.

BACKGROUND: Pharmaceutical companies and regulatory agencies endeavor to relate their decision making with outcomes to improve future decision making and to ensure that gained knowledge is fed back into a learning system. Nevertheless, such a correlation can only be achieved by documenting the expected outcome of a decision at the time it is made, enabling comparison of the expected outcome with the actual result. METHODS: Participants at an international workshop discussed how the documentation of decisions could be evolved as companies and agencies look to improve their knowledge base. Discussions were informed by a pre-workshop survey of pharmaceutical companies and regulatory agencies. RESULTS: Most survey participants from 12 companies (55% response rate) and 11 agencies (73% response) have a system in place to enable documentation of major decisions, however, systems are used primarily to document outcomes rather than the process, while information from documentation is not always used, and feedback loops are not in place. The majority of participants indicated that their organization currently documents most decision-making practices included in the proposed template. Workshop participants agreed that all major past decisions should be referenceable and suggested incentives to enable decisions to be referenced, and confirmed elements and characteristics of a decision-documentation template. CONCLUSIONS: This survey and workshop identified the current landscape and gaps in the documentation of decision making and suggested revisions for a proposed documentation template. The use of technology to enable information extraction with support from artificial intelligence and future decision making was a recommendation highlighted by participants.

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.

Nellix Endobag rupture associated with a fatal outcome.

Endovascular treatment of a type IA endoleak was conducted using a Nellix chimney graft technique for an expanding abdominal aortic aneurysm in an 84-year-old man. During the procedure, a polymer leak occurred from one of the endobags. Postoperatively, the patient developed hemodynamic instability and a swollen leg on the side of the leaking endobag, resulting in a fatal outcome.

A Comparison of Reimbursement Recommendations by European HTA Agencies: Is There Opportunity for Further Alignment?

Introduction: In Europe and beyond, the rising costs of healthcare and limited healthcare resources have resulted in the implementation of health technology assessment (HTA) to inform health policy and reimbursement decision-making. European legislation has provided a harmonized route for the regulatory process with the European Medicines Agency, but reimbursement decision-making still remains the responsibility of each country. There is a recognized need to move toward a more objective and collaborative reimbursement environment for new medicines in Europe. Therefore, the aim of this study was to objectively assess and compare the national reimbursement recommendations of 9 European jurisdictions following European Medicines Agency (EMA) recommendation for centralized marketing authorization. Methods: Using publicly available data and newly developed classification tools, this study appraised 9 European reimbursement systems by assessing HTA processes and the relationship between the regulatory, HTA and decision-making organizations. Each national HTA agency was classified according to two novel taxonomies. The System taxonomy, focuses on the position of the HTA agency within the national reimbursement system according to the relationship between the regulator, the HTA-performing agency, and the reimbursement decision-making coverage body. The HTA Process taxonomy distinguishes between the individual HTA agency's approach to economic and therapeutic evaluation and the inclusion of an independent appraisal step. The taxonomic groups were subsequently compared with national HTA recommendations. Results: This study identified European national reimbursement recommendations for 102 new active substances (NASs) approved by the EMA from 2008 to 2012. These reimbursement recommendations were compared using a novel classification tool and identified alignment between the organizational structure of reimbursement systems (System taxonomy) and HTA recommendations. However, there was less alignment between the HTA processes and recommendations. Conclusions: In order to move forward to a more harmonized HTA environment within Europe, it is first necessary to understand the variation in HTA practices within Europe. This study has identified alignment between HTA recommendations and the System taxonomy and one of the major implications of this study is that such alignment could support a more collaborative HTA environment in Europe.

Evaluating Quality of Decision-Making Processes in Medicines' Development, Regulatory Review, and Health Technology Assessment: A Systematic Review of the Literature.

Introduction: Although pharmaceutical companies, regulatory authorities, and health technology assessment (HTA) agencies have been increasingly using decision-making frameworks, it is not certain whether these enable better quality decision making. This could be addressed by formally evaluating the quality of decision-making process within those organizations. The aim of this literature review was to identify current techniques (tools, questionnaires, surveys, and studies) for measuring the quality of the decision-making process across the three stakeholders. Methods: Using MEDLINE, Web of Knowledge, and other Internet-based search engines, a literature review was performed to systematically identify techniques for assessing quality of decision making in medicines development, regulatory review, and HTA. A structured search was applied using key words and a secondary review was carried out. In addition, the measurement properties of each technique were assessed and compared. Ten Quality Decision-Making Practices (QDMPs) developed previously were then used as a framework for the evaluation of techniques identified in the review. Due to the variation in studies identified, meta-analysis was inappropriate. Results: This review identified 13 techniques, where 7 were developed specifically to assess decision making in medicines' development, regulatory review, or HTA; 2 examined corporate decision making, and 4 general decision making. Regarding how closely each technique conformed to the 10 QDMPs, the 13 techniques assessed a median of 6 QDMPs, with a mode of 3 QDMPs. Only 2 techniques evaluated all 10 QDMPs, namely the Organizational IQ and the Quality of Decision Making Orientation Scheme (QoDoS), of which only one technique, QoDoS could be applied to assess decision making of both individuals and organizations, and it possessed generalizability to capture issues relevant to companies as well as regulatory authorities. Conclusion: This review confirmed a general paucity of research in this area, particularly regarding the development and systematic application of techniques for evaluating quality decision making, with no consensus around a gold standard. This review has identified QoDoS as the most promising available technique for assessing decision making in the lifecycle of medicines and the next steps would be to further test its validity, sensitivity, and reliability.

Health Technology Assessment (HTA) Case Studies: Factors Influencing Divergent HTA Reimbursement Recommendations in Australia, Canada, England, and Scotland.

OBJECTIVES: To evaluate the national regulatory, health technology assessment (HTA), and reimbursement pathways for public health care in Australia, Canada, England, and Scotland, to compare initial Canadian national HTA recommendations with the initial decisions of the other HTA agencies, and to identify factors for differing national HTA recommendations between the four HTA agencies. METHODS: Information from the public domain was used to develop a regulatory process map for each jurisdiction and to compare the HTA agencies' reimbursement recommendations. Medicines that were reviewed by all four agencies and received a negative recommendation from only one agency were selected as case studies. RESULTS: All four countries have a national HTA agency. Their reimbursement recommendations are guided by both clinical efficacy and cost-effectiveness, and the necessity for patient input. Their activities, however, vary because of different mandates and their unique political, social, and population needs. All have an implicit or explicit quality-adjusted life-year threshold. The seven divergent case studies demonstrate examples in which new medicine-indication pairs have been rejected because of uncertainties surrounding a range of factors including cost-effectiveness, comparator choice, clinical benefit, safety, trial design, and submission timing. CONCLUSIONS: The four HTA agencies selected for inclusion in this study share common factors, including a focus on clinical efficacy and cost-effectiveness in their decision-making processes. The differences in recommendations could be considered to be due to an individual agency's approach to risk perception, and the comparator choice used in clinical and cost-effectiveness studies.

Evaluating alignment between Canadian Common Drug Review reimbursement recommendations and provincial drug plan listing decisions: an exploratory study.

BACKGROUND: The CADTH Common Drug Review was established in 2002 to prepare national health technology assessment reports to guide listing decisions for 18 participating drug plans. The aim of this study was to compare the nonmandatory recommendations from the Common Drug Review in Canada with the listing decisions of provincial payers to determine alignment. METHODS: We identified the recommendations issued by the Common Drug Review from Jan. 1, 2009, to Jan. 1, 2015, and compared these with the listing decisions of 3 provincial public payers (Alberta, British Columbia and Ontario) that participate in the Common Drug Review and the recommendations from Quebec. RESULTS: We identified 174 medicine-indication pairs in CADTH Common Drug Review reports issued from Jan. 1, 2009, to Jan. 1, 2015; 110 of these met the inclusion criterion. Among the 110 medicine-indication pairs, listing decisions were available for 95 in Alberta, 102 in Quebec, 104 in Ontario and 106 in BC. There was moderate to substantial agreement between provincial listing decisions and Common Drug Review recommendations: 74.5% (κ = 0.47, 95% confidence interval [CI] 0.31-0.64) for Quebec, 78.8% (κ = 0.56, 95% CI 0.41-0.72) for Ontario, 78.9% (κ = 0.58, 95% CI 0.42-0.74) for Alberta and 81.1% (κ = 0.62, 95% CI 0.47-0.77) for BC. INTERPRETATION: Our study showed moderate to substantial agreement between Common Drug Review recommendations and provincial listing decisions. Future studies can build on this research by evaluating the concordance between Common Drug Review recommendations and listing decisions of all participating federal, provincial and territorial drug plans.

Surviving an abdominal aortic aneurysm type II endoleak rupture without surgical intervention.

We describe a patient who survived a ruptured abdominal aortic aneurysm without any surgical intervention. The patient had previously had endovascular repair of the aneurysm and surveillance of a stable persistent type II endoleak. This case highlights the difficulties surrounding type II endoleak, its natural history, and the ongoing controversies of its management.

Evaluation of the Gulf Cooperation Council Centralized Procedure: The Way Forward.

The aim of the study was to evaluate the Gulf Cooperation Council (GCC) centralized regulatory review process. Regulatory review times-including submission and application dates for new active substances (NASs) and existing active substances (EASs) using a standardized template for the period of 2006 to 2010-were collected directly from the GCC office located in Riyadh, Saudi Arabia. A total of 413 products (96 NASs and 317 EASs) were approved during the period, with an overall significant increase in the EASs ( P < .001). The median approval times increased from 107 calendar days in 2006 to 265 in 2010 ( P < .001). The lowest approval time was for EASs submitted by the Gulf companies (134 days) and the longest for NASs submitted by international companies (346 days) ( P < .001). These data were also analyzed according to therapeutic classes and dosage forms. The results also showed that the lowest number (n = 16) approved during the period was in 2010, and this was due to a major regulatory change implementing the International Conference on Harmonisation product stability guideline for the region. The findings indicate that the delay and the wide range in approval times could be reduced by utilizing a standard assessment template for product review and the implementation of a clock stop system for company responses to questions from the GCC central registration committee. Furthermore, using information technology tools would speed up the registration process rather than the manual exchange of product registration files between the executive office and the member states.

Randomized, blinded study to assess the effect of povidone-iodine on the groin wound of patients undergoing primary varicose vein surgery.

BACKGROUND: The aim of this study was to assess the effect of povidone-iodine on the groin wounds of patients undergoing primary varicose vein surgery. METHODS: This is a prospective, randomized, blinded, controlled study on patients undergoing primary saphenofemoral ligation. Patients were randomized to a povidone-iodine (Betadine; Pfizer, West Ryde, Australia)-soaked surgical gauze placed in the open wound or a saline-soaked gauze placed in the wound. Patients were then followed up weekly for 6 weeks to observe for signs of wound infection. RESULTS: Sixty-eight legs in 49 patients were recruited. Thirty-seven groin wounds were randomized to saline and 32 to Betadine. There was a reduced incidence of groin wound infections in those randomized to Betadine (3 versus 1), but this was not statistically significant (P = 0.4). CONCLUSION: Although there may be a trend towards a lower wound infection rate when povidone-iodine is use in surgical wounds, this is not significant for varicose vein surgery.

Epithelioid hemangioma of the ulnar artery.

This case report describes a rare vascular tumor (epithelioid hemangioma) in the ulnar artery of a young male patient, treated by excision and bypass grafting.

Endovascular repair of ruptured abdominal aortic aneurysms in a rural center is both feasible and associated with reduced blood product requirements.

Endovascular aneurysm repair (EVAR) of ruptured abdominal aortic aneurysm (rAAA) has been shown to be both feasible and associated with a reduced operative mortality when compared with conventional open repair (OR). The aim of this study was to show the feasibility of EVAR of rAAA in a rural vascular unit and to investigate the blood product requirements when compared to OR. The method used in this study was a retrospective case note review of patients presenting with rAAA to a small, rural vascular unit between February 2004 and November 2008. Admission demographics and hematological variables were recorded. Volumes of crystalloid, colloid and blood products were recorded prior to intensive care unit (ICU) admission and for the first 48 hours following ICU admission. Results are expressed as medians and Mann-Whitney U test was used to compare variables. Of 81 patients presenting with rAAA, 36 were treated palliatively. Of 45 patients who underwent intervention, 7 had EVAR and all survived to discharge (0% operative mortality). Of 38 who had OR, 16 died before discharge for an operative mortality of 42%, 36% if the EVAR patients are included. Admission demographics and hematological variables of patients who had EVAR, patients who had OR and survived (ORS) and patients who had OR and died (ORD) showed no significant difference. When compared with ORS patients, those undergoing EVAR had significantly less pre-ICU crystalloid (3 L vs 7.5 L, p = .001), less red blood cell transfusion (1 unit vs 6.5 units, p = .0006), and less colloid (0 L vs 0.5 L, p = .008). When compared with ORD, those undergoing EVAR had less red blood cell transfusion (1 unit vs 7 units, p = .0001) and less fresh frozen plasma (0 units vs 4 units, p = .03). Within the first 48 hours of admission to ICU, the blood product requirements were no different in those undergoing EVAR when compared with OR. EVAR of rAAA is feasible in a small rural vascular unit and appears to be associated with reduced requirements for blood products.