Uptake of orphan drugs in the WHO essential medicines lists.

Objective: We evaluated the uptake of medicines licensed as orphan drugs by the United States Food and Drug Administration (FDA) or European Medicines Agency (EMA) into the WHO Model list of essential medicines and the WHO Model list of essential medicines for children from 1977 to 2021. Methods: We collated and analysed data on drug characteristics, reasons for adding or rejecting medicines, and time between regulatory approval and inclusion in the lists. We compared trends in listing orphan drugs before and after revisions to the inclusion criteria of the essential medicines lists in 2001, as well as differences in trends for listing orphan and non-orphan drugs, respectively. Findings: The proportion of orphan drugs in the essential medicines lists increased from 1.9% (4/208) in 1977 to 14.6% (70/478) in 2021. While orphan drugs for communicable diseases have remained stable over time, we observed a considerable shift towards more orphan drugs for noncommunicable diseases, particularly for cancer. The median period for inclusion in the essential medicines lists after either FDA or EMA first approval was 13.5 years (range: 1-28 years). Limited clinical evidence base and uncertainty about the magnitude of net benefit were the most frequent reasons to reject proposals to add new orphan drugs to the essential medicines lists. Conclusion: Despite lack of a global definition of rare diseases, the essential medicines lists have broadened their scope to include medicines for rare conditions. However, the high costs of many listed orphan drugs pose accessibility and reimbursement challenges in resource-constrained settings.

Mapping the risk of infections in patients with multiple sclerosis: A multi-database study in the United Kingdom Clinical Practice Research Datalink GOLD and Aurum.

BACKGROUND: People with multiple sclerosis (pwMS) have an increased risk of infections; risk factors include underlying disease, physical impairment and use of some disease-modifying treatments. OBJECTIVE: To quantify changes in population-level infection rates among pwMS and compare these to the general population and people with rheumatoid arthritis (pwRA), and identify patient characteristics predictive of infections after MS diagnosis. METHODS: We conducted a multi-database study using data on 23,226 people with MS diagnosis from the UK Clinical Practice Research Datalink Aurum and GOLD (January 2000-December 2020). PwMS were matched to MS-free controls and pwRA. We calculated infection rates, and estimated incidence rate ratios (IRR) and 95% confidence intervals (CI) of predictors for infections ⩽ 5 years after MS diagnosis using Poisson regression. RESULTS: Among pwMS, overall infection rates remained stable - 1.51-fold (1.49-1.52) that in MS-free controls and 0.87-fold (0.86-0.88) that in pwRA - although urinary tract infection rate per 1000 person-years increased from 98.7 (96.1-101) (2000-2010) to 136 (134-138) (2011-2020). Recent infection before MS diagnosis was most predictive of infections (1 infection: IRR 1.92 (1.86-1.97); ⩾2 infections: IRR 3.00 (2.89-3.10)). CONCLUSION: The population-level elevated risk of infection among pwMS has remained stable despite the introduction of disease-modifying treatments.

The Role of Regulator-Imposed Post-Approval Studies in Health Technology Assessments for Conditionally Approved Drugs.

BACKGROUND: The European Medicines Agency (EMA) aims to resolve uncertainties associated with conditionally approved drugs by imposing post-approval studies. Results from these studies may be relevant for health technology assessment (HTA) organizations. This study investigated the role of regulator-imposed post-approval studies within HTA. METHODS: For all conditionally approved drugs up to December 2018, regulator-imposed post-approval studies were identified from EMA's public assessment reports. The availability for and inclusion of study results in relative effectiveness (re)assessments were analyzed for 4 European HTA organizations: NICE (National Institute for Health and Care Excellence, England/Wales), HAS (Haute Autorité de Santé, France), ZIN (Zorginstituut Nederland, the Netherlands) and the European Network for Health Technology Assessment (EUnetHTA, Europe). When study results became available between an HTA organization's initial assessment and reassessment, it was evaluated whether and how they affected the assessment and its outcome. RESULTS: For 36 conditionally approved drugs, 98 post-approval studies were imposed. In total, 81 initial relative effectiveness assessments (REAs) and 13 reassessments were available, with numbers of drugs (re)assessed varying greatly between jurisdictions. Study results were available for 16 initial REAs (20%) and included in 14 (88%), and available for 10 reassessments (77%) and included in all (100%). Five reassessments had an outcome different from the initial REA, with 4 (2 positive and 2 negative changes) relating directly to the new study results. Reassessments often cited the inability of post-approval studies to resolve the concerns reported in the initial REA. CONCLUSION: Results from regulator-imposed post-approval studies for conditionally approved drugs were not often used in REAs by HTA organizations, because they were often not yet available at the time of initial assessment and because reassessments were scarce. When available, results from post-approval studies were almost always used within HTA, and they have led to changes in conclusions about drugs' relative effectiveness. Post-approval studies can be relevant within HTA but the current lack of alignment between regulators and HTA organizations limits their potential.

Access to oxytocin and misoprostol for management of postpartum haemorrhage in Kenya, Uganda and Zambia: a cross-sectional assessment of availability, prices and affordability.

OBJECTIVE: To assess access (availability and affordability) to oxytocin and misoprostol at health facilities in Kenya, Uganda and Zambia to improve prevention and management of postpartum haemorrhage (PPH). DESIGN: The assessment was undertaken using data from Health Action International (HAI) research on sexual and reproductive health commodities based on a cross-sectional design adapted from the standardised WHO/HAI methodology. SETTING: Data were collected from 376 health facilities in in Kenya, Uganda and Zambia in July and August 2017. OUTCOME MEASURES: Availability was calculated as mean percentage of sampled medicine outlets where medicine was found on the day of data collection. Medicine prices were compared with international reference prices (IRP) and expressed as median price ratios. Affordability was calculated using number of days required to pay for a standard treatment based on the daily income of the lowest paid government worker. RESULTS: Availability of either oxytocin or misoprostol at health facilities was high; 81% in Kenya, 82% in Uganda and 76% in Zambia. Oxytocin was more available than misoprostol, and it was most available in the public sector in the three countries. Availability of misoprostol was highest in the public sector in Uganda (88%). Oxytocin and misoprostol were purchased by patients at prices above IRP, but both medicines cost less than a day's wages and were therefore affordable. Availability of misoprostol was poor in rural settings where it would be more preferred due to lack of trained personnel and cold storage facilities required for oxytocin. CONCLUSION: Availability and affordability of either oxytocin or misoprostol at health facilities met the WHO benchmark of 80%. However, countries with limited resources should explore mechanisms to optimise management of PPH by improving access to misoprostol especially in rural areas.

Application of Managed Entry Agreements for Innovative Therapies in Different Settings and Combinations: A Feasibility Analysis.

The reimbursement of expensive, innovative therapies poses a challenge to healthcare systems. This study investigated the feasibility of managed entry agreements (MEAs) for innovative therapies in different settings and combinations. First, a systematic literature review included studies describing used or conceptual agreements between payers and manufacturers (i.e., MEAs). Identical and similar MEAs were clustered and data were extracted on their benefits and limitations. A feasibility assessment was performed for each individual MEA based on how it could be applied (financial/outcome-based), on what level (individual patients/target population), in which payment setting (centralized pricing and reimbursement authority yes/no), for what type of therapies (one-time/chronic), within what payment structures, and whether combinations with other MEAs were feasible. The literature search ultimately included 82 papers describing 117 MEAs. After clustering, 15 unique MEAs remained, each describing one or multiple similar agreements. Four of those entailed payment structures, while eleven entailed agreements between payers and manufacturers regarding price, usage, and/or evidence generation. The feasibility assessment indicated that most agreements could be applied throughout the different settings that were assessed and could be applied in different payment structures and in combination with multiple other agreements. The potential to combine multiple agreements leads to a multitude of different reimbursement mechanisms that may manage the price, usage, payment structure, and additional conditions for an innovative therapy. This overview of the feasibility of combinations of MEAs can help decision-makers construct a reimbursement mechanism most suited to their preferences, the type of therapy under evaluation, and the applicable healthcare system.

Are Further Interventions Needed to Prevent and Manage Hospital-Acquired Hyponatraemia? A Nationwide Cross-Sectional Survey of IV Fluid Prescribing Practices.

BACKGROUND: Hyponatraemia is associated with increased morbidity, increased mortality and is frequently hospital-acquired due to inappropriate administration of hypotonic fluids. Despite several attempts to minimise the risk, knowledge is lacking as to whether inappropriate prescribing practice continues to be a concern. METHODS: A cross-sectional survey was performed in Danish emergency department physicians in spring 2019. Prescribing practices were assessed by means of four clinical scenarios commonly encountered in the emergency department. Thirteen multiple-choice questions were used to measure knowledge. RESULTS: 201 physicians responded corresponding to 55.4% of the total population of physicians working at emergency departments in Denmark. About a quarter reported that they would use hypotonic fluids in patients with increased intracranial pressure and 29.4% would use hypotonic maintenance fluids in children, both of which are against guideline recommendations. Also, 29.4% selected the correct fluid, a 3% hypertonic saline solution, for a patient with hyponatraemia and severe neurological symptoms, which is a medical emergency. Most physicians were unaware of the impact of hypotonic fluids on plasma sodium in acutely ill patients. CONCLUSION: Inappropriate prescribing practices and limited knowledge of a large number of physicians calls for further interventions to minimise the risk of hospital-acquired hyponatraemia.

Publication rates and reported results in a cohort of gene- and cell-based therapy trials.

Aim: We investigated publication rates and reported results for gene- and cell-based therapy trials. Materials & methods: In a cohort of Institutional Review Board (IRB)-authorized trials during 2007-2017 in the Netherlands (n = 105), we examine publication rates and reported results in scientific papers and conference abstracts as well as associations with the occurrence of trial characteristics. Results: The publication rate for scientific papers was 27% and 17% for conference abstracts (median survival time: 1050 days). Academic hospitals published more in scientific papers whereas private sponsors published more in conference abstracts. Manufacturing protocols were underreported compared with clinical outcomes. Most publications reported positive results (78%). Conclusion: Publication rates are currently suboptimal indicating a need for enhanced knowledge sharing to stimulate gene- and cell-based therapy development.

Identification of potentially inappropriate medications with risk of major adverse cardiac and cerebrovascular events among elderly patients in ambulatory setting and long-term care facilities.

PURPOSE: Cardiovascular diseases (CVDs) are extremely common among the elderly, but information on the use of potentially inappropriate medications (PIMs) with cardiovascular risk is scarce. We aimed to determine the prevalence of PIMs with risk of cardiac and cerebrovascular adverse events (CCVAEs), including major adverse cardiac and cerebrovascular events (MACCE). PATIENTS AND METHODS: A cross-sectional study was performed using a convenience sample from four long-term care facilities and one community pharmacy in Portugal. Patients were included if they were aged 65 or older and presented at least one type of medication in their medical and pharmacotherapeutic records from 2015 until December 2017. The main outcome was defined as the presence of PIMs with risk of MACCE and was assessed by applying a PIM-MACCE list that was developed from a previous study. All medications included in this list were assessed for their availability in Portugal. RESULTS: A total of 680 patients were included. Of those, 428 (63%) were female with a mean age of 78.4±8.1 years. Four-hundred and four (59.4%) patients were taking medications associated with CCVAEs risk (mean =1.7±1.0 drugs/patient), including 264 patients (38.8%) who used drugs with MACCE risk (mean =1.4±0.8 drugs/patient). Fifty percent of patients with a previous history of CVD (n=521) were taking PIMs with risk of CCVAEs, including 30.0% with risk of MACCE. CONCLUSION: Our findings show that 50% of patients with previous history of CVD were taking drugs with risk of CCAVEs and 30% with risk of MACCE. More tailored tools for the management of drug therapy in elderly patients with CVD are of major importance in clinical practice.

Learning from patients: Identifying design features of medicines that cause medication use problems.

Usability is a key factor in ensuring safe and efficacious use of medicines. However, several studies showed that people experience a variety of problems using their medicines. The purpose of this study was to identify design features of oral medicines that cause use problems among older patients in daily practice. A qualitative study with semi-structured interviews on the experiences of older people with the use of their medicines was performed (n=59). Information on practical problems, strategies to overcome these problems and the medicines' design features that caused these problems were collected. The practical problems and management strategies were categorised into 'use difficulties' and 'use errors'. A total of 158 use problems were identified, of which 45 were categorized as use difficulties and 113 as use error. Design features that contributed the most to the occurrence of use difficulties were the dimensions and surface texture of the dosage form (29.6% and 18.5%, respectively). Design features that contributed the most to the occurrence of use errors were the push-through force of blisters (22.1%) and tamper evident packaging (12.1%). These findings will help developers of medicinal products to proactively address potential usability issues with their medicines.

Adverse events and patients' perceived health-related quality of life at the end of multidrug-resistant tuberculosis treatment in Namibia.

PURPOSE: The health-related quality of life (HRQoL) of patients completing multidrug-resistant tuberculosis (MDR-TB) treatment in Namibia and whether the occurrence of adverse events influenced patients' rating of their HRQoL was evaluated. PATIENTS AND METHODS: A cross-sectional analytic survey of patients completing or who recently completed MDR-TB treatment was conducted. The patients rated their HRQoL using the simplified Short Form-™ (SF-8) questionnaire consisting of eight Likert-type questions. Three supplemental questions on the adverse events that the patients may have experienced during their MDR-TB treatment were also included. Scoring of HRQoL ratings was norm-based (mean =50, standard deviation =10) ranging from 20 (worst health) to 80 (best health), rather than the conventional 0-100 scores. We evaluated the internal consistency of the scale items using the Cronbach's alpha, performed descriptive analyses, and analyzed the association between the patients' HRQoL scores and adverse events. RESULTS: Overall, 36 patients (20 males, 56%) aged 17-54 years (median =40 years) responded to the questionnaire. The median (range) HRQoL score for the physical component summary was 58.6 (35.3-60.5), while the median score for the mental component summary was 59.3 (26.6-61.9), indicating not-so-high self-rating of health. There was good internal consistency of the scale scores, with a Cronbach's alpha value of >0.80. In all, 32 (89%) of the 36 patients experienced at least one adverse drug event of any severity during their treatment (median events =3, range 1-6), of which none was life-threatening. The occurrence of adverse events was not related to HRQoL scores. For patients reporting zero to two events, the median (range) HRQoL score was 56.8 (44.4-56.8), while for those reporting three or more events, the median score was 55.2 (38.6-56.8); P=0.34 for difference between these scores. CONCLUSION: Patients completing treatment for MDR-TB in Namibia tended to score moderately low on their HRQoL, using the generic SF-8 questionnaire. The occurrence of adverse events did not lead to lower HRQoL scores upon treatment completion.

National medicines policies - a review of the evolution and development processes.

OBJECTIVES: Continuous provision of appropriate medicines of assured quality, in adequate quantities, and at reasonable prices is a concern for all national governments. A national medicines policy (NMP) developed in a collaborative fashion identifies strategies needed to meet these objectives and provides a comprehensive framework to develop all components of a national pharmaceutical sector. To meet the health needs of the population, there is a general need for medicine policies based on universal principles, but nevertheless adapted to the national situation. This review aims to provide a quantitative and qualitative (describing the historical development) study of the development process and evolution of NMPs. METHODS: The number of NMPs and their current status has been obtained from the results of the assessment of WHO Level I indicators. The policy formulation process is examined in more detail with case studies from four countries: Sri Lanka, Australia, former Yugoslav Republic of Macedonia and South Africa. RESULTS: The number of NMPs worldwide has increased in the last 25 years with the highest proportional increase in the last 5-10 years in high-income countries. Higher income countries seem to have more NMP implementation plans available and have updated their NMP more recently. The four case studies show that the development of a NMP is a complex process that is country specific. In addition, it demonstrates that an appropriate political window is needed for the policy to be passed (for South Africa and the FYR Macedonia, a major political event acted as a trigger for initiating the policy development). Policy-making does not stop with the official adoption of a policy but should create mechanisms for implementation and monitoring. The NMPs of the FYR Macedonia and Australia provide indicators for monitoring. CONCLUSIONS: To date, not all countries have a NMP since political pressure by national experts or non-governmental organizations is generally needed to establish a NMP. Case studies in four countries showed that the policy process is just as important as the policy document since the process must create a mechanism by which all stakeholders are brought together and a sense of collective ownership of the final policy may be achieved.

Testing bias in clinical databases: methodological considerations.

BACKGROUND: Laboratory testing in clinical practice is never a random process. In this study we evaluated testing bias for neutrophil counts in clinical practice by using results from requested and non-requested hematological blood tests. METHODS: This study was conducted using data from the Utrecht Patient Oriented Database. This clinical database is unique, as it contains physician requested data, but also data that are not requested by the physician, but measured as result of requesting other hematological parameters. We identified adult patients, hospitalized in 2005 with at least two blood tests during admission, where requests for general blood profiles and specifically for neutrophil counts were contrasted in scenario analyses. Possible effect modifiers were diagnosis and glucocorticoid use. RESULTS: A total of 567 patients with requested neutrophil counts and 1,439 patients with non-requested neutrophil counts were analyzed. The absolute neutrophil count at admission differed with a mean of 7.4 x 109/l for requested counts and 8.3 x 109/l for non-requested counts (p-value < 0.001). This difference could be explained for 83.2% by the occurrence of cardiovascular disease as underlying disease and for 4.5% by glucocorticoid use. CONCLUSION: Requests for neutrophil counts in clinical databases are associated with underlying disease and with cardiovascular disease in particular. The results from our study show the importance of evaluating testing bias in epidemiological studies obtaining data from clinical databases.

Medication changes prior to hospitalization for obstructive lung disease: a case-crossover study.

BACKGROUND: Hospitalizations have always been seen as a solid outcome parameter in pharmacoepidemiology. However, the period leading to hospitalization and prehospital management of the patient are equally important. OBJECTIVE: To evaluate medication changes in the period prior to hospitalization for obstructive lung disease and to quantify the association between medication use and the risk of hospitalization. METHODS: We conducted a case-crossover study using the PHARMO record linkage system, which contains drug dispensing data from community pharmacies and hospital admission data. Patients included in the study were adults hospitalized for obstructive lung disease between 2005 and 2007. The index date of the case period was the date of hospitalization, and control moments were set at 3, 6, 9, and 12 months before admission. For each patient, all prescriptions prior to the date of hospitalization were identified. Medication use was ascertained in a 90-day time window prior to each case or control moment. RESULTS: We identified 1481 patients who were hospitalized for obstructive lung disease. It appeared that respiratory medication use increased in the 90 days prior to hospitalization. Hospitalization was associated with the use of 3 or more respiratory drugs (OR 2.2; 95% CI 1.8 to 2.8), systemic glucocorticoids (OR 4.5; 95% CI 3.8 to 5.4), and antibiotics (OR 3.1; 95% CI 2.7 to 3.6). CONCLUSIONS: The use of systemic glucocorticoids, antibiotics, and other respiratory drugs increased prior to hospitalization for obstructive lung disease. These results could be indicative of the development and/or treatment of an exacerbation. There is a need for markers to detect exacerbations in an early phase in order to start treatment as early as possible and possibly prevent hospitalizations for obstructive lung disease.

Towards equitable access to medicines for the rural poor: analyses of insurance claims reveal rural pharmacy initiative triggers price competition in Kyrgyzstan.

BACKGROUND: A rural pharmacy initiative (RPI) designed to increase access to medicines in rural Kyrgyzstan created a network of 12 pharmacies using a revolving drug fund mechanism in 12 villages where no pharmacies previously existed. The objective of this study was to determine if the establishment of the RPI resulted in the unforeseen benefit of triggering medicine price competition in pre-existing (non-RPI) private pharmacies located in the region. METHODS: We conducted descriptive and multivariate analyses on medicine insurance claims data from Kyrgyzstan's Mandatory Health Insurance Fund for the Jumgal District of Naryn Province from October 2003 to December 2007. We compared average quarterly medicine prices in competitor pharmacies before and after the introduction of the rural pharmacy initiative in October 2004 to determine the RPI impact on price competition. RESULTS: Descriptive analyses suggest competitors reacted to RPI prices for 21 of 30 (70%) medicines. Competitor medicine prices from the quarter before RPI introduction to the end of the study period decreased for 17 of 30 (57%) medicines, increased for 4 of 30 (13%) medicines, and remained unchanged for 9 of 30 (30%) medicines. Among the 9 competitor medicines with unchanged prices, five initially decreased in price but later reverted back to baseline prices. Multivariate analyses on 19 medicines that met sample size criteria confirm these findings. Fourteen of these 19 (74%) competitor medicines changed significantly in price from the quarter before RPI introduction to the quarter after RPI introduction, with 9 of 19 (47%) decreasing in price and 5 of 19 (26%) increasing in price. CONCLUSIONS: The RPI served as a market driver, spurring competition in medicine prices in competitor pharmacies, even when they were located in different villages. Initiatives designed to increase equitable access to medicines in rural regions of developing and transitional countries should consider the potential to leverage medicine price competition as a means of achieving their goal. Evaluations of interventions to increase rural access to medicines should include impact assessment on both formal and informal pharmaceutical markets.

Difference in risks of allergic reaction to sulfonamide drugs based on chemical structure.

BACKGROUND: The chemical structure of sulfonamide antibiotics and sulfonamide nonantibiotics can affect the potential for adverse reactions. OBJECTIVE: To assess whether differences in chemical structure of the various sulfonamide drugs influence the risk of allergic events. METHODS: A case-control study was conducted among patients with diabetes mellitus (DM) using data from the General Practice Research Database. Cases were defined as patients with a diagnosis of hypersensitivity or allergic reaction. The date of the last event was the index date. Controls were matched on practice, type of DM, and index date. Current use of sulfonamides was defined as use in a 14 day time window before the index date. Sulfonamides were classified according to the presence/absence of an N1 substituent (N1(+)/(-)) and/or an arylamine (N4(+)/(-)). Conditional logistic regression was used to estimate strength of association and expressed as odds ratios and 95% confidence intervals. RESULTS: Overall, current use of N1(+) N4(+) sulfonamide drugs was associated with the outcome (adjusted OR 3.71; 95% CI 1.40 to 9.81). Current use of N1(+) N4(-) and N1(-) N4(-) sulfonamide drugs was also associated with the occurrence of allergic reactions, although not as strongly: adjusted OR 2.48 (95% CI 2.12 to 2.89) and 2.07 (95% CI 1.74 to 2.46), respectively. Sex and age seemed to be effect modifiers. There was no clear evidence for effect modification by immune disease state. CONCLUSIONS: Although we did not identify major differences between the groups, we believe that this approach is an innovative manner to examine adverse drug reactions by using chemical structure instead of therapeutic drug classes to classify exposure.