Outer packaging labelling of medicines in Southern African Development Community (SADC) countries: comparative analysis of requirements and transition terms for harmonisation.

INTRODUCTION: The COVID-19 pandemic highlighted an urgent need for harmonised requirements for the regulation of medicines. To fully implement harmonised medicines regulations across Africa, common technical standards of medicine regulations are needed. One such technical standard is the labelling of medicines on outer packaging. In this study, we compared outer packaging labelling requirements and transition terms for harmonization for countries in the Southern African Development Community (SADC) region. METHODS: Data on legislation and/or regulatory guidelines for medicine outer packaging labelling from National Medicines Regulatory Authorities (NMRAs) were obtained for countries in the SADC region (n = 16) by February 2023. A detailed comparative content analysis was conducted to determine alignment with the requirements of the Southern African Development Community (SADC) harmonised labelling guidelines to assess readiness levels of each country to transition to the SADC harmonised labelling guideline for outer packaging of medicines. RESULTS: Content analysis showed at least 11 out of 16 countries require national legal reform to transition to the SADC harmonised labelling guideline. In all cases where countries specified labelling requirements for outer packaging of medicines, these were stipulated in national medicines legislation. CONCLUSION: Even though there is a high level of alignment across the countries in terms of national labelling requirements, most countries in the SADC region would still require national legislative reform to transition to regional harmonised labelling requirements and then ultimately to continental requirements of the African Medicines Agency (AMA).

Pharmaceutical Scientists' Perspectives on Capacity Building in Pharmaceutical Sciences.

With the anticipated health challenges brought by demographic and technological changes, ensuring capacity in underlying workforce in place is essential for addressing patients' needs. Therefore, a timely identification of important drivers facilitating capacity building is important for strategic decisions and workforce planning. In 2020, internationally renowned pharmaceutical scientists (N = 92), largely from the academia and pharmaceutical industry, with mostly pharmacy and pharmaceutical sciences educational background were approached (through a questionnaire) for their considerations on influencing drivers to facilitate meeting current capacity in pharmaceutical sciences research. From a global view, based on the results of the questionnaire, the top drivers were better alignment with patient needs as well as strengthening education - both through continuous learning and deeper specialisation. The study also showed that capacity building is more than simply increasing the influx of graduates. Pharmaceutical sciences are being influenced by other disciplines, and we can expect more diversity in scientific background and training. Capacity building of pharmaceutical scientists should allow flexibility for rapid change driven by the clinic and need for specialised science and it should be underpinned by lifelong learning.

Unmet Medical Need as a Driver for Pharmaceutical Sciences - A Survey Among Scientists.

Historical antecedents of pharmaceutical sciences are sound on product orientation based on (analytical) chemistry, drug delivery and basic pharmacology. Over the last decades we have seen a transition towards a stronger disease orientation. This raises questions on whether, how and to what extent unmet medical need (UMN) is important in priority setting, funding and impact in pharmaceutical sciences. An online survey in 2020 collected perspectives of internationally recognised pharmaceutical scientists (N = 92), mainly from academia and industry, on drivers and influencing factors in pharmaceutical sciences. The study offers a unique global perspective, demonstrating a solid command of the global needs in pharmaceutical sciences. The survey revealed that UMN is currently seen as one of the three most important drivers, also in addition to emerging trends in science and opportunities driven by collaboration. There are expectations that UMN's impact becomes more influential. This was consistent for both industry and academic respondents. The majority of respondents also indicated that anticipated lessons learned from COVID-19 will strengthen the impact of UMN on science and leadership. This is important as prioritisation of research towards UMN can address the clinical needs where needed the most.

Linking market authorizations of medicines with disease burden in South Africa.

BACKGROUND: Sub-Saharan Africa is going through an epidemiological transition, including an impressive increase in non-communicable diseases. The introduction of medicines has not kept pace with the needs in developing countries. The objectives of this study were to (i) examine the correlation between the number of medicine approvals and disease burden and (ii) compare approval timelines of medicines with disease burden in South Africa in the period 2012-2017. METHODS: The dataset was compiled from publicly available data on medicines registered in South Africa between 2012 and 2017. A correlation analysis was conducted to determine the level of alignment between the number and nature of medicines registered, as determined by the WHO ATC Classification and the Lancet Global Burden of Disease data. Median registration timelines were determined to assess whether medicines for diseases of higher burden were registered faster. RESULTS: A total of 3059 registered medicines were included in the study, including 2779 generic medicines, 267 new chemical entities and 13 vaccines. There was a high level of alignment between the number of medicines registered to treat diseases with higher disease burden levels more effectively, except for lower respiratory tract infections and HIV/AIDS which showed less medicines registered as compared to expectations based on disease burden, respectively. HIV/AIDS showed a lower level of correlation with a much higher disease burden compared to number of medicines registered, but simultaneously also a much shorter median registration timeline (32 months) compared to the other disease areas. CONCLUSIONS: There was generally a high level of alignment between disease burden and number of medicines authorised, except for HIV/AIDS and lower respiratory tract infections. Regulatory authorities should continue to consider burden of disease data to ensure that public health needs are met.

Access to medicines in Turkey: Evaluation of the process of medicines brought from abroad.

OBJECTIVE: Turkey's health reforms started in 2003 with providing changes in regulatory, financing, and healthcare services. Access to health care and pharmaceuticals increased rapidly, and this resulted with an increase in public pharmaceutical expenditures. Our study aims to quantify and to evaluate the impact of a specific process within the Turkish system called "Medicines Brought From Abroad" (MBFA). METHODS: We reviewed the general reimbursement legislations of Social Security Institution (SSI), the guideline on MBFA, the SSI reimbursement list, the list of MBFA published by the Ministry of Health to describe the current supply mechanism of medicines and, in particular, the role of MBFA. RESULTS: Total costs of the of MBFA medicines over the period 2011-17 went up to more than $520 million, which takes 7.5 percent of total public pharmaceutical expenditure for 2017. Our results showed that MBFA provides access to many orphan drugs and in total, forty-two orphan drugs listed in MBFA accounted for 83 percent of all MBFA budget in the year 2017. Nine of the top ten MBFA medicines were orphan drugs and total costs were $408 million. The highest budget impact was for eculizumab for "paroxysmal nocturnal hemoglobinuria" (PNH), covering 31 percent of total MBFA costs and 2.3 percent of overall drug costs in 2017. CONCLUSIONS: Turkey faced significant challenges for creating an access pathway for innovative medicines while continuing the sustainability of the public pharmaceutical budget like many other countries. Therefore, it may be argued that Turkey needs to create an independent health technology assessment organization to provide sustainable access to medicines in the future.

Adverse events related to biologicals used for patients with multiple sclerosis: a comparison between information originating from regulators and information originating from the scientific community.

BACKGROUND AND PURPOSE: Clinical decision making is facilitated by healthcare professionals' and patients' adequate knowledge of the adverse events. This is especially important for biologicals used for treating multiple sclerosis (MS). So far, little is known about whether different information sources report adverse events consistently. METHODS: Biologicals authorized by the European Medicines Agency for the treatment of MS were included in this study. Information on adverse events derived from phase 3 clinical trials from European Public Assessment Reports (EPARs) and from scientific publications was compared. RESULTS: In the study, eight biologicals used for the treatment of MS were included for which the EPAR and/or scientific publication reported a total of 707 adverse events. Approximately one-third of the adverse events was reported in both the EPAR and scientific publication, one-third was only reported in the EPAR and one-third only in the scientific publication. Serious adverse events and adverse events that regulators classified as 'important identified risk' were significantly more often reported in both sources compared to adverse events not classified as such (respectively, 38% vs. 30% and 49% vs. 30%). Adverse events only reported in the EPAR or in the scientific publication were, in general, not described in the benefit-risk section or abstract, which were considered to be the most important sections of the documents. CONCLUSIONS: This study showed that there is substantial discordance in the reporting of adverse events on the same phase 3 trials between EPARs and scientific publications. To support optimal clinical decision making, both documents should be considered.

The EU regulatory landscape of non-biological complex drugs (NBCDs) follow-on products: Observations and recommendations.

"Non-biological complex drugs" (NBCDs), such as liposomal formulations, iron-carbohydrate complexes and glatiramoids, gained increased interest from a regulatory perspective in recent years. Similar to biologics, the quality of NBCD products is highly dependent on a robust and well-controlled manufacturing process. This provides challenges for generic drug developers to replicate NBCD products once market exclusivity of the originator product is expired. However, unlike biologics for which a consistent regulatory framework was established with the biosimilars pathway, NBCDs are not recognised as a distinct category of medicines and hence no formal regulatory pathway for their approval is defined. Currently, a "case-by-case" approach is applied for regulating NBCD follow-on products in the EU. Furthermore, NBCDs can follow a non-centralised authorisation procedure, leaving regulatory approvals to national competent authorities. This can lead to heterogeneity in the regulatory approach and outcomes when assessing NBCD follow-on products throughout the EU, which for some product classes has already resulted in some safety and efficacy implications. Here, we explore the regulatory landscape of NBCDs and their follow on products. This study shows that almost all of the 85 NBCD follow-on products available in the EU in 2018 have been approved via various non-centralised procedures. Although most NBCD follow-on products followed an Article 10(1) procedure, we clearly see a recent increase of the use of the hybrid pathway via Article 10(3). This study shows the heterogeneity in the regulatory approach taken for many NBCD follow on products. To what extent this may have consequences for their safety and efficacy evaluations is unknown and needs to be further investigated. The present study should stimulate the rethinking to design prudent regulatory pathways for NBCD follow-on products.

The use of real-world data in cancer drug development.

Excitement about the dramatic increase in potential successful anticancer medicines in recent years is hampered by the high costs involved as well as the length of time traditional pathways take for regulatory approval. The translation of experimental clinical data into real-world evidence is also problematic. While the randomised controlled trial remains the gold standard for assessing efficacy and safety, there is increasing interest in the use of observational data to enable more rapid, informed and widespread availability and access to important anticancer medicines. Taking real-world evidence into account in regulatory and health technology assessment in a thoughtful and balanced fashion will enrich and justify sound decision-making.

Selection of essential medicines for the prevention and treatment of cardiovascular diseases in low and middle income countries.

BACKGROUND: The incidence and mortality of cardiovascular diseases (CVDs) in low and middle income countries (LMICs) have been increasing, while access to CVDs medicines is suboptimal. We assessed selection of essential medicines for the prevention and treatment of CVDs on national essential medicines lists (NEMLs) of LMICs and potential determinants for selection. METHODS: Only operational NEMLs were considered eligible for this study. A selection of medicines listed under "cardiovascular medicines" or "blood products and plasma substitutes" in the NEMLs were included if they were present on international guidelines for the prevention and treatment of CVDs (hyperlipidemia, hypertension, platelet inhibition, ischemic stroke, stable ischemic heart disease, acute coronary syndromes, heart failure, atrial fibrillation, peripheral arterial disease and acute limb ischemia). The number and diversity of essential medicines selected for CVDs were studied. Moreover, determinants of selection of essential medicines for CVDs at a national level were explored. Data analysis was done using univariate linear regression and non-parametric tests. RESULTS: All medicine groups listed by the international guidelines were selected by the majority of the 34 countries studied with the exception of adenosine diphosphate receptor inhibitors which appeared on less than half of the NEMLs studied (41% of countries). The total number of essential medicines for the prevention and treatment of cardiovascular diseases (median 24 (range 16-50)) differed significantly across income levels (median range: 19.5-25, p = 0.014) and across regions (median range: 20-32, p = 0.049). When recommendations of the international guidelines were considered, over 75% of the NEMLs contained essential medicines for the majority of CVDs. CONCLUSION: The main medicine classes for the management of CVDs were represented on NEMLs. Consequently, for the majority of CVDs, evidence-based guideline-recommended treatment is possible as far as selection of essential medicines is concerned. Selection will therefore not be the limiting step in access to medicines for cardiovascular diseases.

A decade of marketing approval of gene and cell-based therapies in the United States, European Union and Japan: An evaluation of regulatory decision-making.

There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management. Product characteristics are very heterogeneous and only three products are marketed in multiple jurisdictions. Almost half of all approved GCTs received an orphan designation. Overall, confirmatory evidence or indications of clinical benefit were evident in US and EU applications, whereas in Japan approval was solely granted based on non-confirmatory evidence. Due to scientific uncertainties and safety risks, substantial post-marketing risk management activities were requested in the EU and Japan. EU and Japanese authorities often took unmet medical needs into consideration in decision-making for approval. These observations underline the effects of implemented legislation in these two jurisdictions that facilitate an adaptive approach to licensing. In the US, the recent assessments of two chimeric antigen receptor-T cell (CAR-T) products are suggestive of a trend toward a more permissive approach for GCT approval under recent reforms, in contrast to a more binary decision-making approach for previous approvals. It indicates that all three regulatory agencies are currently willing to take risks by approving GCTs with scientific uncertainties and safety risks, urging them to pay accurate attention to post-marketing risk management.

Safety Experience During Real-World Use of Injectable Artesunate in Public Health Facilities in Ghana and Uganda: Outcomes of a Modified Cohort Event Monitoring Study (CEMISA).

INTRODUCTION: Injectable artesunate (Inj AS) is the World Health Organization (WHO)-recommended product for treating severe malaria. However, despite widespread usage, there are few published safety studies involving large populations in real-world settings. In this study, we sought to assess the incidence of common adverse events (AEs) following the intake of Inj AS in real-life settings. METHODS: This is a modified cohort event monitoring study involving patients who were administered with Inj AS at eight sites (four each in Ghana and Uganda) between May and December 2016. Patients were eligible for inclusion if they had severe/complicated malaria and were able and willing to participate in the study. Eligible patients were followed up by telephone or hospital or home visit on Days 7, 14, 21 and 28 after drug administration to document AEs and serious AEs (SAEs). Patients were also encouraged to report all AEs at any time during the study period. The Kaplan-Meier method was used to estimate the proportion of patients with any AEs by end of Day 28. Causality assessment was made on all AEs/SAEs using the WHO/UMC (Uppsala Monitoring Centre) causality method. RESULTS: A total of 1103 eligible patients were administered Inj AS, of which 360 patients were in Ghana and 743 in Uganda. The incidence of any AE by the end of follow-up among patients treated with AS was estimated to be 17.9% (197/1103) (95% confidence interval [CI] 15.8-20.3). The median time-to-onset of any AEs was 9 days (interquartile range (IQR) = 4, 14). The top five AEs recorded among patients treated with AS were pyrexia (3.5%), abdominal pain (2.5%), diarrhoea (1.7%), cough (1.5%) and asthenia (1.5%). Most of these top five AEs occurred in the first 14 days following treatment. Regarding the relatedness of these AEs to Inj AS, 78.9% of pyrexia (30/38), 63.0% of pain (17/27), 68.4% of diarrhoea (13/19), 85.5% of cough (14/16) and 75.0% of asthenia (12/16) were assessed as 'possibly' related. There were 17 SAEs including 13 deaths. Two of the deaths are 'possibly' related to Inj AS, as were three non-fatal SAEs: severe abdominal pain, failure of therapy and severe anaemia. CONCLUSION: The incidence of common AEs among patients treated with Inj AS in real-world settings was found to be relatively low. Future studies should consider larger cohorts to document rare AEs as well. CLINICALTRIALS. GOV IDENTIFIER: NCT02817919.

Variability in market uptake of psychotropic medications in Europe reflects cultural diversity.

BACKGROUND: In the last 20-30 years, many international studies have found substantial differences in the use of (older) psychotropic medication between European countries. The majority mentioned an important role for attitudes and beliefs towards psychotropic medication. So far, no studies have looked into the effects of cultural diversity on the use of new medications entering the market. As national cultures relate deeply to held values regarding, for example, what is seen as effective versus ineffective or safe versus dangerous, (cultural) diversity in decision making around the role of new medications in clinical practice may already be expected from the first day after market authorization. METHODS: This study examined the relation between cultural diversity, described in Hofstede's model of cultural dimensions (Power Distance, Individualism, Masculinity, Uncertainty Avoidance, Indulgence and Long-Term Orientation) and utilization of three new psychotropic medications, namely aripiprazole, duloxetine and pregabalin in Europe. Country level sales data of the case study medications were correlated to country-specific scores of Hofstede's cultural dimensions. IMS Health's MIDAS database has been used for sales data (converted to Defined Daily Doses/1000 inhabitants/day) for the case study medications from the market authorization date in 2004 until December 2009 for 23 EU member states. RESULTS: Consumption of the case study medications was seen in all countries. In general, pregabalin was used more often than aripiprazole and duloxetine. In 2 years after market authorization, approximately 80% of all countries have reported use of all three molecules. Correlations between Hofstede dimensions individualism, long-term orientation and indulgence and total use of the case study medications tended to become stronger over time, but they were only statistically significant for indulgence at two years after market authorization (rho = 0.51, p = 0.014) and three years after market authorization (rho = 0.54, p = 0.008). A more detailed analysis showed (slight) variation by molecule. CONCLUSIONS: This study is a first step in including cultural dimensions when explaining cross-national variation in the use of new medications. The results indicate that indulgence, however marginally, is a cultural aspect that relates to the utilization of new psychotropic medications, suggesting that within the cultural context, less regulation of social norms is a main factor in explaining cross-national variation in uptake of these medications.

[Non-publication is common among phase 1, single-center, not prospectively registered, or early terminated clinical drug trials]. / Hoeveel klinische geneesmiddelenstudies worden uiteindelijk gepubliceerd?

The objective of this study was to investigate the occurrence and determinants of non-publication of clinical drug trials in the Netherlands. All clinical drug trials reviewed by the 28 Institutional Review Boards (IRBs) in the Netherlands in 2007 were followed-up from approval to publication. Candidate determinants were the sponsor, phase, applicant, centers, therapeutic effect expected, type of trial, approval status of the drug(s), drug type, participant category, oncology or other disease area, prospective registration, and early termination. The main outcome was publication as peer reviewed article. The percentage of trials that were published, crude and adjusted odds ratio (OR), and 95% confidence interval (CI) were used to quantify the associations between determinants and publication. In 2007, 622 clinical drug trials were reviewed by IRBs in the Netherlands. By the end of follow-up, 19 of these were rejected by the IRB, another 19 never started inclusion, and 10 were still running. Of the 574 trials remaining in the analysis, 334 (58%) were published as peer-reviewed article. The multivariable logistic regression model identified the following determinants with a robust, statistically significant association with publication: phase 2 (60% published; adjusted OR 2.6, 95% CI 1.1-5.9), phase 3 (73% published; adjusted OR 4.1, 95% CI 1.7-10.0), and trials not belonging to phase 1-4 (60% published; adjusted OR 3.2, 95% CI 1.5 to 6.5) compared to phase 1 trials (35% published); trials with a company or investigator as applicant (63% published) compared to trials with a Contract Research Organization (CRO) as applicant (50% published; adjusted OR 1.7; 95% CI 1.1-2.8); and multicenter trials also conducted in other EU countries (68% published; adjusted OR 2.2, 95% CI 1.1-4.4) or also outside the European Union (72% published; adjusted OR 2.0, 95% CI 1.0-4.0) compared to single-center trials (45% published). Trials that were not prospectively registered (48% published) had a lower likelihood of publication compared to prospectively registered trials (75% published; adjusted OR 0.5, 95% CI 0.3-0.8), as well as trials that were terminated early (33% published) compared to trials that were completed as planned (64% published; adjusted OR 0.2, 95% CI 0.1-0.3). The non-publication rate of clinical trials seems to have improved compared to previous inception cohorts, but is still far from optimal, in particular among phase 1, single-center, not prospectively registered, and early terminated trials.

Renal function of MDR-TB patients treated with kanamycin regimens or concomitantly with antiretroviral agents.

SETTING: To compare renal insufficiency among multidrug-resistant tuberculosis (MDR-TB) patients treated with kanamycin (KM) based regimens and those treated concomitantly with tenofovir disoproxil fumarate (TDF) or other antiretroviral therapy (ART) regimens in Namibia. DESIGN: Retrospective review of the treatment records and laboratory tests of patients initiated on MDR-TB treatment (January-December 2014). The glomerular filtration rates (eGFR) estimated pre- and post-treatment were compared using the analysis of variance test. Renal insufficiency was defined as an eGFR of <60 ml/min/1.73 m2. Use of KM or TDF and association with renal insufficiency was assessed using Kaplan-Meier plots and Cox proportional hazards analysis. RESULTS: The baseline mean eGFR for the three groups was similar (P = 0.24): 139.3 ± 25.6 ml/min for the KM group (n = 68), 131.1 ± 25.7 ml/min for the KM+TDF group (n = 44) and 134.2±34.4 ml/min for the KM+Other group (n = 23). After 8 months, the values had declined significantly to respectively 104.8 ± 37.5 ml/min (P < 0.001), 101.5 ± 38.3 ml/min (P < 0.001) and 111.5 ± 41.7 ml/min (P = 0.01). Co-treatment with KM+ART was associated with an increased risk of renal insufficiency (hazard ratio [HR] 1.8, 95%CI 0.7-4.1, P = 0.20 for KM+TDF, and HR 3.5, 95%CI 1.4-8.2, P = 0.005 for KM+Other ART). CONCLUSION: Renal function declined at a similar rate in MDR-TB patients treated with KM-based regimens compared with patients treated concomitantly with TDF-based or other ART. The risk of renal insufficiency was greater for patients on ART.

[Immunogenicity of biosimilars]. / Immunogeniciteit van biosimilars.

Biosimilars of more complex recombinant protein drugs, such as monoclonal antibodies and fusion proteins, are entering the market. The manufacturer should demonstrate that its product does not show any relevant differences in terms of quality characteristics, biological activity, safety and efficacy compared to the reference product, as outlined in EMA guidelines. This should be established with an extensive comparability exercise. One aspect that is subject to particular scrutiny is the immunogenicity of the biosimilar and the reference medicinal product. For three cases, one etanercept and two infliximab biosimilars, we describe how data are assessed and an opinion is reached by authorities. Not in all cases unanimity exists whether all remaining uncertainties on biosimilarity have been resolved satisfactorily before marketing authorisation. The Dutch Medicines Evaluation Board therefore emphasises that even after marketing authorisation, biosimilars and other biologicals should be properly monitored.

Risk of vertebral and non-vertebral fractures in patients with sarcoidosis: a population-based cohort.

UNLABELLED: In this retrospective cohort study using the Clinical Practice Research Datalink (CPRD), patients with sarcoidosis have an increased risk of clinical vertebral fractures and when on recent treatment with oral glucocorticoids, also an increased risk of any fractures and osteoporotic fractures. INTRODUCTION: Sarcoidosis is a chronic inflammatory disease, in which fragility fractures have been reported despite normal BMD. The aim of this study was to assess whether patients with sarcoidosis have an increased risk of clinical fractures compared to the general population. METHODS: A retrospective cohort study was conducted using the CPRD. All patients with a CPRD code for sarcoidosis between January 1987 and September 2012 were included. Cox proportional hazards models were used to derive adjusted relative risks (RRs) of fractures in all sarcoidosis patients compared to matched controls, and within the sarcoidosis group according to use and dose of systemic glucocorticoids. RESULTS: Five thousand seven hundred twenty-two sarcoidosis patients (mean age 48.0 years, 51 % females, mean follow-up 6.7 years) were identified. Compared to 28,704 matched controls, the risk of any fracture was not different in patients with sarcoidosis. However, the risk of clinical vertebral fractures was significantly increased (adj RR 1.77; 95 % CI 1.06-2.96) and the risk of non-vertebral fractures was decreased although marginally significant (adj RR 0.87; 95 % CI 0.77-0.99). Compared to sarcoidosis patients not taking glucocorticoids, recent use of systemic glucocorticoids was associated with an increased risk of any fracture (adj RR 1.50; 95 % CI 1.20-1.89) and of an osteoporotic fracture (adj RR 1.47; 95 % CI 1.07-2.02). CONCLUSIONS: Patients with sarcoidosis have an increased risk of clinical vertebral fractures, and when using glucocorticoid therapy, an increased risk of any fractures and osteoporotic fractures. In contrast, the risk of non-vertebral fractures maybe decreased. Further investigation is needed to understand the underlying mechanisms of these contrasting effects on fracture risk.

Use of incretin agents and risk of pancreatic cancer: a population-based cohort study.

AIM: To investigate the association between the use of incretin agents and the risk of pancreatic cancer. METHODS: A retrospective population-based cohort study, using data from the Clinical Practice Research Datalink, 2007-2012, was conducted. Patients (n = 182 428) with at least one non-insulin antidiabetic drug (NIAD) prescription and aged ≥18 years during data collection, were matched one-to-one to control patients without diabetes. Multivariable Cox proportional hazards models and a new user design were used to estimate the hazard ratio (HR) of pancreatic cancer in incretin users (n = 28 370) compared with control subjects without diabetes and other NIAD-treated patients. Time-dependent adjustments were made for age, sex, lifestyle, comorbidities and drug use. RESULTS: The mean duration of follow-up was 4.1 years for incretin users. Current NIAD use was associated with a fourfold increased risk of pancreatic cancer [HR 4.28, 95% confidence interval (CI) 3.49-5.24]. This risk was almost doubled among current incretin users as compared with control subjects. Incretin use was not associated with pancreatic cancer when compared with control subjects with diabetes (HR 1.36, 95% CI 0.94-1.96); however, the 'new user' design did show an association between incretin use and pancreatic cancer when compared with control subjects with diabetes. In both cohorts with prevalent and incident users of antidiabetic drugs, the risk of pancreatic cancer almost doubled in those who had recently initiated incretin therapy (up to seven prescriptions), whereas this elevated risk dropped to baseline levels with prolonged use. CONCLUSIONS: We found that incretin use was not associated with pancreatic cancer after adjustment for the severity of the underlying Type 2 Diabetes Mellitus (T2DM). The elevated risk of pancreatic cancer in those recently initiating incretin agents is likely to be caused by protopathic bias or other types of unknown distortion. The presence of considerable confounding by disease severity and the lack of a duration-of-use relationship do not support a causal explanation for the association between incretin agents and pancreatic cancer.

Drug-induced progressive multifocal leukoencephalopathy: Lessons learned from contrasting natalizumab and rituximab.

Progressive multifocal leukoencephalopathy (PML) has been identified as a serious adverse drug reaction (ADR) of several immunomodulatory biologicals. In this study, we contrasted the reporting patterns of PML for two biologicals for which the risk was identified at different points in their lifecycle: natalizumab (before reapproval) and rituximab (nine years postapproval). We found that, apart from the differences in clinical characteristics (age, gender, indication, time to event, fatality), which reflect the diversity in context of use, PML reports for natalizumab were more complete and were received sooner after occurrence. This study serves as an important reminder that spontaneous reports should only be used with great caution to quantify and compare safety profiles across products over time. The observed variability in reporting patterns and heterogeneity of PML cases presents challenges to such comparisons. Lumping uncharacterized PML reports together without taking these differences into account may result in biased comparisons and flawed conclusions about differential safety.

Does conditional approval for new oncology drugs in Europe lead to differences in health technology assessment decisions?

An early access pathway of conditional approval for potentially beneficial medicines is available within the European regulatory framework. However, marketing authorization does not necessarily result in recommendations for public funding by health technology assessment (HTA) agencies. As conditional approval goes along with less than complete data on benefits and risks of a treatment option for a high medical need, this raises the question how HTA decision-making is affected by these uncertainties.

Essential medicines for breast cancer in low and middle income countries.

BACKGROUND: Breast cancer is the most common type of cancer among women worldwide. In low and middle-income countries (LMICs), appropriate selection of medicines on national essential medicines lists (NEMLs) is a first step towards adequate access to treatment. We studied selection of systemic treatments for breast cancer on NEMLs and assessed its alignment with treatment guidelines for different types of early and advanced breast cancer. Furthermore, influence of country characteristics on the selection was investigated. METHOD: NEMLs from 75 LMICs were studied for inclusion of all components of therapy in each stage of breast cancer according to international consensus guidelines. The results were then grouped by income level, WHO region and the NEMLs' release date. Non parametric tests were used for statistical analysis. RESULTS: Unlike HER2-targeted therapies (<10%), aromatase inhibitors (12%) and taxanes (28%); tamoxifen and first generation chemotherapeutic regimens (e.g., anthracycline-based regimens) were frequently found in the NEMLs (71-78%). Consequently, all components of treatment for "Luminal A" early breast cancer and non HER2 overexpressed advanced breast cancer were found on the NEMLs of over 70% of countries. However, 40% of the low income countries did not have all the components of therapy for any type of early breast cancer in their NEMLs, and adequate treatment of HER2 overexpressed breast cancer was hardly possible with the current selections. Recent NEMLs were more aligned with the guidelines (p < 0.05). Eastern Mediterranean and African regions less frequently incorporated all components of breast cancer treatment in their NEMLs. CONCLUSION: Alignment of selection with guidelines' recommendations was inconsistent for different types of early and advanced breast cancer in NEMLs. Regular updates and more attention to clinical guidelines is therefore recommended.