Healthcare decision-making for tumour-agnostic therapies in Europe: lessons learned.

The tumour-agnostic authorisations of larotrectinib and entrectinib shifted the paradigm for indication setting. European healthcare decision-makers agreed on their therapeutic potential but diverged primarily in identified uncertainties concerning basket trial designs and endpoints, prognostic value of neurotrophic tropomyosin receptor kinase (NTRK) gene fusions, and resistance mechanisms. In addition, assessments of relevant comparators, unmet medical needs (UMNs), and implementation of NTRK-testing strategies diverged. In particular, the tumour-specific reimbursement recommendations and guidelines do not reflect tumour-agnostic thinking. These differences indicate difficulties experienced in these assessments and provide valuable lessons for future disruptive therapies. As we discuss here, early multistakeholder dialogues concerning minimum evidence requirements and involving clinicians are essential.

Added benefit and revenues of oncology drugs approved by the European Medicines Agency between 1995 and 2020: retrospective cohort study.

OBJECTIVES: To evaluate the added benefit and revenues of oncology drugs, explore their association, and investigate potential discrepancies between added benefit and revenues across different approval pathways of the European Medicines Agency (EMA). DESIGN: Retrospective cohort study. SETTING: Oncology drugs and their indications approved by the EMA between 1995 and 2020. MAIN OUTCOME MEASURES: Added benefit was evaluated using ratings published by seven organisations: health technology assessment agencies from the United States, France, Germany, and Italy, two medical oncology societies, and a drug bulletin. All retrieved ratings were recategorised using a four point ranking scale to indicate negative or non-quantifiable, minor, substantial, or major added benefit. Revenue data were extracted from publicly available financial reports and compared with published estimates of research and development (R&D) costs. Finally, the association between added benefit and revenue was evaluated. All analyses were performed within the overall study cohort, and within subgroups based on the EMA approval pathway: standard marketing authorisation, conditional marketing authorisation, and authorisation under exceptional circumstances. RESULTS: 131 oncology drugs with 166 indications were evaluated for their added benefit by at least one organisation within the required timeframe, yielding a total of 458 added benefit ratings; 189 (41%) were negative or non-quantifiable. The median time to offset the median R&D costs ($684m, £535m, €602m, adjusted to 2020 values) was three years; 50 of 55 (91%) drugs recovered these costs within eight years. Drugs with higher added benefit ratings generally had greater revenues. Negative or non-quantifiable added benefit ratings were more frequent for conditional marketing authorisations and authorisations under exceptional circumstances than for standard marketing authorisations (relative risk 1.53, 95% confidence interval 1.23 to 1.89). Conditional marketing authorisations generated lower revenues and took longer to offset R&D costs than standard marketing authorisations (four years compared with three years). CONCLUSIONS: While revenues seem to align with added benefit, most oncology drugs recover R&D costs within a few years despite providing little added benefit. This is particularly true for drugs approved through conditional marketing authorisations, which inherently appear to lack comprehensive evidence. Policy makers should evaluate whether current regulatory and reimbursement incentives effectively promote development of the most effective drugs for patients with the greatest needs.

Alignment in the registration, selection, procurement and reimbursement of essential medicines for childhood cancers in South Africa.

INTRODUCTION: The effectiveness of a health system in providing access to medicines is in part determined by the alignment of several core pharmaceutical processes. For South Africa's public health sector, these include the registration of medicines, selection and subsequent procurement through national tenders. Registration, selection and reimbursement are key processes in the private sector. This study assessed the alignment of forementioned processes for essential paediatric oncology medicines in South Africa. METHODS: A selection of priority chemotherapeutics, antiemetics and analgesics in the treatment of five prevalent childhood cancers in South Africa was compared with those listed in 1) the WHO Essential Medicines List for Children (WHO EMLc) 2021, 2) the registered health products database of South Africa, 3) the relevant South African National Essential Medicines Lists (NEML), 4) bid packs and awarded tenders for oncology medicines for 2020 and 2022 and 5) oncology formularies from the leading Independent Clinical Oncology Network (ICON) and two private sector medical aid schemes. Consistency between these sources was assessed descriptively. RESULTS: There was full alignment for 25 priority chemotherapeutics for children between the NEML, the products registered in South Africa and those included on tender. Due to unsuccessful procurement, access to seven chemotherapeutics was potentially constrained. For antiemetics and analgesics, eight of nine active ingredients included on the WHO EMLc were also registered in South Africa and on its NEML. An exploratory assessment of private sector formularies showed many gaps in ICON's formulary and two medical scheme formularies (listing 33% and 24% of the chemotherapeutics, respectively). CONCLUSION: Despite good alignment in public sector pharmaceutical processes, access constraints to essential chemotherapeutics for children may stem from unsuccessful tenders. Private sector formularies show major gaps; however, it is unclear how this translates to access in clinical practice.

Pre-approval and post-approval availability of evidence and clinical benefit of conditionally approved cancer drugs in Europe: A comparison with standard approved cancer drugs.

AIMS: Cancer drugs are increasingly approved through expedited regulatory pathways including the European conditional marketing authorization (CMA). Whether, when taking CMA post-approval confirmatory trials into account, the level of evidence and clinical benefit between CMA and standard approved (SMA) drugs differs remains unknown. METHODS: We identified all CMA cancer indications converted to SMA in 2006-2020 and compared these to similar SMA indications with regard to pivotal trial and CMA post-approval confirmatory trial design, outcomes and demonstrated clinical benefit (per the European Society for Medical Oncology Magnitude of Clinical Benefit Scale). We tested for differences in clinical benefit and whether substantial clinical benefit was demonstrated. To account for the clinical benefit of unconverted CMA indications, we performed sensitivity analyses. RESULTS: We included 15 SMA and 15 converted CMA cancer indications (17 remained unconverted). Approval of 11 SMA (73%) and four CMA indications (27%) was supported by a controlled trial. Improved overall survival (OS) was demonstrated for four SMA indications (27%). Improved quality of life (QoL) was demonstrated for three SMA (20%) and one CMA indication(s) (7%). Of subsequent CMA post-approval confirmatory trials, 11 were controlled (79%), one demonstrated improved OS (7%) and five improved QoL (36%). After conversion, CMA indications were associated with similar clinical benefit (P = .31) and substantial clinical benefit as SMA indications (risk ratio 1.4, 95% confidence interval 0.57-3.4). CONCLUSION: While CMA cancer indications are initially associated with less comprehensive evidence than SMA indications, levels of evidence and clinical benefit are similar after conversion from CMA to SMA.

Efficacy gap between phase II and subsequent phase III studies in oncology.

AIMS: There is a trend for more flexibility in timing of evidence generation in relation to marketing authorization, including the option to complete phase III trials after authorization or not at all. This paper investigated the relation between phase II and III clinical trial efficacy in oncology. METHODS: All oncology drugs approved by the European Medicines Agency (2007-2016) were included. Phase II and phase III trials were matched based on indication and treatment and patient characteristics. Reported objective response rates (ORR), median progression-free survival (PFS) and median overall survival (OS) were analysed through weighted mixed-effects regression with previous treatment, treatment regimen, blinding, randomization, marketing authorization type and cancer type as covariates. RESULTS: A total of 81 phase II-III matches were identified including 252 trials. Mean (standard deviation) weighted difference (phase III minus II) was -4.2% (17.4) for ORR, 2.1 (6.7) months for PFS and -0.3 (5.1) months for OS, indicating very small average differences between phases. Differences varied substantially between individual indications: from -46.6% to 47.3% for ORR, from -5.3 to 35.9 months for PFS and from -13.3 to 10.8 months for OS. All covariates except blinding were associated with differences in effect sizes for at least 1 outcome. CONCLUSIONS: The lack of marked average differences between phases may encourage decision-makers to regard the quality of design and total body of evidence instead of differentiating between phases of clinical development. The large variability emphasizes that replication of study findings remains essential to confirm efficacy of oncology drugs and discern variables associated with demonstrated effects.

Tenofovir-associated renal toxicity in a cohort of HIV infected patients in Ghana.

OBJECTIVE: Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue recommended in international HIV treatment guidelines. Purpose of this study was to estimate the long term effects of TDF on renal profile in a cohort of HIV patients in Ghana. Three hundred (300) consecutive HIV-positive patients who initiated TDF-based antiretroviral treatment in 2008 at the Korle-Bu Teaching Hospital were sampled. Creatinine clearance (CrCl) was calculated using the Cockcroft-Gault equation at baseline and renal impairment was defined as CrCl values of 30.0-49.9 mL/min (moderate renal impairment) and < 30 mL/min (severe renal impairment) as per institutional guidelines for renal function test. RESULTS: Median follow up time was 2.9 years (IQR 2.3-3.4 years). At study endpoint, 63 participants (21.0% [95% CI 6.5-26.1]) recorded CrCl rate below 50 mL/min indicating incident renal impairment, made up of 18.3% moderate renal impairment and 2.3% severe renal impairment. Factors associated with incidence of renal impairment were increasing age, decrease in creatinine clearance rate at baseline, WHO HIV stage III/IV and participants with BMI of < 18.5 kg/m2. Patients with identified renal impairment risk factors at ART initiation should be targeted and monitored effectively to prevent renal injury.

Disease awareness campaigns in printed and online media in Latvia: cross-sectional study on consistency with WHO ethical criteria for medicinal drug promotion and European standards.

BACKGROUND: European legislation prohibits direct-to-consumer advertising of prescription medicines, but allows drug manufacturers to provide information to the public on health and diseases. Our aim was to measure the frequency of disease awareness campaigns in Latvian media and assess their compliance with international and European standards. METHODS: Materials on health/disease and treatments were collected between April and September 2015 from 12 newspapers and magazines and six online portals. Disease awareness campaigns were assessed using a previously developed instrument based on the WHO Ethical Criteria for Medicinal Drug promotion and European standards (EU law and pharmaceutical industry self-regulatory guidelines). Collected materials were used to examine the information provided on medical conditions and their diagnosis and treatment. The inter-rater reliability was calculated. RESULTS: We collected 263 materials from print (n = 149) and online media (n = 114); 94 were news items and 169 were disease-awareness advertisements. Cancer, cardiovascular problems, allergies and respiratory diseases were common topics. Of the 157 campaigns assessed, non-compliance was identified in 149 cases (inter-rater reliability 90%), mainly due to misleading or incomplete information, lack of balance and the absence of a listed author/sponsor. Six disease awareness campaigns directly mentioned a pharmaceutical product by brand name and other four included the logo or name of a manufacturer, referred to a condition and indirectly mentioned a treatment, all in contravention with European law. CONCLUSIONS: The compliance of disease awareness campaigns in Latvian media with international and European standards is low. This raises concerns about the nature of information being conveyed. Through lack of balance, missing sponsorship information, and misleading or incomplete information, these campaigns could contribute to inaccurate self-diagnosis and generate demand among those who might not need medical treatment.

Barriers to access to opioid medicines for patients with opioid dependence: a review of legislation and regulations in eleven central and eastern European countries.

BACKGROUND AND AIMS: Barriers linked to drug control systems are considered to contribute to inequitable access to controlled medicines, leaving millions of people in pain and suffering. Most studies focus on access to opioids for the treatment of severe (cancer) pain. This study aims to identify specific access barriers for patients with opioid dependence in legislation and regulations of 11 central and eastern European countries. METHODS: This study builds on a previous analysis of legislation and regulations as part of the EU 7th Framework Access To Opioid Medication in Europe (ATOME) project. An in-depth analysis was undertaken to determine specific barriers for patients with opioid dependence in need of opioid analgesics or opioid agonist therapy (OAT). For each country, the number and nature of specific potential barriers for these patients were assessed according to eight categories: prescribing; dispensing; manufacturing; usage; trade and distribution; affordability; penalties; and other. An additional keyword search was conducted to minimize the omission of barriers. Barriers in an additional category, language, were recorded qualitatively. Countries included Bulgaria, Cyprus, Estonia, Greece, Hungary, Latvia, Lithuania, Serbia, Slovakia, Slovenia and Turkey. RESULTS: Ten of the 11 countries (all except Estonia) showed specific potential barriers in their legislation and regulations. The total number of barriers varied from two (Slovenia) to 46 (Lithuania); the number of categories varied from one (Slovenia) to five (Lithuania). Most specific potential barriers were shown in the categories 'prescribing', 'usage' and 'other'. The total number in a single category varied from one to 18 (Lithuania, prescribing). Individual differences between countries in the same specific potential barrier were shown; for example, variation in minimum age criteria for admission to OAT ranging from 15 (Lithuania, in special cases) to 20 years (Greece). All countries had stigmatizing language in their legislation. CONCLUSIONS: Patients with opioid dependence are likely to experience specific barriers to accessing opioids in addition to those experienced by other non-dependent patients.

Barriers to access to opioid medicines: a review of national legislation and regulations of 11 central and eastern European countries.

Control measures designed to prevent the misuse of opioid medicines can often unintentionally restrict legitimate medical use, leaving patients with cancer in pain. This study aimed to develop and validate an assessment instrument based on WHO policy guidelines to systematically identify legal and regulatory barriers to opioid access in 11 European countries (Bulgaria, Cyprus, Estonia, Greece, Hungary, Latvia, Lithuania, Serbia, Slovakia, Slovenia, and Turkey) as part of the Access to Opioid Medication in Europe project. Relevant legislation and regulations were independently assessed by three reviewers and potential barriers were identified within nine categories including prescribing, penalties, and others. Potential barriers were identified in all countries, ranging from 22 potential barriers (Cyprus) to 128 potential barriers (Lithuania). The total number of barriers in a single category varied from one (Slovenia, usage category) to 49 (Greece, prescribing category). Differences, such as prescription validity, varied within one category, ranging from 5 days (Hungary) to 13 weeks (Cyprus). The results of this Review should give rise to a national review and revision of provisions that impede access to opioids, disproportionate to their (intended) benefit in preventing misuse, in these 11 European countries.

Increasing trends in the incidence and prevalence rates of type 1 diabetes among children and adolescents in the Netherlands.

OBJECTIVE: To assess the trends in the incidence and prevalence rates of type 1 diabetes (T1D) among children and adolescents in the Netherlands. METHODS: A population-based cohort study was conducted in the Dutch PHARMO record linkage system (1998-2011). All children and adolescents aged ≤19 yr with at least one insulin dispensing (as a proxy for T1D) were identified and the numbers of incident and prevalent cases (numerators) were calculated. Overall age-adjusted (0-19 yr) incidence and prevalence rates together with age- and sex-specific rates of T1D and their 95% confidence intervals (CI) were calculated using data from the Dutch Central Bureau of Statistics as denominator. Trends over time were assessed using Joinpoint regression software (National Cancer Institute, Bethesda, MD, USA). RESULTS: In 2011, the overall age-adjusted incidence and prevalence rates of T1D were 25.2/100 000 (95% CI, 23.7-26.8) person-years (PY) and 174.4/100 000 (95% CI, 170.2-178.5) children, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence and prevalence rate was 3.7% (95% CI, 1.8-5.7) and 3.8% (95% CI, 2.4-5.2), respectively. While during the study period the largest increases in the incidence and prevalence rates of T1D were observed for the oldest age groups (10-14 and 15-19 yr), a decreasing trend was detected for the 0- to 4-yr-old category (with AAPCs of -1.8 (95% CI, -9.9 to 7.1) and -6.9% (95% CI, -11.5 to -2.1) for incidence and prevalence, respectively). CONCLUSION: Age-adjusted incidence (1999-2011) and prevalence rates (1998-2011) of T1D in Dutch children (aged 0-19 yr) continued to increase and a shift was observed to a later onset of the disease.

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.

Chronic comorbidities in children with type 1 diabetes: a population-based cohort study.

OBJECTIVE: To determine the incidence of chronic comorbidities among children with type 1 diabetes (T1D) and to compare incidences with a group of children without diabetes. DESIGN: Population-based cohort study. SETTING: Dutch PHARMO database (1998-2010). PATIENTS: All patients (<19 years old) with T1D between 1999 and 2009 (T1D cohort) and a group of age- and sex-matched (ratio: 1-4) children without diabetes (reference cohort). MAIN OUTCOME MEASURE: The incidence of nine common chronic comorbidities was assessed on the basis that they were treated pharmacologically and/or resulted in hospital admission. Cox proportional hazard analysis was used to estimate the strength of the association between T1D and comorbidities, expressed as HRs and 95% CIs. RESULTS: A total of 915 patients with T1D and 3590 children in the reference cohort (51% boys, mean age of 10.1 (SD 4.5) years) were included. T1D was associated with an increased risk (HR; 95% CI) of hospitalisation for any comorbidity (3.7; 2.5 to 5.5), thyroid disease (14.2; 6.7 to 31.0), non-infectious enteritis and colitis (5.9; 3.0 to 11.5), cardiovascular disorders (3.1; 2.3 to 4.2), mental disorders (2.0; 1.4 to 3.1), epilepsy (2.0; 1.1 to 3.7) and (obstructive) pulmonary disease (1.5; 1.2 to 2.0). There was no significant difference in the incidences of other comorbidities (malignant disorders, anaemia and migraine) between the two cohorts. CONCLUSIONS: Our longitudinal study showed that incidences of six chronic diseases were significantly higher in T1D children during the early years of developing this disease compared with the reference children.

Pediatric drug formulations: a review of challenges and progress.

Children differ from adults in many aspects of pharmacotherapy, including capabilities for drug administration, medicine-related toxicity, and taste preferences. It is essential that pediatric medicines are formulated to best suit a child's age, size, physiologic condition, and treatment requirements. To ensure adequate treatment of all children, different routes of administration, dosage forms, and strengths may be required. Many existing formulations are not suitable for children, which often leads to off-label and unlicensed use of adult medicines. New regulations, additional funding opportunities, and innovative collaborative research initiatives have resulted in some recent progress in the development of pediatric formulations. These advances include a paradigm shift toward oral solid formulations and a focus on novel preparations, including flexible, dispersible, and multiparticulate oral solid dosage forms. Such developments have enabled greater dose flexibility, easier administration, and better acceptance of drug formulations in children. However, new pediatric formulations address only a small part of all therapeutic needs in children; moreover, they are not always available. Five key issues need to be addressed to stimulate the further development of better medicines for children: (1) the continued prioritization of unmet formulation needs, particularly drug delivery in neonates and treatment gaps in pediatric cancers and childhood diseases in developing countries; (2) a better use of existing data to facilitate pediatric formulation development; (3) innovative technologies in adults that can be used to develop new pediatric formulations; (4) clinical feedback and practice-based evidence on the impact of novel formulations; and (5) improved access to new pediatric formulations.

Legal barriers in accessing opioid medicines: results of the ATOME quick scan of national legislation of eastern European countries.

CONTEXT: Overregulation of controlled medicines is one of the factors contributing to limited access to opioid medicines. OBJECTIVES: The purpose of this study was to identify legal barriers to access to opioid medicines in 12 Eastern European countries participating in the Access to Opioid Medication in Europa project, using a quick scan method. METHODS: A quick scan method to identify legal barriers was developed focusing on eight different categories of barriers. Key experts in 12 European countries were requested to send relevant legislation. Legislation was quick scanned using World Health Organization guidelines. Overly restrictive provisions and provisions that contain stigmatizing language and incorrect definitions were identified. The selected provisions were scored into two categories: 1) barrier and 2) uncertain, and reviewed by two authors. A barrier was recorded if both authors agreed the selected provision to be a barrier (Category 1). RESULTS: National legislation was obtained from 11 of 12 countries. All 11 countries showed legal barriers in the areas of prescribing (most frequently observed barrier). Ten countries showed barriers in the areas of dispensing and showed stigmatizing language and incorrect use of definitions in their legislation. Most barriers were identified in the legislation of Bulgaria, Greece, Lithuania, Serbia, and Slovenia. The Cypriot legislation showed the fewest total number of barriers. CONCLUSION: The selected countries have in common as main barriers prescribing and dispensing restrictions, the use of stigmatizing language, and incorrect use of definitions. The practical impact of these barriers identified using a quick scan method needs to be validated by other means.

Measures of biosimilarity in monoclonal antibodies in oncology: the case of bevacizumab.

Biosimilars have been available on the European market since 2006 and experience with their use is increasing. The next wave of biopharmaceuticals that are about to lose patent protection consists of more-complicated products, including many monoclonal antibodies. Guidance has been released on the particulars of a biosimilarity exercise involving these products. Considerable challenges exist to establish biosimilarity for anticancer products. An especially challenging product is bevacizumab (Avastin(®)). On the basis of data available for the innovator product (bevacizumab) we will discuss strengths and weaknesses of preclinical and clinical models and explore the application of novel endpoints to the biosimilar comparability exercise.

Incidence of adverse events among healthcare workers following H1N1 Mass immunization in Ghana: a prospective study.

BACKGROUND: Cases of the A(H1N1) 2009 influenza were first recorded in Ghana in July 2009. In June 2010 when prioritized vaccination against the novel A(H1N1) 2009 influenza virus started in the country, health workers were among the selected groups to receive the vaccination. OBJECTIVE: The aim of this study was to determine the distribution and types of adverse events reported following immunization of healthcare workers at the Korle-Bu Teaching Hospital from the day vaccination started until 1 week after the end of vaccination. METHODS: Safety data collected during the A(H1N1) 2009 influenza vaccination of health workers at the Korle-Bu Teaching Hospital (Accra, Ghana) were used for this study. All workers aged 18 years and over were eligible for vaccination. For uniformity, 0.5 mL of Pandemrix(®) (equivalent to 3.75 µg of hemagglutinin antigen) was administered intramuscularly into the deltoid muscle of the left arm. Each vaccinee was issued with a card and was advised to report any adverse events following immunization (AEFI) to designated health workers for follow-up. Incidence rates of adverse events were estimated and compared with the Pandemrix(®) Summary of Product Characteristics (SPC) RESULTS: A total of 5870 people (64.9 % females) with a mean age of 34.0 years were vaccinated. In total, 140 vaccinees reported adverse events. The mean age among vaccinees reporting adverse events was 36.1 years. The overall incidence of vaccinees reporting adverse events and the overall incidence of adverse events was 232 (95 % CI 199-320) per 10,000 people and 930 (95 % CI 820-1070) per 10,000 people, respectively. In particular, we found no difference in the way males reported AEFI compared with females (Chi-squared [χ(2)] = 0.59; p > 0.2), and we did not find any association between age as a categorical variable and vaccine adverse event reporting (χ(2) = 5.24; p > 0.1). There were only three serious cases that led to hospitalization. All three cases occurred within 24 hours of receiving the vaccine. The incidence rates for the various reported events were all lower compared with those in the Pandemrix(®) SPC, but while injection-site pain was the most frequent in the SPC and other foreign studies, we recorded headache as the most frequent. Even fatigue, muscle/joint aches and fever had higher incidence rates compared with injection-site pain. Tachycardia (n = 6), tinnitus (n = 1) and decreased appetite (n = 4) were reported although were not included in the SPC. CONCLUSION: The most prominent adverse events reported were headaches, dizziness, muscle and joint aches, weakness, fever and injection-site pain. Although similar events were reported in other studies, the incidence was different and there were a few differences in the most frequently reported events. More studies of a similar nature should be encouraged in low- and medium-income countries to bridge the information gap with the developed world.

Differences between post-authorization adverse drug reactions of biopharmaceuticals and small molecules.

BACKGROUND: The nature of adverse drug reactions observed post-authorization for biopharmaceuticals differs from that observed for chemically synthesized, small molecules (SMs). However, it remains unclear how much of the observed differences can be attributed to differences in authorized indications of the two product groups. OBJECTIVE: To investigate if the nature of adverse drug reactions identified post-authorization for biopharmaceuticals differs from those of SMs within the same anatomical therapeutic chemical (ATC) group. METHODS: We analyzed safety issues included in post-authorization, changes to the Summary of Product Characteristics of centrally approved products in the European Union classified in the ATC main group of 'antineoplastic and immunomodulating agents'. Generics and biosimilars were excluded. All issues identified during 2004-2011 were analyzed for differences in nature and timing between biopharmaceutical and SM products, at different ATC levels. RESULTS: A total of 747 adverse drug reactions were identified; 361 for biopharmaceuticals and 386 for SMs. Within the sub group of immunosuppressants, neoplasms (20 % vs 2 %, p < 0.01) and infections and infestations (22 % vs 9 %, p < 0.01) occurred significantly more frequent for biopharmaceuticals. Adverse drug reactions of SMs were more often renal and urinary disorders (7 % vs 0 %, p < 0.01), blood and lymphatic system disorders (10 % vs 3 %, p = 0.04), and vascular disorders (7 % vs 1 %, p = 0.02). In the subgroup of antineoplastics, immune system disorders occurred more frequently for biopharmaceuticals, (6 % vs 1 %, p = 0.04). With the exception of immune system disorders and renal disorders, the overall differences between biopharmaceuticals and SMs were mostly caused by products authorized as immunosuppressants. For the subset of products authorized after 2004, the median time to the first safety issue was 18 months (95 % CI 12.4-21.5) for biopharmaceuticals and 17 months (95 % CI 12.5-21.5) for SMs and did not differ significantly within subgroups. CONCLUSION: Even within a group of medicinal products approved in the same indication, differences were observed in the nature of adverse drug reactions between biopharmaceuticals and SMs. The considerable differences in the nature of adverse drug reactions between biopharmaceuticals and SMs were not associated with differences in the timing of regulatory actions.

Rituximab-induced thrombocytopenia: a cohort study.

The combined information of drug exposure and laboratory test results on an individual patient level obtained in daily clinical practice can add important information about the safety of a drug. Thrombocytopenia is a known adverse drug reaction of rituximab, which has already been identified during the preregistration trials, but knowledge on incidence and risk factors in clinical practice is limited. We, therefore, aimed to estimate the incidence and explore the risk factors for the development of rituximab-induced thrombocytopenia (a platelet count, <100 × 10(9) platelets/L) in clinical practice. Ninety patients were eligible for inclusion of which 27 developed thrombocytopenia (cumulative incidence, 30%) within 30 days after administration of rituximab and 18 patients developed grade 3/4 thrombocytopenia (cumulative incidence, 20%). Patients with and without thrombocytopenia were compared to explore risk factors. Patients with a relatively low platelet count (217 vs. 324 × 10(9) /L, P = 0.011) before administration of rituximab had a higher risk for the development of thrombocytopenia, and although not statistically significant, patients treated with rituximab within the oncology setting (OR, 4.7; 95% CI, 1.0-23.3), independent of concomitant use of cytostatics, as compared to the autoimmune diseases and patients with a high platelet distribution width (PDW) (16.1 vs. 15.8, P = 0.051). In conclusion, the incidence of rituximab-induced thrombocytopenia was higher than that identified during the clinical trials. Healthcare professionals should consider thrombocytopenia as a relevant reaction during treatment with rituximab. More frequent monitoring of the platelet count is especially advised in patients treated in the oncology indication and/or with a low platelet count and high PDW.

A cohort study exploring determinants of safety-related regulatory actions for biopharmaceuticals.

BACKGROUND: The characteristics of biopharmaceuticals may require a tailored approach to their safety management. However, information on what tools and methods are employed to assess the safety of biopharmaceuticals post-authorization is lacking. OBJECTIVE: This study investigates determinants that contribute to the post-authorization management of biopharmaceuticals. METHODS: A cohort study was performed including all centrally approved biopharmaceuticals for which a Direct Healthcare Professional Communication (DHPC) was issued during 1997-2009. Safety-related regulatory actions were defined as updates of the summary of product characteristics through type II variations. Determinants of these actions were identified based on publicly available data. Urgent variations, defined as variations accompanied by a DHPC, were compared with other, 'non-urgent', safety-related variations. RESULTS: We identified 133 variations relating to 15 products, 24 urgent and 109 other variations. For 55% of urgent variations, spontaneous reports were the sole source of regulatory action, post-approval studies accounted for 33%, and 12% were based on other sources or combinations of sources. For the non-urgent variations, spontaneous reports were the sole source for 36%, post-approval studies for 28%, and 36% were based on other sources or combinations. Overall, most variations included safety issues categorized as 'infections and infestations' (33.1%), 'general disorders and administration site conditions' (25.6%), and 'neoplasms' (14.3%). CONCLUSION: Determinants of urgent and non-urgent safety-related regulatory actions of biopharmaceuticals are largely similar. Spontaneous reports are an important pillar for both urgent and non-urgent actions and remain an important tool in the post-authorization safety management of biopharmaceuticals.