The challenges of access to innovative medicines with limited evidence in the European Union.

The European Medicines Agency (EMA) fosters access to innovative medicines through accelerated procedures and flexibility in the authorization requirements for diseases with unmet medical needs, such as many rare diseases as well as oncological diseases. However, the resulting increase of medicines being marketed with conditional authorizations and in exceptional circumstances has lead to higher clinical uncertainty about their efficacy and safety than when the standard authorizations are applied. This uncertainty has significant implications for clinical practice and the negotiation of pricing and reimbursement, particularly as high prices are based on assumptions of high value, supported by regulatory prioritization. The burden of clinical development is often shifted towards public healthcare systems, resulting in increased spending budgets and opportunity costs. Effective management of uncertainty, through appropriate testing and evaluation, and fair reflection of costs and risks in prices, is crucial. However, it is important not to sacrifice essential elements of evidence-based healthcare for the sake of access to new treatments. Balancing sensitive and rational access to new treatments, ensuring their safety, efficacy, and affordability to healthcare systems requires thoughtful decision-making. Ultimately, a responsible approach to timely access to innovative medicines that balances the needs of patients with healthcare systems' concerns is necessary. This approach emphasizes the importance of evidence-based decision-making and fair pricing and reimbursement.

Unknown adverse drug reactions from spontaneous reports in a hospital setting: characterization, follow-up, and contribution to the pharmacovigilance system.

Introduction: Post-marketing identification and report of unknown adverse drug reactions (ADRs) are crucial for patient safety. However, complete information on unknown ADRs seldom is available at the time of spontaneous ADR reports and this can hamper their contribution to the pharmacovigilance system. Methods: In order to characterize the seriousness and outcome of unknown ADRs at the time of report and at follow-up, and analyze their contribution to generate pharmacovigilance regulatory actions, a retrospective observational study of those identified in the spontaneous ADR reports of patients assisted at a hospital (January, 2016-December, 2021) was carried out. Information on demographic, clinical and complementary tests was retrieved from patients' hospital medical records. To evaluate the contribution to pharmacovigilance system we reviewed the European Union SmPCs, the list of the pharmacovigilance signals discussed by the Pharmacovigilance Risk Assessment Committee, and its recommendations reports on safety signals. Results: A total of 15.2% of the spontaneous reported cases during the study contained at least one unknown drug-ADR pair. After exclusions, 295 unknown drug-ADR pairs were included, within them the most frequently affected organs or systems were: skin and subcutaneous tissue (34, 11.5%), hepatobiliary disorders (28, 9.5%), cardiac disorders (28, 9.5%) and central nervous system disorders (27, 9.2%). The most frequent ADRs were pemphigus (7, 2.4%), and cytolytic hepatitis, sudden death, cutaneous vasculitis and fetal growth restriction with 6 (2%) each. Vaccines such as covid-19 and pneumococcus (68, 21.3%), antineoplastics such as paclitaxel, trastuzumab and vincristine (39, 12.2%) and immunosuppressants such as methotrexate and tocilizumab (35, 11%) were the most frequent drug subgroups involved. Sudden death due to hydroxychloroquine alone or in combination (4, 1.4%) and hypertransaminasemia by vincristine (n = 3, 1%) were the most frequent unknown drug-ADR pairs. A total of 269 (91.2%) of them were serious. Complementary tests were performed in 82.7% of unknown-ADR pairs and helped to reinforce their association in 18.3% of them. A total of 18 (6.1%) unknown drug-ADR pairs were evaluated by the EMA, in 8 (2.7%) the information was added to the drug's SmPC and in 1 case the risk prevention material was updated. Conclusion: Identification and follow-up of unknown ADRs can be of great relevance for patient safety and for the enrichment of the pharmacovigilance system.

Review on the management of cardiovascular risk factors in the elderly.

Cardiovascular risk factors (CVRF) are very prevalent in the elderly population and in addition to predisposing to cardiovascular disease they are related to functional decline, which limits the quality of life in this population. The objective of this work is to offer a review of the current evidence in the management of CVRF in the elderly population. The search strategy was executed in PubMed, Clinicalstrials.org and Embase, to search for clinical trials, observational cohort or cross-sectional studies, reviews, and clinical practice guidelines focused or including elderly population. The results provided were refined after reading the title and abstract, as well as elimination of duplicates, and were finally identified and assessed following the GRADE methodology. A total of 136 studies were obtained for all predefined risk factors, such as sedentary lifestyle, smoking, obesity and metabolic syndrome, hypertension, diabetes mellitus, dyslipidemia and alcohol. We described the results of the studies identified and assessed according to their methodological quality in different recommendation sections: diagnostic and prevention, intervention, or treatment in the elderly population. As the main limitation to the results of this review, there is the lack of quality studies whose target population is elderly patients. This issue limits the recommendations that can be made in this population. Due to this reason, comprehensive geriatric assessment seems the best tool currently available to implement the most appropriate treatment plans based on the baseline situation and comorbidity of each elderly patient.

Management of Cancer-Associated Myositis.

Purpose of the Review: Cancer-associated myositis (CAM) is defined as when cancer appears within 3 years of myositis onset. Dermatomyositis and seronegative immune-mediated necrotizing myopathy are the phenotypes mostly related to cancer. In general, treatment principles in myositis patients with and without CAM are similar. However, some aspects of myositis management are particular to CAM, including (a) the need for a multidisciplinary approach and a close relationship with the oncologist, (b) the presence of immunosuppressive and antineoplastic drug interactions, and (c) the role of the long-term immunosuppressive therapy as a risk factor for cancer relapse or development of a second neoplasm. In this review, we will also discuss immunotherapy in patients treated with checkpoint inhibitors as a treatment for their cancer. Recent Findings: Studies on cancer risk in patients treated with long-term immunosuppressive drugs, in autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis, and in solid organ transplant recipients have shed some light on this topic. Immunotherapy, which has been a great advance for the treatment of some types of malignancy, may be also of interest in CAM, given the special relationship between both disorders. Summary: Management of CAM is a challenge. In this complex scenario, therapeutic decisions must consider both diseases simultaneously. Supplementary Information: The online version contains supplementary material available at 10.1007/s40674-022-00197-2.

Adverse Reactions to Drugs of Special Interest in a Pediatric Oncohematology Service.

Introduction: Drugs used in oncological diseases are frequently related to adverse drug reactions (ADR). Few studies have analyzed the toxicity of cancer treatments in children in real practice. Methods: An observational, longitudinal and prospective study has been carried out in an Oncohematology Service of a tertiary hospital. During 2017, patients exposed to one or more drugs of a previously agreed list were identified and followed-up for at least 6 months each. Characteristics of ADR, incidence, causality and possible preventability, have been evaluated. Results: 72 patients have been treated with at least one study drug, and 159 ADR episodes involving at least one of these drugs have been identified, with a total of 293 ADR. Most episodes required hospital admission (35.2%) or happened during the hospital stay (33%), and 91.2% were severe. Blood disorders were the most frequent ADR (96; 32.8%), related to thioguanine (42) and pegaspargase (39) mainly, followed by infections (86; 29.4%) related to thioguanine (32), pegaspargase (27), Erwinia asparaginase (14) and rituximab (13). Two ADR were unknown. Most ADR were dose-dependent or expectable (>90%). The global incidence of ADR was 3.1/100 days at risk (95% CI 2.7-3.5), with 3.5 ADR/100 days at risk with pegaspargase (95% CI 2.9-4.2), 1.2/100 days at risk with rituximab (95% CI 0.8-1.8) and 11.6/100 days at risk with thioguanine (95% CI 9.4-14.2). Controversial additional measures of prevention, other than those already used, were identified. Conclusion: ADR are frequent in pediatric oncohematological patients, mainly blood disorders and infectious diseases. Findings regarding incidence and preventability may be useful to compare data between different centers and to evaluate new possibilities for action or prevention.

Adverse Drug Reactions in Pediatric Oncohematology: A Systematic Review.

Introduction: Adverse drug reactions (ADR) are an important cause of morbidity and mortality in pediatric patients. Due to the disease severity and chemotherapy safety profile, oncologic patients are at higher risk of ADR. However, there is little evidence on pharmacovigilance studies evaluating drug safety in this specific population. Methods: In order to assess the incidence and characteristics of ADR in pediatric patients with oncohematogical diseases and the methodology used in the studies, a systematic review was carried out using both free search and a combination of MeSH terms. Data extraction and critical appraisal were performed independently using a predefined form. Results: Fourteen studies were included, of which eight were prospective and half focused in inpatients. Sample size and study duration varied widely. Different methods of ADR identification were detected, used alone or combined. Causality and severity were assessed frequently, whereas preventability was lacking in most studies. ADR incidence varied between 14.4 and 67% in inpatients, and 19.6-68.1% in admissions, mainly in the form of hematological, gastrointestinal and skin toxicity. Between 11 and 16.4% ADR were considered severe, and preventability ranged from 0 to 74.5%. Conclusion: ADR in oncohematology pediatric patients are frequent. A high variability in study design and results has been found. The use of methodological standards and preventability assessment should be reinforced in order to allow results comparison between studies and centers, and to detected areas of improvement. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=96513, identifier CRD42018096513.

Integrated health intervention on polypharmacy and inappropriate prescribing in elderly people with multimorbidity: Results at the end of the intervention and at 6 months after the intervention.

BACKGROUND AND OBJECTIVE: To analyse the impact of an integrated health intervention focused on polypharmacy and inappropriate prescribing (IP) in elderly people with multimorbidity. MATERIAL AND METHODS: Patients were referred for assessment and intervention from primary care or hospital to an interdisciplinary team composed of primary and hospital medical staff and nurses. Pharmacological assessment was centred on polypharmacy and IP using the STOPP/START criteria. Changes in polypharmacy and in IP were analysed at the end of the intervention and at 6 months. RESULTS: One hundred consecutive patients (mean (SD) age 81.5(8.0) years, 54(54%) male) were analysed. Mean prescribed medicines at baseline was > 10. There were no significant changes at the end of the intervention and at 6 months. The proportion of patients with two or more STOPP criteria reduced from 37% at the beginning of the intervention to 18% at the end (p< .001), and the proportion of those with START criteria from 13% to 6% (p = .004). These differences persisted at 6 months. The number of STOPP and START criteria before the intervention was associated with a decrease in the STOPP and START criteria at the end of the intervention and at 6 months. A reduction in polypharmacy (p= .041) and in falls (p= .034) was observed at 6 months in those with a decrease in the STOPP criteria at the end of the intervention. CONCLUSIONS: An integrated health intervention centred on polypharmacy and IP in elderly people improves inappropriate prescribing that persists beyond the intervention.

Reimbursement Status and Recommendations Related to Orphan Drugs in European Countries.

Objective: To review the reimbursement recommendations issued by selected European health technology assessment agencies for orphan drugs and the reimbursement status of these drugs; to assess the relationship between the type of recommendation and reimbursement status. Methods: The list of orphan drugs to be included in the analysis was obtained from the European Medicines Agency and Orphanet. Seven European states were included in the analysis: Belgium, England, France, Germany, Poland, Scotland, and Spain. For all identified orphan drugs, relevant data on the reimbursement status and type of recommendation were collected for each country. The relationship between the type of recommendation and reimbursement status was evaluated separately for each considered country, using Cohen's kappa coefficient for the measurement of agreement; sub-analyses for oncology and metabolic drugs were performed. Results: Most reimbursement recommendations for orphan drugs were positive (71%), while approximately 17% were negative and almost 13% were conditional. The highest percentage of positive reimbursement recommendations was observed in Spain (97%) and France (95%) and the highest percentage of negative reimbursement recommendations was revealed for Poland (49%). On average, 65% of the 163 analyzed orphan drugs were reimbursed from public funds. The highest number of reimbursed orphan drugs was observed in Germany (n = 148), while the lowest, in Poland (n = 41). Considering all analyzed drugs, the highest agreement between recommendations and reimbursement status was observed for Spain (value of 1), and the lowest, for Germany (κ = -0.03). Conclusions: On average, more than 60% of identified orphan drugs were reimbursed from public funds in the included countries, and the majority of reimbursement recommendations were found to be positive. The agreement between reimbursement recommendations and reimbursement status differed between the countries, but overall, it did not show any patterns, as it ranged from -0.03 to 1 (κ coefficient).

[Characteristics of potentially inappropriate prescribing of drugs in elderly polypathological patients]. / Características del uso inadecuado de medicamentos en pacientes pluripatológicos de edad avanzada.

OBJECTIVE: To analyse potentially inappropriate prescribing (PIP) in elderly polypathological patients (PP). METHOD: Multicentre observational, prospective study of 672 patients aged 75 years and older hospitalised in Internal Medicine between April 2011 and March 2012. The Beers, STOPP-START and ACOVE criteria were used to detect potentially inappropriate prescribing and the results of PP and non-PP patients were compared. RESULTS: Of the 672 patients included, 419 (62%) were polypathological, of which 89.3% met PIP criteria versus 79.4% of non-polypathological patients (p <0.01). 40.3% of polypathological patients met at least one Beers criteria, 62.8% at least one STOPP criteria, 62.3% at least one START criteria and 65.6% at least one ACOVE criteria. The rate of potentially inappropriate prescribing was higher in polypathological patients regardless of the tool used. CONCLUSIONS: Given the high rate of potentially inappropriate prescribing in polypathological patients, strategies to improve prescribing adequacy must be developed.

Impact of Implementing a Protocol on the Perioperative Management in Patients Treated with Antithrombotics Admitted for Hip Fracture Surgery: an Observational Study.

This study aimed to describe the impact of implementing a protocol on the perioperative management of patients admitted for hip fracture treated with antithrombotics. A protocol was designed based on the recommendations from the American College of Chest Physicians (ACCP). After its implementation (May 2012), information on antithrombotic management was collected from admission to 3 months after surgery in retrospective (October 2011-March 2012) and prospective (October 2012-March 2013) cohorts. Patients' thromboembolic risk was classified into high, moderate or low according to the ACCP categories. A total of 113 and 101 cases were included in the retrospective and prospective cohorts, respectively. No differences in age, gender, American Society of Anaesthesiology score or thrombotic risk categories were observed between cohorts. Most patients were treated with aspirin or triflusal (55.1% and 48.1% in each cohort, respectively), clopidogrel (24.5% and 26.6%) or acenocoumarol (16.3% and 20.2%). In moderate to high thromboembolic risk patients, a higher rate of bridging therapy with full doses of enoxaparin (18.5% and 50%, p = 0.04 before and 9.1% and 43.7%, p = 0.02 after surgery) and a lower rate of aspirin discontinuation (76% and 55.3%, p = 0.03) were observed in the prospective cohort. Both cohorts had a similar percentage of cases with bleeding (68.1% and 68.3%) and thrombotic events (11.5% and 13%). No differences in the timing between surgery and the discontinuation or resumption of antithrombotics were noted. After the protocol implementation, aspirin was less often stopped and bridging therapy with therapeutic doses of enoxaparin was used more often. However, interruption and resumption times of antithrombotics remained almost unchanged. In order to achieve these goals, more efforts should be made to implement the protocol in clinical practice.

Elderly patients treated with psychotropic medicines admitted to hospital: associated characteristics and inappropriate use.

PURPOSE: The purpose of this study is to describe the characteristics of older patients treated with psychotropic medicines and the associated factors and to assess their inappropriate use. METHODS: An observational, prospective study was carried out in 672 elderly patients admitted to seven hospitals for a year. A comparison of sociodemographic characteristics, geriatric variables, multimorbidity and the number of prescribed medicines taken in the preceding month before hospitalization between patients treated with psychotropics and those not treated was performed. To assess factors associated with psychotropics, multivariate logistic regression analyses were performed. Inappropriate use was assessed using the Beers and the STOPP criteria. RESULTS: A total of 57.5 % patients (median [Q1-Q3] age 81.7 [78.2-86.1], 65.7 % female) were treated with psychotropics (44.2 % anxiolytics, 22.6 % antidepressants and 10.8 % antipsychotics). Independent factors associated with the use of psychotropics were female gender (OR = 2.3; CI 95 %,1.6-3.5), some degree of disability on admission (slight [OR = 2.2; 1.2-4.2], moderate [OR = 3.2, 1.6-6.6], severe [OR = 3.4; 1.4-8] and very severe [OR = 5.1; 2.0-12.8]) and polypharmacy (5-9 medicines [OR = 3.0; 1.3-6.9] and ≥10 medicines [OR = 6.0; 2.7-13.6]). The associated factors varied depending on the different types of psychotropics. In patients treated with psychotropics, the percentage of those with at least one Beers (61.6 %) or at least one STOPP (71.4 %) criteria was significantly higher in comparison with those not treated with psychotropics (30.7 and 47.7 %, respectively, p < 0.001). CONCLUSIONS: Psychotropics are widely used in the elderly population and often their use is inappropriate. Female gender, a poor functional status and polypharmacy, are the characteristics linked to their use. Interventional strategies should be focused on patients with these characteristics.

Inappropriate prescribing to the oldest old patients admitted to hospital: prevalence, most frequently used medicines, and associated factors.

BACKGROUND: Scientific evidence on treatments of chronic diseases in patients 85 years old or older is very limited, as is available information on inappropriate prescription (IP) and its associated factors. The study aimed to describe medicine prescription, potentially inappropriate medicines (PIM) and potentially prescribing omissions (PPO) and their associated factors on this population. METHODS: In the context of an observational, prospective and multicentric study carried out in elderly patients admitted to seven Spanish hospitals for a year, a sub-analysis of those aged 85 years and over was performed. To assess PIMs, the Beers and STOPP criteria were used, and to assess PPOs, the START and the ACOVE-3 criteria were used. To assess factors associated with IP, a multivariate logistic regression analysis was performed. Patients were selected randomly every week on consecutive days from the hospitalization lists. RESULTS: A total of 336 patients were included in the sub-analysis with a median (Q1-Q3) age of 88 (86-90) years. The median medicines taken during the month prior to admission was 10 (7-13). Forty-seven point two per cent of patients had at least one Beers-listed PIM, 63.3% at least one STOPP-listed PIM, 53.6% at least one START-listed PPO, and 59.4% at least one ACOVE-3-listed PPO. Use of benzodiazepines in patients who are prone to falls (18.3%) and omission of calcium and vitamin D supplements in patients with osteoporosis (13.3%) were the most common PIM and PPO, respectively. The main factor associated with the Beers-listed and the STOPP-listed PIM was consumption of 10 or more medicines (OR = 5.7, 95% CI 1.8-17.9 and OR = 13.4, 95% CI 4.0-44.0, respectively). The main factors associated with the START-listed PPO was a non-community dwelling origin (OR 2.3, 95% CI 1.0-5.0), and multimorbidity (OR1.8, 95% CI 1.0-3.1). CONCLUSIONS: Prescribed medicines and PIM and PPO prevalence were high among patients 85 years and over. Benzodiazepine use in those who are prone to falls and omission of calcium and vitamin D in those with osteoporosis were the most frequent PIM and PPO, respectively. Factors associated with PIM and PPO differed with polypharmacy being the most important factor associated with PIM.

Inappropriate prescribing to older patients admitted to hospital: a comparison of different tools of misprescribing and underprescribing.

PURPOSE: This study aims to assess inappropriate prescribing (IP) to elderly patients during the month prior to hospitalization and to compare different IP criteria. METHODS: An observational, prospective and multicentric study was carried out in the internal medicine services of seven Spanish hospitals. Patients aged 75years and older were randomly selected after hospital admission for a year. To assess potentially inappropriate medicines (PIMs), the Beers and STOPP criteria were used and to assess potentially prescribing omissions (PPOs), the START criteria and ACOVE-3 medicine quality indicators were used. An analysis to assess factors associated with IP was performed. RESULTS: 672 patients [median age (Q1-Q3) 82 (79-86) years, 55.9% female] were included. Median prescribed medicines in the month prior to hospitalization were 10(Q1-Q3 7-13). The prevalence of IP was 87.6%, and 54.3% of patients had PIMs and PPOs concurrently. A higher prevalence rate of PIMs was predicted using the STOPP criteria than with the Beers criteria (p<0.001) and a higher prevalence of PPOs using the ACOVE-3 criteria than using the START criteria (p<0.001) was observed. Polypharmacy (≥ 10 medicines) was the strongest predictor of IP [OR=11.34 95% confidence interval (CI) 4.96-25.94], PIMs [OR=14.16, 95% CI 6.44-31.12], Beers-listed PIMs [OR=8.19, 95% CI 3.01-22.28] and STOPP-listed PIMs [OR=8.21, 95% CI 3.47-19.44]. PIMs was the strongest predictor of PPOs [OR=2.79, 95% CI 1.81-4.28]. CONCLUSIONS: A high prevalence of polypharmacy and PIMs and PPOs were reported. More than half the patients had simultaneous PIMs and PPOs. The related factors to PIMs and PPOs were different.