Repurposing of Medicines in the EU: Launch of a Pilot Framework.

Repurposing of authorised medicines has been under discussion for a long time. Drug repurposing is the process of identifying a new use for an existing medicine in an indication outside the scope of the original approved indication. Indeed, the COVID-19 health crisis has brought the concept to the frontline by proving the usefulness of this practise in favour of patients for an early access to treatment. Under the umbrella of the Pharmaceutical Committee and as a result of the discussions at the European Commission Expert Group on Safe and Timely Access to Medicines for Patients (STAMP) a virtual Repurposing Observatory Group (RepOG) was set up in 2019 to define and test the practical aspects of a pilot project thought to provide support to "not-for-profit" stakeholders generating or gathering data for a new therapeutic use for an authorised medicine. The group's initial plan was impacted by the outbreak of the SARS-CoV-2 pandemic and the launch of the pilot needed to be postponed. This article describes the progress and the activities conducted by the group during this past and yet extraordinary 2020-2021 to keep the project alive and explores on the background of this topic together with the obvious opportunities this health crisis has brought up in terms of repurposing of medicines.

Effect of ceftaroline on normal human intestinal microflora.

Ceftaroline is a new broad-spectrum cephalosporin being developed for the treatment of serious bacterial infections, including those caused by aerobic Gram-positive and Gram-negative bacteria. The purpose of the present study was to investigate the effect of administration of ceftaroline on the intestinal flora of healthy subjects. Twelve healthy subjects (6 males and 6 females), 20 to 41 years of age, received ceftaroline (600 mg) by intravenous infusion every 12 h (q12h) for 7 days. Plasma and feces were collected for determination of ceftaroline concentration and analysis of fecal flora. Fecal specimens were cultured on nonselective and selective media. Different colony types were counted, isolated in pure culture, and identified to the genus level. All new strains of colonizing bacteria were tested for susceptibility to ceftaroline. The concentrations of ceftaroline in plasma were as follows: on day 2, 17.5 to 34.8 mg/liter; on day 5, 19.7 to 33.2 mg/liter; and on day 7, 18.0 to 29.8 mg/liter. No ceftaroline concentrations were found on day -1, 9, 14, or 21. No measurable concentrations in feces were found on day -1, 2, 5, 7, 9, 14, or 21. There was a minor impact on the numbers of Escherichia coli strains, while the numbers of enterococci and Candida albicans strains were not affected. There were moderate decreases in the numbers of bifidobacteria and lactobacilli during the first 7 days, while the numbers of clostridia increased during the same period. No impact on the numbers of Bacteroides bacteria was noticed. No new colonizing aerobic or anaerobic bacteria resistant to ceftaroline (MIC >or= 4 mg/liter) were found. Ceftaroline had no significant ecological impact on the human intestinal microflora.

Adverse Drug Reactions in a Tertiary Care Emergency Medicine Ward - Prevalence, Preventability and Reporting.

PURPOSE: To identify the prevalence and preventability of adverse drug reactions (ADRs) in an emergency ward setting in a tertiary hospital in Sweden and to what extent the detected ADRs were reported to the Medical Product Agency (MPA). METHODS: In this prospective cross sectional observational study, 706 patients admitted to one of the Emergency Wards, at the Karolinska University Hospital in Solna, Stockholm during September 2008 -September 2009, were included. The electronic patient records were reviewed for patients' demographic parameters, prevalence of possible ADRs and assessment of their preventability. In addition, the extent of formal and required ADR reporting to national registers was studied. RESULTS: Approximately 40 percent of the patient population had at least one possible ADR (n = 284). In the multivariable regression model, age and number of drugs were significantly associated with risk of presenting with an ADR (p<0.01 and p<0.001, respectively). Sex was not identified as a significant predictor of ADRs (p = 0.27). The most common ADRs were cardiovascular, followed by electrolyte disturbances, and hemorrhage. In 18 percent of the patient population ADRs were the reason for admission or had contributed to admission and 24% of these ADRs were assessed as preventable. The under-reporting of ADRs to the MPA was 99%. CONCLUSIONS: ADRs are common in Emergency Medicine in tertiary care in Sweden, but under-reporting of ADRs is substantial. The most frequent ADRs are caused by cardiovascular drugs, and significantly associated with age and number of drugs. However, only a minority of the detected serious ADRs contributing to admission could have been avoided by increased risk awareness.

Rheumatoid arthritis, anti-tumour necrosis factor treatment, and risk of squamous cell and basal cell skin cancer: cohort study based on nationwide prospectively recorded data from Sweden.

OBJECTIVE: To investigate the risk of squamous cell and basal cell skin cancer in patients with rheumatoid arthritis naive to biologic drugs, in patients starting tumour necrosis factor (TNF) inhibitor treatment, and in the general population. DESIGN: Population based cohort study. SETTING: Nationwide data from Sweden. PARTICIPANTS: Cohort of patients with rheumatoid arthritis naive to biologics (n=46 409), cohort of patients with rheumatoid arthritis starting TNF inhibitor treatment as first biologic in 1998-2012 (n=12 558), and matched general population comparator cohort, identified through national quality of care and health registers. MAIN OUTCOME MEASURE: Hazard ratio of first in situ or invasive squamous cell skin cancer (1998-2012) and first basal cell cancer (2004-12). RESULTS: For basal cell cancer, the hazard ratio was 1.22 (95% confidence interval 1.07 to 1.41) comparing biologics-naive rheumatoid arthritis patients with the general population and 1.14 (0.98 to 1.33; 236 v 1587 events) comparing TNF inhibitor treated patients with biologics-naive patients. For squamous cell cancer, the hazard ratio was 1.88 (1.74 to 2.03) comparing biologics-naive rheumatoid arthritis patients with the general population and 1.30 (1.10 to 1.55; 191 v 847 events) comparing TNF inhibitors with biologics-naive patients; the latter translated to an annual number needed to harm in the order of 1600. Among people with a history of squamous cell or basal cell cancer, TNF inhibitors did not further increase risks. CONCLUSION: A small to moderately increased risk of basal cell cancer was seen in biologics-naive rheumatoid arthritis patients, with no further effect of TNF inhibitors. For squamous cell cancer, the risk was nearly doubled in biologics-naive patients, with a further 30% increase in risk among patients treated with TNF inhibitors; this translates to one additional case for every 1600 years of treatment experience, assuming that this association reflected causality. Vigilance regarding skin malignancies may be advisable in rheumatoid arthritis, irrespective of TNF inhibitor treatment. Most of the increase in risk for non-melanoma skin cancer in patients with rheumatoid arthritis treated with TNF inhibitors originates from factors other than that treatment.

Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study.

BACKGROUND: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients' refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits. MATERIALS AND METHODS: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation. RESULTS AND CONCLUSION: MTD was defined as 10.2 mg/m(2), with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m(2) under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.

Which Medication Is the Patient Taking at Admission to the Emergency Ward? Still Unclear Despite the Swedish Prescribed Drug Register.

INTRODUCTION: Correct information on patients' medication is crucial for diagnosis and treatment in the Emergency Department. The aim of this study was to investigate the concordance between the admission chart and two other records of the patient's medication. METHODS: This cohort study includes data on 168 patients over 18 years admitted to the Emergency Ward between September 1 and 30, 2008. The record kept by the general practitioner and the patient record of dispensed drugs in the Swedish Prescribed Drug Register were compared to the admission chart record. RESULTS: Drug record discrepancies of potential clinical significance between the admission chart record and the Swedish Prescribed Drug Register or general practitioner record were present in 79 and 82 percent, respectively. For 63 percent of the studied patients the admission chart record did not include all drugs registered in the Swedish Prescribed Drug Register. For 62 percent the admission chart record did not include all drugs registered in the general practitioner record. In addition, for 32 percent of the patients the admission chart record included drugs not registered in the Swedish Prescribed Drug Register and for 52 percent the admission chart record included drugs not found in the general practitioner record. The most discordant drug classes were cardiovascular and CNS-active drugs. Clinically significant drug record discrepancies were more frequent in older patients with multiple medication and caregivers. CONCLUSION: The apparent absence of an accurate record of the patient's drugs at admission to the Emergency Ward constitutes a potential patient safety hazard. The available sources in Sweden, containing information on the drugs a particular patient is taking, do not seem to be up to date. These results highlight the importance of an accurate list of currently used drugs that follows the patient and can be accessed upon acute admission to the hospital.

Typical investigational medicinal products follow relatively uniform regulations in 10 European Clinical Research Infrastructures Network (ECRIN) countries.

BACKGROUND: In order to facilitate multinational clinical research, regulatory requirements need to become international and harmonised. The EU introduced the Directive 2001/20/EC in 2004, regulating investigational medicinal products in Europe. METHODS: We conducted a survey in order to identify the national regulatory requirements for major categories of clinical research in ten European Clinical Research Infrastructures Network (ECRIN) countries-Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and United Kingdom-covering approximately 70% of the EU population. Here we describe the results for regulatory requirements for typical investigational medicinal products, in the ten countries. RESULTS: Our results show that the ten countries have fairly harmonised definitions of typical investigational medicinal products. Clinical trials assessing typical investigational medicinal products require authorisation from a national competent authority in each of the countries surveyed. The opinion of the competent authorities is communicated to the trial sponsor within the same timelines, i.e., no more than 60 days, in all ten countries. The authority to which the application has to be sent to in the different countries is not fully harmonised. CONCLUSION: The Directive 2001/20/EC defined the term 'investigational medicinal product' and all regulatory requirements described therein are applicable to investigational medicinal products. Our survey showed, however, that those requirements had been adopted in ten European countries, not for investigational medicinal products overall, but rather a narrower category which we term 'typical' investigational medicinal products. The result is partial EU harmonisation of requirements and a relatively navigable landscape for the sponsor regarding typical investigational medicinal products.

Effect of ceftobiprole on the normal human intestinal microflora.

Ceftobiprole is a new broad-spectrum pyrrolidinone cephem active against meticillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis and Gram-negative bacteria such as Enterobacteriaceae and Pseudomonas spp. The purpose of the present study was to investigate the effect of administration of ceftobiprole on the normal intestinal microflora. Twelve healthy subjects (six males and six females) aged 20-31 years received ceftobiprole 500 mg by intravenous infusion every 8h for 7 days. Plasma samples were collected on Days -1, 1, 4, 7, 10, 14 and 21 for determination of drug concentration by biological and chemical methods. Faecal samples were collected on Days -1, 2, 4, 7, 10, 14 and 21. For analysis of the microflora, faecal specimens were cultured on non-selective and selective media. Different colony types were counted, isolated in pure culture and identified to genus level. All new colonising aerobic and anaerobic bacteria were tested for susceptibility to ceftobiprole. Plasma concentrations of ceftobiprole 10 min after completion of infusion were as follows: Day 1, 14.7-23.6 mg/L; Day 4, 15.9-24.5 mg/L; and Day 7, 15.9-23.9 mg/L. No ceftobiprole was detected in plasma on Days -1, 10, 14 and 21. No measurable concentrations of ceftobiprole were found in faeces on Days -1, 2, 4, 7, 10, 14 and 21. There were minor changes in the numbers of enteric bacteria, enterococci and Candida albicans and there were moderate changes in the numbers of bifidobacteria, lactobacilli, clostridia and Bacteroides spp. during the same period. No Clostridium difficile strains or toxins were found. No new colonising aerobic and anaerobic bacteria with ceftobiprole minimum inhibitory concentrations of ≥ 4 mg/L were found. Ceftobiprole had no significant ecological impact on the human intestinal microflora.

Compassionate use of interventions: results of a European Clinical Research Infrastructures Network (ECRIN) survey of ten European countries.

BACKGROUND: 'Compassionate use' programmes allow medicinal products that are not authorised, but are in the development process, to be made available to patients with a severe disease who have no other satisfactory treatment available to them. We sought to understand how such programmes are regulated in ten European Union countries. METHODS: The European Clinical Research Infrastructures Network (ECRIN) conducted a comprehensive survey on clinical research regulatory requirements, including questions on regulations of 'compassionate use' programmes. Ten European countries, covering approximately 70% of the EU population, were included in the survey (Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and the UK). RESULTS: European Regulation 726/2004/EC is clear on the intentions of 'compassionate use' programmes and aimed to harmonise them in the European Union. The survey reveals that different countries have adopted different requirements and that 'compassionate use' is not interpreted in the same way across Europe. Four of the ten countries surveyed have no formal regulatory system for the programmes. We discuss the need for 'compassionate use' programmes and their regulation where protection of patients is paramount. CONCLUSIONS: 'Compassionate use' is a misleading term and should be replaced with 'expanded access'. There is a need for expanded access programmes in order to serve the interests of seriously ill patients who have no other treatment options. To protect these patients, European legislation needs to be more explicit and informative with regard to the regulatory requirements, restrictions, and responsibilities in expanded access programmes.

Common definition for categories of clinical research: a prerequisite for a survey on regulatory requirements by the European Clinical Research Infrastructures Network (ECRIN).

BACKGROUND: Thorough knowledge of the regulatory requirements is a challenging prerequisite for conducting multinational clinical studies in Europe given their complexity and heterogeneity in regulation and perception across the EU member states. METHODS: In order to summarise the current situation in relation to the wide spectrum of clinical research, the European Clinical Research Infrastructures Network (ECRIN) developed a multinational survey in ten European countries. However a lack of common classification framework for major categories of clinical research was identified, and therefore reaching an agreement on a common classification was the initial step in the development of the survey. RESULTS: The ECRIN transnational working group on regulation, composed of experts in the field of clinical research from ten European countries, defined seven major categories of clinical research that seem relevant from both the regulatory and the scientific points of view, and correspond to congruent definitions in all countries: clinical trials on medicinal products; clinical trials on medical devices; other therapeutic trials (including surgery trials, transplantation trials, transfusion trials, trials with cell therapy, etc.); diagnostic studies; clinical research on nutrition; other interventional clinical research (including trials in complementary and alternative medicine, trials with collection of blood or tissue samples, physiology studies, etc.); and epidemiology studies. Our classification was essential to develop a survey focused on protocol submission to ethics committees and competent authorities, procedures for amendments, requirements for sponsor and insurance, and adverse event reporting following five main phases: drafting, consensus, data collection, validation, and finalising. CONCLUSION: The list of clinical research categories as used for the survey could serve as a contribution to the, much needed, task of harmonisation and simplification of the regulatory requirements for clinical research in Europe.