Quantitative analysis of antibiotic usage in British sheep flocks

The aim of this study was to examine the variation in antibiotic usage between 207 commercial sheep flocks using their veterinary practice prescribing records. Mean and median prescribed mass per population corrected unit (mg/PCU) was 11.38 and 5.95, respectively and closely correlated with animal defined daily dose (ADDD) 1.47 (mean), 0.74 (median) (R2=0.84, P<0.001). This is low in comparison with the suggested target (an average across all the UK livestock sectors) of 50 mg/PCU. In total, 80 per cent of all antibiotic usage occurred in the 39 per cent of flocks where per animal usage was greater than 9.0 mg/PCU. Parenteral antibiotics, principally oxytetracycline, represented 82 per cent of the total prescribed mass, 65.5 per cent of antibiotics (mg/PCU) were prescribed for the treatment of lameness. Oral antibiotics were prescribed to 49 per cent of flocks, 64 per cent of predicted lamb crop/farm. Lowland flocks were prescribed significantly more antibiotics than hill flocks. Variance partitioning apportioned 79 per cent of variation in total antibiotic usage (mg/PCU) to the farm level and 21 per cent to the veterinary practice indicating that veterinary practices have a substantial impact on overall antimicrobial usage. Reducing antibiotic usage in the sheep sector should be possible with better understanding of the drivers of high usage in individual flocks and of veterinary prescribing practices

Evaluating Quality of Decision-Making Processes in Medicines' Development, Regulatory Review, and Health Technology Assessment : A Systematic Review of the Literature.

Introduction: Although pharmaceutical companies, regulatory authorities, and health technology assessment (HTA) agencies have been increasingly using decision-making frameworks, it is not certain whether these enable better quality decision making. This could be addressed by formally evaluating the quality of decision-making process within those organizations. The aim of this literature review was to identify current techniques (tools, questionnaires, surveys, and studies) for measuring the quality of the decision-making process across the three stakeholders. Methods: Using MEDLINE, Web of Knowledge, and other Internet-based search engines, a literature review was performed to systematically identify techniques for assessing quality of decision making in medicines development, regulatory review, and HTA. A structured search was applied using key words and a secondary review was carried out. In addition, the measurement properties of each technique were assessed and compared. Ten Quality Decision-Making Practices (QDMPs) developed previously were then used as a framework for the evaluation of techniques identified in the review. Due to the variation in studies identified, meta-analysis was inappropriate. Results: This review identified 13 techniques, where 7 were developed specifically to assess decision making in medicines' development, regulatory review, or HTA; 2 examined corporate decision making, and 4 general decision making. Regarding how closely each technique conformed to the 10 QDMPs, the 13 techniques assessed a median of 6 QDMPs, with a mode of 3 QDMPs. Only 2 techniques evaluated all 10 QDMPs, namely the Organizational IQ and the Quality of Decision Making Orientation Scheme (QoDoS), of which only one technique, QoDoS could be applied to assess decision making of both individuals and organizations, and it possessed generalizability to capture issues relevant to companies as well as regulatory authorities. Conclusion: This review confirmed a general paucity of research in this area, particularly regarding the development and systematic application of techniques for evaluating quality decision making, with no consensus around a gold standard. This review has identified QoDoS as the most promising available technique for assessing decision making in the lifecycle of medicines and the next steps would be to further test its validity, sensitivity, and reliability.Peer reviewedFinal Published versio

Approval of cancer drugs with uncertain therapeutic value: a comparison of regulatory decisions in Europe and the United States

Policy Points Regulatory agencies may have limited evidence on the clinical benefits and harms of new drugs when deciding whether new therapeutic agents are allowed to enter the market and under which conditions, including whether approval is granted under special regulatory pathways and obligations to address knowledge gaps through postmarketing studies are imposed. In a matched comparison of marketing applications for cancer drugs of uncertain therapeutic value reviewed by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), we found frequent discordance between the two agencies on regulatory outcomes and the use of special regulatory pathways. Both agencies often granted regular approval, even when the other agency judged there to be substantial uncertainty about drug benefits and risks that needed to be resolved through additional studies in the postmarketing period. Postmarketing studies imposed by regulators under special approval pathways to address remaining questions of efficacy and safety may not be suited to deliver timely, confirmatory evidence due to shortcomings in study design and delays, raising questions over the suitability of the FDA's Accelerated Approval and the EMA's Conditional Marketing Authorization as tools for allowing early market access for cancer drugs while maintaining rigorous regulatory standards. Context: Regulatory agencies are increasingly required to make market approval decisions for new drugs on the basis of limited clinical evidence, a situation commonly encountered in cancer. We aimed to investigate how regulators manage uncertainty in the benefit-risk profiles of new cancer drugs by comparing decisions for the world's two largest regulatory bodies—the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA)—over a 5-year period. Methods: We systematically identified a set of cancer drug-indication pairs for which data on efficacy and safety was less complete than that required for regular approval at time of market entry from 2009 to 2013, as determined by the FDA's use of Accelerated Approval (AA) or the EMA's use of Conditional Marketing Authorization (CMA) pathways, and matched these across the two agencies. Using publicly available information, we compared regulatory pathways and outcomes, final approved indications, and postmarketing obligations imposed by the agencies. Findings: We identified 21 cancer drug-indication pairs that received FDA AA, EMA CMA, or both. Although most applications relied on identical pivotal trials across the FDA and the EMA, regulatory pathways often differed; 57% of indications received either FDA AA or EMA CMA, and regular approval by the other agency. After approval, the EMA more often accepted single-arm studies to confirm clinical benefit compared to the FDA (75% vs. 29% of indications), and the FDA more commonly requested randomized controlled trials (85% vs. 50%). Forty-one percent of confirmatory trials after FDA AA were conducted in different populations than the approved indication, compared to 13% after EMA CMA. Both agencies relied primarily on surrogate measures of patient benefit for postmarketing obligations. After a median follow-up of 7.25 years, 40% of FDA and 61% of EMA postmarketing obligations after AA and CMA, respectively, were delayed. Conclusions: US and European regulators often deemed early and less complete evidence on benefit-risk profiles of cancer drugs sufficient to grant regular approval, raising questions over regulatory standards for the approval of new medicines. Even when imposing confirmatory studies in the postmarketing period through special approval pathways, meaningful evidence may not materialize due to shortcomings in study design and delays in conducting required studies with due diligence

A 'good' ethical review: audit and professionalism in research ethics

How does one conduct, measure and record a ‘good’ ethical review of biomedical research? To what extent do ethics committees invoke professionalism in researchers and in themselves, and to what extent do they see competence as adherence to a set of standard operating procedures for ethical review? Drawing on ethnographic fieldwork with the Forum of Ethics Review Committees of Asia and the Pacific (FERCAP), a capacity-building NGO that runs ethics committee trainings and reviews in the Asia Pacific region, I develop an analysis of ethical review and its effects. I focus on a ‘second-order audit’ run by FERCAP, which recognises committees according to a set of standards that are designed to render ‘local’ committees internationally legible. The article adds to a growing comparative literature that expands studies of audit-like measuring and disciplining activities beyond western contexts and enriches readings of ‘ethics’. I begin and end with a reflection on the ethical effects of a measurement practice that takes ethics itself as its object

N2 Gas Flushing Limits the Rise of Antibiotic-Resistant Bacteria in Bovine Raw Milk during Cold Storage

Antibiotic resistance has been noted to be a major and increasing human health issue. Cold storage of raw milk promotes the thriving of psychrotrophic/psychrotolerant bacteria, which are well known for their ability to produce enzymes that are frequently heat stable. However, these bacteria also carry antibiotic resistance (AR) features. In places, where no cold chain facilities are available and despite existing recommendations numerous adulterants, including antibiotics, are added to raw milk. Previously, N-2 gas flushing showed real potential for hindering bacterial growth in raw milk at a storage temperature ranging from 6 to 25 degrees C. Here, the ability of N-2 gas (N) to tackle antibiotic-resistant bacteria was tested and compared to that of the activated lactoperoxidase system (HT) for three raw milk samples that were stored at 6 degrees C for 7 days. To that end, the mesophiles and psychrotrophs that were resistant to gentamycin (G), ceftazidime (Ce), levofloxacin (L), and trimethoprim-sulfamethoxazole (TS) were enumerated. For the log(10) ratio (which is defined as the bacterial counts from a certain condition divided by the counts on the corresponding control), classical Analyses of Variance (ANOVA) was performed, followed by a mean comparison with the Ryan-Einot-Gabriel-Welsch multiple range test (REGWQ). If the storage "time" factor was the major determinant of the recorded effects, cold storage alone or in combination with HT or with N promoted a sample-dependent response in consideration of the AR levels. The efficiency of N in limiting the increase in AR was highest for fresh raw milk and was judged to be equivalent to that of HT for one sample and superior to that of HT for the two other samples; moreover, compared to HT, N seemed to favor a more diverse community at 6 degrees C that was less heavily loaded with antibiotic multi-resistance features. Our results imply that N-2 gas flushing could strengthen cold storage of raw milk by tackling the bacterial spoilage potential while simultaneously hindering the increase of bacteria carrying antibiotic resistance/multi-resistance features.Peer reviewe

Surveillance of Gram-negative bacteria: impact of variation in current European laboratory reporting practice on apparent multidrug resistance prevalence in paediatric bloodstream isolates.

This study evaluates whether estimated multidrug resistance (MDR) levels are dependent on the design of the surveillance system when using routine microbiological data. We used antimicrobial resistance data from the Antibiotic Resistance and Prescribing in European Children (ARPEC) project. The MDR status of bloodstream isolates of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa was defined using European Centre for Disease Prevention and Control (ECDC)-endorsed standardised algorithms (non-susceptible to at least one agent in three or more antibiotic classes). Assessment of MDR status was based on specified combinations of antibiotic classes reportable as part of routine surveillance activities. The agreement between MDR status and resistance to specific pathogen-antibiotic class combinations (PACCs) was assessed. Based on all available antibiotic susceptibility testing, the proportion of MDR isolates was 31% for E. coli, 30% for K. pneumoniae and 28% for P. aeruginosa isolates. These proportions fell to 9, 14 and 25%, respectively, when based only on classes collected by current ECDC surveillance methods. Resistance percentages for specific PACCs were lower compared with MDR percentages, except for P. aeruginosa. Accordingly, MDR detection based on these had low sensitivity for E. coli (2-41%) and K. pneumoniae (21-85%). Estimates of MDR percentages for Gram-negative bacteria are strongly influenced by the antibiotic classes reported. When a complete set of results requested by the algorithm is not available, inclusion of classes frequently tested as part of routine clinical care greatly improves the detection of MDR. Resistance to individual PACCs should not be considered reflective of MDR percentages in Enterobacteriaceae

Recommendations from the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL)

International audienceAbstractRare diseases are an important public health issue with high unmet need. The introduction of the EU Regulation on orphan medicinal products (OMP) has been successful in stimulating investment in the research and development of OMPs. Despite this advancement, patients do not have universal access to these new medicines. There are many factors that affect OMP uptake, but one of the most important is the difficulty of making pricing and reimbursement (P&R) decisions in rare diseases. Until now, there has been little consensus on the most appropriate assessment criteria, perspective or appraisal process. This paper proposes nine principles to help improve the consistency of OMP P&R assessment in Europe and ensure that value assessment, pricing and funding processes reflect the specificities of rare diseases and contribute to both the sustainability of healthcare systems and the sustainability of innovation in this field. These recommendations are the output of the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL), a collaboration between rare disease experts, patient representatives, academics, health technology assessment (HTA) practitioners, politicians and industry representatives. ORPH-VAL reached its recommendations through careful consideration of existing OMP P&R literature and through a wide consultation with expert stakeholders, including payers, regulators and patients. The principles cover four areas: OMP decision criteria, OMP decision process, OMP sustainable funding systems and European co-ordination. This paper also presents a guide to the core elements of value relevant to OMPs that should be consistently considered in all OMP appraisals. The principles outlined in this paper may be helpful in drawing together an emerging consensus on this topic and identifying areas where consistency in payer approach could be achievable and beneficial. All stakeholders have an obligation to work together to ensure that the promise of OMP’s is realised

EFSA BIOHAZ Panel (EFSA Panel on Biologicial Hazards), 2013. Scientific Opinion on the public health hazards to be covered by inspection of meat (solipeds)

A risk ranking process identified Trichinella spp. as the most relevant biological hazard in the context of meat inspection of domestic solipeds. Without a full and reliable soliped traceability system, it is considered that either testing all slaughtered solipeds for Trichinella spp., or inactivation meat treatments (heat or irradiation) should be used to maintain the current level of safety. With regard to general aspects of current meat inspection practices, the use of manual techniques during current post-mortem soliped meat inspection may increase microbial cross-contamination, and is considered to have a detrimental effect on the microbiological status of soliped carcass meat. Therefore, the use of visual-only inspection is suggested for “non-suspect” solipeds. For chemical hazards, phenylbutazone and cadmium were ranked as being of high potential concern. Monitoring programmes for chemical hazards should be more flexible and based on the risk of occurrence, taking into account Food Chain Information (FCI), covering the specific on-farm environmental conditions and individual animal treatments, and the ranking of chemical substances, which should be regularly updated and include new hazards. Sampling, testing and intervention protocols for chemical hazards should be better integrated and should focus particularly on cadmium, phenylbutazone and priority “essential substances” approved for treatment of equine animals. Implementation and enforcement of a more robust and reliable identification system throughout the European Union is needed to improve traceability of domestic solipeds. Meat inspection is recognised as a valuable tool for surveillance and monitoring of animal health and welfare conditions. If visual only post-mortem inspection is implemented for routine slaughter, a reduction in the detection of strangles and mild cases of rhodococcosis would occur. However, this was considered unlikely to affect the overall surveillance of both diseases. Improvement of FCI and traceability were considered as not having a negative effect on animal health and welfare surveillance