Search

International drug regulators use conditional drug approval mechanisms to facilitate faster patient access to drugs based on a lower evidentiary standard typically required of drug approvals. Faster and earlier access is justified by limiting eligibility to drugs intended for serious and life-threatening diseases and by requiring post-market evidence collection to confirm clinical benefit. One such mechanism in Canada, the Notice of Compliance with Conditions (NOC/c) policy, was introduced in 1998. Today, most of the drugs approved under the NOC/c policy are for oncology indications. We analyze oncology drugs approvals under the NOC/c policy to inform discussions of two tradeoffs applied to conditional drug approvals, eligibility criteria and post-market evidence. Our analysis informs recommendations for Canada's proposed regulatory reforms approach to conditional approvals pathways. Our analysis demonstrates that under the current policy, eligibility criteria are insufficiently defined, resulting in their inconsistent application by Health Canada. Regulatory responsiveness to post-market evidence from post-market clinical trial and foreign jurisdiction regulatory decisions is slow and insufficient. In the absence of sufficient regulatory responsiveness, physicians and patients must make clinical decisions without the benefit of the best available evidence. Together, our analysis of the two core tradeoffs in Canada's conditional drug approval provides insight to inform the further development of Canada's proposed agile regulatory approach to drugs and devices that will expand the use of terms and conditions.

Background: In China, over 5 million people have been identified and registered by the public security institutions for using illicit drugs. The aim of this study is to compare the influence of different types of illicit drugs on the self-reported mental health of Chinese people. In particular, we want to assess the damage of Heroin, Methamphetamine and Ketamine to mental health in a social environment where drug use is strictly regulated., Methods: The study is based on survey with 6,906 people who use drugs in Guangdong province, China. Risk of mental health issue is measured using the Brief Symptoms Inventory 18 (BSI-18) Scale, and a higher BSI-18 score indicates more severe mental health problems. The data was analyzed through multilevel regression analysis, propensity score matching analysis and mediation analysis., Results: The three major types of illicit drugs have both moderating and mediating effects on the length of drug-use history, that Heroin use leads to longer drug-use duration, while Ketamine use causes more damage on mental health per unit time of drug-use duration. Average duration of Methamphetamine use is 0.7 year shorter than average duration of Heroin use, and average duration of Ketamine use is 1.7 year shorter than average duration of Heroin use. For each year of increase of drug-use duration, Ketamine use leads to 1.2 times more of BSI score increase than Heroin use, and 2.3 times more of BSI score increase than Methamphetamine use., Conclusion: These three drugs are associated with severe mental health issue in a society with strict drug regulation. Attention should be paid to the mental health of people regardless of the type of drugs they use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The Editor declared a shared parent affiliation with the author CY at the time of review. The reviewer SL declared a shared parent affiliation with the author CY to the handling editor at the time of review., (Copyright © 2024 Zhou, Tan, Li and Yu.)

Policy PointsMuch concern about generic drug markets has emerged in recent policy debates.Important changes in regulations, the structure of purchasing, and the length of the drug supply chain have affected generic drug markets.Effective price competition remains the rule in generic markets for large‐selling drugs. Smaller markets and those for injectable products often have less price competition and are more susceptible to supply disruptions. Context: The image of generic drugs as a commodity sold in competitive markets is an oversimplification, as evidenced by increasing accounts of price spikes, sustained high price‐cost margins, and market disruptions. The mismatch between the canonical economic model of generic drug markets and reality motivated our empirical project. Methods: To explore recent changes in those factors impacting the supply and demand for generic drugs, we studied, from a variety of sources, the data on price, competition, supply disruptions and recalls, changes to the supply chain, and buy‐side concentration. We examined quarterly data through 2018 for a cohort of 77 molecules that lost patent protection during the so‐called patent cliff between 2010 and 2013. Findings: On the supply side, we found that for large‐market oral solids, generic entry and price declines were consistent with past studies showing a significant number of market entrants and substantial reductions in the average price of a molecule. In smaller markets for oral solids and injectable products, we observed fewer entrants, higher rates of exit, smaller price reductions, and, in some cases, considerable price instability. The number of reported shortages increased across all generic market types over time, with the rate of shortage increases especially pronounced in markets for injectable products. The number of product recalls also rose over our study period. Although we did not estimate causal effects, we did find several changes in the market environment for generic drugs that may contribute to these phenomena. The demand side for generics has become more concentrated. Supply chains rely more on producers outside the United States (particularly from China and India). Contracting practices have undergone changes that may inhibit competition in product supply. FDA regulatory scruitiny has increased. Conclusions: Competition in generic drug markets varies widely by market size and product form. Recent changes in demand‐side market structure imply more downward pressure on prices stemming from buy‐side concentration. The FDA's greater regulatory oversight puts upward pressure on costs, and the lengthening of the supply chain increases production uncertainty for producers. Demand and supply‐side changes point to further market instabilities across all generic markets due to producers' changing economic position. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Bulletin of Medical History is the property of University of Toronto Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

For decades, farmers in the most marginalised regions of Mexico have depended for survival on the illicit cultivation of opium poppy for the US heroin market. In 2017 they could earn up to 20,000 pesos ($950–$1,050 dollars) per kilo of opium, which channelled around 19 billion pesos ($1 billion dollars) into the country’s poorest communities, sustaining regional economies, religious ceremonies, and intra-community relations while stemming out-migration to Mexican cities and the US. With the recent upsurge in fentanyl use in the US, however, the demand for Mexican heroin has fallen sharply, meaning that farmers are now being paid around 6000 to 8000 pesos ($315–415 dollars) per kilo of raw opium. Thus the total money being paid to opium producing villages has dropped to an unprecedented low of 7 billion pesos ($370 million dollars). Drawing on fieldwork conducted in two poppy-producing regions of Mexico – one in the State of Nayarit, one in the State of Guerrero – this article shows that today, farmers cannot make a profit from opium once fertilizers and other capital inputs have been taken into account; village economies are starting to dry up; and out-migration is on the up. But this economic emergency opens the possibility of wrestling Mexico’s opium-growing regions from the control of Mexico’s Drug Trafficking Organizations (DTOs). This article concludes by addressing several possible solutions to what we term ‘the Mexican Opium Crisis’ – including crop substitution or opium legalization for medicinal use – and evaluates how realistic they are in the Mexican context.

Abstract Background This research reviewed major Clinical Trial Registries (CTRs) and assessed the availability of fields on quality assurance for approved medicines used as Investigational Medicinal Products (IMPs) in phase IV clinical trials. Methods Two reviewers independently assessed CTRs of the International Committee of Medical Journal Editors (ICJME) and of World Health Organization (WHO) platforms. Each CTR was checked by two reviewers on availability of fields on brand name, manufacturer’s name, approval status, approving authority, compliance with Good Manufacturing Practices, and quality testing. In case of discrepancy, consensus was sought between the two reviewers. Results Of 19 identified CTRs, 8 and 6 belonged to WHO and ICMJE, respectively, while 5 were equally part of both platforms. All CTRs had an ‘intervention’ field where data on IMPs and IMP comparators are captured. The Canadian CTR used ‘drug name’ rather than ‘intervention’. The EU, Peruvian, and UK CTRs had fields for ‘brand name’. However, only the EU CTR had fields for ‘manufacturer’s name’, ‘approval status’, and ‘approving authority’. None of the CTRs had fields on ‘compliance with Good Manufacturing Practices’ or ‘quality testing’. Conclusion This study demonstrates that none of the CTRs of ICMJE and WHO platforms has adequate fields to establish that the source of post-marketing IMPs is of assured quality. This is astonishing given the lengthy requirements in WHO and ICMJE guidelines. Considering the relation between IMP quality and safety of clinical trial participants, the gap of quality assurance fields should be bridged at CTRs concurrently to adjustments of WHO and ICMJE guidelines on CTRs. Specifically, IMP quality testing addressing issues on IMP appearance, impurities, microbial contamination, and dosing should be conducted and reported before, during, and after clinical trial conduct. Until adoption of these measures, the EU CTR should be preferred for registration of phase IV clinical trials conducted in countries lacking stringent regulatory capacities.

Scientific advice (SA) is an important tool offered by regulators to help developers generate robust evidence on a medicine's benefits and risks. Drawing on accumulated experience and looking at the SA provided by the European Medicines Agency in 2018 to advanced therapy medicinal products originally developed by public bodies, we discuss most commonly raised issues and the complexity and timings of the questions posed. Earlier and more frequent SA could help advanced therapy medicinal product developers to pre‐empt delays at the marketing authorisation stage. Carefully addressing quality and nonclinical issues before entering the pivotal phase of development will clear the path for a smooth clinical development and successful marketing authorisation. [ABSTRACT FROM AUTHOR]

A fundamental concept in two‐arm non‐parametric survival analysis is the comparison of observed versus expected numbers of events on one of the treatment arms (the choice of which arm is arbitrary), where the expectation is taken assuming that the true survival curves in the two arms are identical. This concept is at the heart of the counting‐process theory that provides a rigorous basis for methods such as the log‐rank test. It is natural, therefore, to maintain this perspective when extending the log‐rank test to deal with non‐proportional hazards, for example, by considering a weighted sum of the "observed ‐ expected" terms, where larger weights are given to time periods where the hazard ratio is expected to favor the experimental treatment. In doing so, however, one may stumble across some rather subtle issues, related to difficulties in the interpretation of hazard ratios, that may lead to strange conclusions. An alternative approach is to view non‐parametric survival comparisons as permutation tests. With this perspective, one can easily improve on the efficiency of the log‐rank test, while thoroughly controlling the false positive rate. In particular, for the field of immuno‐oncology, where researchers often anticipate a delayed treatment effect, sample sizes could be substantially reduced without loss of power. [ABSTRACT FROM AUTHOR]

New Drug Applications and Biologics Licensing Applications submitted to the US Food and Drug Administration (FDA) are reviewed by an interdisciplinary team of regulatory scientists that includes medical officers, clinical pharmacologists, toxicologists, statisticians, and drug labeling experts. Upon review of an applicant's submitted evidence from nonclinical studies, clinical trials, and manufacturing capabilities, the review team evaluates the benefits and risks of the drug and makes a scientifically-informed decision. As part of a multi-year, multi-phase New Drugs Regulatory Program Modernization effort, the FDA has recently redesigned how it reviews and documents its decisions with regard to marketing applications. This article describes the origins and rationale of the new Integrated Assessment process and Integrated Review document, summarizes how these differ from the FDA's traditional review of marketing applications, and discusses what industry can expect from a modernized drug review. [ABSTRACT FROM AUTHOR]

Drug development in oncology has broadened from mainly considering randomized clinical trials to also including single‐arm trials tailored for very specific subtypes of cancer. They often use historical controls, and this article discusses benefits and risks of this paradigm and provide various regulatory and statistical considerations. While leveraging the information brought by historical controls could potentially shorten development time and reduce the number of patients enrolled, a careful selection of the past studies, a prespecified statistical analysis accounting for the heterogeneity between studies, and early engagement with regulators will be key to success. Although both the European Medicines Agency and the U.S. Food and Drug Administration have already approved medicines based on nonrandomized experiments, the evidentiary package can be perceived as less comprehensive than randomized experiments. Use of historical controls, therefore, is better suited for cases of high unmet clinical need, where the disease course is well characterized and the primary endpoint is objective. Implications for Practice: Incorporating historical data in single‐arm oncology trials has the potential to accelerate drug development and to reduce the number of patients enrolled, compared with standard randomized controlled clinical trials. Given the lack of blinding and randomization, such an approach is better suited for cases of high unmet clinical need and/or difficult experimental situations, in which the trajectory of the disease is well characterized and the endpoint can be measured objectively. Careful pre‐specification and selection of the historical data, matching of the patient characteristics with the concurrent trial data, and innovative statistical methodologies accounting for between‐study variation will be needed. Early engagement with regulators (e.g., via Scientific Advice) is highly recommended. Drug development in oncology has broadened from mainly considering randomized clinical trials to also including single‐arm trials tailored for very specific subtypes of cancer. They often use historical controls, and this article discusses benefits and risks of this paradigm and provide regulatory and statistical considerations. [ABSTRACT FROM AUTHOR]

Policy Points Spending on prescription drugs is much higher per capita in the United States than in most other industrialized nations, including France. Lower prescription drug spending in France is due to different approaches to managing drug prices, volume of prescribing, and global health budgets. Linking a drug's price to value both at the launch of the drug and over its lifetime is key to controlling spending. Regulations on prescription volume and global spending complement the interventions on prices. If the United States adopted the French approach to regulating drug pricing, Medicare could potentially save billions of dollars annually on prescription drug spending. Context: Prescription drug spending per capita in the United States is higher than in most other industrialized countries. Policymakers seeking to lower drug spending often suggest benchmarking prices against other countries, including France, which spends half as much as the United States per capita on prescription drugs. Because differences in drug prices may result from how markets are organized in each nation, we sought to directly compare drug prices and pricing regulations between the United States and France. Methods: For the six brand‐name drugs with the highest gross expenditures in Medicare Part D in 2017, we compared the price dynamics in France and the United States between 2010 and 2018 and analyzed associations between price changes in each country and key regulatory events. We also comprehensively reviewed US and French laws and regulations related to drug pricing. Findings: Prices for the six drugs studied were higher in the United States than in France. In 2018, if Medicare had paid French prices for the brand‐name drugs in our cohort, the agency would have saved $5.1 billion. We identified 12 factors that explain why the United States spends more than France on drugs, including variations in unit prices and the volume of prescriptions, driven by use of health technology assessment and value‐based pricing in France. Conclusions: Key drivers of lower drug spending in France compared to the United States are that the French government regulates drug prices when products are launched and prohibits substantial price increases after launch. The regulation of prescription drugs in France is governed by rules that can inform discussions of US prescription drug policy and potential Medicare price negotiations. [ABSTRACT FROM AUTHOR]

The recent benefit–risk framework (BRF) developed by the Food and Drug Administration (FDA) is intended to improve the clarity and consistency in communicating the reasoning behind the FDA's decisions, acting as an important advancement in US drug regulation. In the PDUFA VI implementation plan, the FDA states that it will continue to explore more structured or quantitative decision analysis approaches; however, it restricts their use within the current BRF that is purely qualitative. By contrast, European regulators and researchers have been long exploring the use of quantitative decision analysis approaches for evaluating drug benefit–risk balance. In this paper, we show how quantitative modelling, backed by decision theory, could complement and extend the FDA's BRF to better support the appraisal of evidence and improve decision outcomes. After providing relevant scientific definitions for benefit–risk assessment and describing the FDA and European Medicines Agency (EMA) frameworks, we explain the components of and differences between qualitative and quantitative approaches. We present lessons learned from the EMA experience with the use of quantitative modelling and we provide evidence of its benefits, illustrated by a real case study that helped to resolve differences of judgements among EMA regulators. [ABSTRACT FROM AUTHOR]

Performance-based managed entry agreements (PB-MEAs) might allow patient access to new medicines, but practical hurdles make competent authorities for pricing and reimbursement (CAPR) reluctant to implement PB-MEAs. We explored if the feasibility of PB-MEAs might improve by better aligning regulatory postauthorization requirements with the data generation of PB-MEAs and by active collaboration and data sharing. Reviewers from seven CAPRs provided structured assessments of the information available at the European Medicines Agency (EMA) Web site on regulatory postauthorization requirements for fifteen recently authorized products. The reviewers judged to what extent regulatory postauthorization studies could help implement PB-MEAs by addressing uncertainty gaps. Study domains assessed were: patient population, intervention, comparators, outcomes, time horizon, anticipated data quality, and anticipated robustness of analysis. Reviewers shared general comments about PB-MEAs for each product and on cooperation with other CAPRs. Reviewers rated regulatory postauthorization requirements at least partly helpful for most products and across domains except the comparator domain. One quarter of responses indicated that public information provided by the EMA was insufficient to support the implementation of PB-MEAs. Few PB-MEAs were in place for these products, but the potential for implementation of PB-MEAs or collaboration across CAPRs was seen as more favorable. Responses helped delineate a set of conditions where PB-MEAs may help reduce uncertainty. In conclusion, PB-MEAs are not a preferred option for CAPRs, but we identified conditions where PB-MEAs might be worth considering. The complexities of implementing PB-MEAs remain a hurdle, but collaboration across silos and more transparency on postauthorization studies could help overcome some barriers. [ABSTRACT FROM AUTHOR]

Poor drug regulation in India is not a recent problem. The Indian drug market is full of look-alike, sound-alike (LASA) drugs which have not yet caught the attention of the media or the medical community. This viewpoint highlights the problem of LASA drugs and poor prescription practices and proposes solutions for involving all stakeholders in this unaddressed issue which is a huge public health problem in India., Competing Interests: PS is the founder of Nivarana (www.nivarana.org), a public health information and advocacy platform. Authors have declared no other conflicts of interest., (© 2024 The Authors.)

Background Antibiotic resistance poses a great threat to global health, especially in low- and middle-income countries with a high infectious disease burden and limited resources. In spite of regulations, antibiotics are sold in many settings as non-prescription medicines, resulting in inappropriate use and resistance. Objective This study aimed to investigate the current status of access and use of antibiotics in rural Bangladesh, by exploring the perspectives and sales practices of antibiotic drug dispensers. Methods We used a mixed methods approach (qualitative and quantitative). We mapped and characterized antibiotic purchasing and dispensing sites in the Matlab Health and Demographic Surveillance System catchment area. Furthermore, we investigated the volume of provision of systemic antibiotics in 10 drug outlets. We held 16 in-depth interviews with randomly selected antibiotics dispensers. Interviews explored factors associated with antibiotic selling. Responses were transcribed, coded for themes, and summarized. We used ATLAS.ti 5.2 for conducting a thematic analysis. Results A total of 301 antibiotic dispensers were identified, of whom 92% (n = 278) were private and 8% (n = 23) public. 52% (n = 155) operated informally (i.e. without legal authorization). In order to promote and survive in their business, dispensers sell antibiotics for a range of conditions without a qualified physician’s prescription. Factors that facilitate these inappropriate sales include lack of access to healthcare in the rural community, inadequate doctor: population ratio, limited dispenser knowledge, poor pharmacovigilance concerning safety of self medication, lack of enforcement of policies, financial benefits for both customers and dispensers, and high dependency on pharmaceutical companies’ information. Conclusion Dispensers in rural Bangladesh sell antibiotics inappropriately by ignoring existing national regulations. They operate the antibiotic sales without facing any legal barriers and primarily with a view to sustain their business, resulting in inappropriate sales of antibiotics to the rural community. The influence of the drug industry needs to be replaced with evidence-based, not commercially driven information. Awareness programs for antibiotic providers that promote understanding of antibiotics and antibiotic resistance through tailored interventions may be helpful in changing current antibiotic sales practices.

Autophagy is an important component of the innate immune system in mammals. Low levels of basic autophagy are sustained in normal cells, to help with the clearance of aging organelles and misfolded proteins, thus maintaining their structural and functional stability. However, when cells are faced with challenges, such as starvation or pathogenic infection, their level of autophagy increases significantly. Salmonella is a facultative intracellular pathogen, which imposes an economic burden on the poultry farming industry and human public health. Previous studies have shown that Salmonella can induce the autophagy of cells following invasion, which to a certain extent helps to protect the cells from bacterial colonization. This review summarizes the latest research in the field of Salmonella-induced autophagy, including: (i) the autophagy induction and escape mechanisms employed by Salmonella during the infection of host cells; (ii) the effect of autophagy on intracellular Salmonella; (iii) the important autophagy adaptors that recognize intracellular Salmonella in host cells; and (iv) the effect of autophagy-modulating drugs on Salmonella infection.

Antibiotic resistance is one of the major challenges that humankind shall face in the short term. (Bacterio)phage therapy is a valuable therapeutic alternative to antibiotics and, although the concept is almost as old as the discovery of phages, its wide application was hindered in the West by the discovery and development of antibiotics in the mid-twentieth century. However, research on phage therapy is currently experiencing a renaissance due to the antimicrobial resistance problem. Some countries are already adopting new ad hoc regulations to favor the short-term implantation of phage therapy in clinical practice. In this regard, the Phage Therapy Work Group from FAGOMA (Spanish Network of Bacteriophages and Transducing Elements) recently contacted the Spanish Drugs and Medical Devices Agency (AEMPS) to promote the regulation of phage therapy in Spain. As a result, FAGOMA was asked to provide a general view on key issues regarding phage therapy legislation. This review comes as the culmination of the FAGOMA initiative and aims at appropriately informing the regulatory debate on phage therapy.

Abstract Background The available evidence on the benefits and harms of novel drugs and therapeutic biologics at the time of approval is reported in publicly available documents provided by the US Food and Drug Administration (FDA). We aimed to create a comprehensive database providing the relevant information required to systematically analyze and assess this early evidence in meta-epidemiological research. Methods We designed a modular and flexible database of systematically collected data. We identified all novel cancer drugs and therapeutic biologics approved by the FDA between 2000 and 2016, recorded regulatory characteristics, acquired the corresponding FDA approval documents, identified all clinical trials reported therein, and extracted trial design characteristics and treatment effects. Herein, we describe the rationale and design of the data collection process, particularly the organization of the data capture, the identification and eligibility assessment of clinical trials, and the data extraction activities. Discussion We established a comprehensive database on the comparative effects of drugs and therapeutic biologics approved by the FDA over a time period of 17 years for the treatment of cancer (solid tumors and hematological malignancies). The database provides information on the clinical trial evidence available at the time of approval of novel cancer treatments. The modular nature and structure of the database and the data collection processes allow updates, expansions, and adaption for a continuous meta-epidemiological analysis of novel drugs. The database allows us to systematically evaluate benefits and harms of novel drugs and therapeutic biologics. It provides a useful basis for meta-epidemiological research on the comparative effects of innovative cancer treatments and continuous evaluations of regulatory developments.

Aims: The aim of this study was to elucidate drug prescription patterns in older European people with the objective to support regulatory contextualisation of (1) the suitability of enrolment criteria for new clinical trials; and (2) the understanding of the potential interactions/incompatibilities of newly authorised medicines with those most frequently used by older people. Methods: Medicines agencies in Portugal, Poland, Slovakia and England were approached to provide a list of the 10 most frequent prescriptions in 2016 for systemically used medicines per active substances (i.e. ATC level 5), in older people. For each active substance and for the most common therapeutic subgroups (i.e. ATC level 2), the percentages of older patients receiving at least one prescription were calculated per older age categories (65–74; 75–84; 85+) and gender. Results: There was considerable alignment in the most commonly prescribed active substances and therapeutic subgroups represented; these were gastroprotectants (A02), lipid‐modifying agents (C10) and analgesics (N02). Some gender differences were observed (A02 and N02 were prescribed more frequently to women), but trends on age categories were consistent; A02 and N02 prescriptions continued to rise with age, while C10 slightly decreased in the 85+ age group in all countries. Conclusions: The findings of this study are consistent with the major chronic diseases reported in the older European population. Evidence on co‐medication of newly applied medicines with the currently identified most commonly used medicines in older people should be generated during the (non)clinical development of new medicines to support regulatory assessment and adequate user information. [ABSTRACT FROM AUTHOR]

Aims: To identify, characterize and compare all Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals that included real‐world data on efficacy from expanded access (EA) programmes. Methods: Cross‐sectional study of FDA (1955–2018) and EMA (1995–2018) regulatory approval documentation. We automated searching for terms related to EA in 22,506 documents using machine learning techniques. We included all approvals where EA terms appeared in the regulatory documentation. Our main outcome was the inclusion of EA data as evidence of clinical efficacy. Characterization was based on approval date, disease area, orphan designation and whether the evidence was supportive or pivotal. Results: EA terms appeared in 693 out of 22,506 (3.1%) documents, which referenced 187 approvals. For 39 approvals, data from EA programmes were used to inform on clinical efficacy. The yearly number of approvals with EA data increased from 1.25 for 1993–2013 to 4.6 from 2014–2018. In 13 cases, these programmes formed the main evidence for approval. Of these, patients in EA programmes formed over half (median 71%, interquartile range: 34–100) of the total patient population available for efficacy evaluation. Almost all (12/13) approvals were granted orphan designation. In 8/13, there were differences between regulators in approval status and valuation of evidence. Strikingly, 4 treatments were granted approval based solely on efficacy from EA. Conclusion: Sponsors and regulators increasingly include real‐world data from EA programmes in the efficacy profile of a treatment. The indications of the approved treatments are characterized by orphan designation and high unmet medical need. [ABSTRACT FROM AUTHOR]

Choosing a noninferiority margin is one of the main challenges when designing a noninferiority trial. The European Medicines Agency (EMA) published a guidance report on the choice of margins in 2005. Nonetheless, in 2008 and 2009 they did not accept 41% (35 of 86) of the noninferiority margins that were proposed by pharmaceutical companies in the context of scientific-advice letters. In this study, we focus on whether the EMA's recommendations were followed by pharmaceutical companies, and on a possible relationship with eventual drug approval. Five of the 35 unaccepted margins were equivalence margins; we considered only the 30 unaccepted noninferiority margins in our analysis. Twelve of these margins were defined based on clinical and statistical considerations (the approach recommended by the EMA) and were rejected due to unacceptable clinical considerations. The other 18 margins were rejected because they were considered too wide. The EMA's recommendations were followed in the cases of 10 of the 15 margins (67%) for which information on follow-through of recommendations was available. The main reason for ignoring the EMA's recommendation in the other 5 cases was that the margins had been accepted by the US Food and Drug Administration. The proportions of approved drugs for which recommendations were and were not followed were similar, yet numbers were too low for formal statistical testing. This study shows that the main concern of regulators with regard to noninferiority trials was the strictness of margins from a clinical perspective. Future studies using more recent data, including data on the US Food and Drug Administration, may help in assessing the impact of guideline recommendations on noninferiority margins used for drug approval and may assist in reaching consensus among regulators about the choice of margins. [ABSTRACT FROM AUTHOR]

There has been increasing interest in recent years in the possibility of increasing the efficiency of clinical trials by using historical controls. There has been a general recognition that in replacing concurrent by historical controls, the potential for bias is serious and requires some down-weighting to the apparent amount of historical information available. However, such approaches have generally assumed that what is required is some modification to the standard inferential model offered by the parallel group trial. In our opinion, the correct starting point that requires modification is a trial in which treatments are allocated to clusters. This immediately shows that the amount of information available is governed not just by the number of historical patients but also by the number of centres and of historical studies. Furthermore, once one accepts that external patients may be used as controls, this raises the issue as to which patients should be used. Thus, abandoning concurrent control has implications for many aspects of design and analysis of trials, including (a) identification, pre-specification and agreement on a suitable historical dataset; (b) an agreed, enforceable and checkable plan for recruiting the experimental arm; (c) a finalised analysis plan prior to beginning the trial and (d) use of a hierarchical model with sufficient complexity. We discuss these issues and suggest approaches to design and analysis making extensive reference to the partially randomised Therapeutic Arthritis Research and Gastrointestinal Event Trial study. We also compare some Bayesian and frequentist approaches and provide some important regulatory considerations. We conclude that effective use of historical data will require considerable circumspection and discipline. [ABSTRACT FROM AUTHOR]

Background: Antibiotic resistance poses a great threat to global health, especially in low- and middle-income countries with a high infectious disease burden and limited resources. In spite of regulations, antibiotics are sold in many settings as non-prescription medicines, resulting in inappropriate use and resistance. Objective: This study aimed to investigate the current status of access and use of antibiotics in rural Bangladesh, by exploring the perspectives and sales practices of antibiotic drug dispensers. Methods: We used a mixed methods approach (qualitative and quantitative). We mapped and characterized antibiotic purchasing and dispensing sites in the Matlab Health and Demographic Surveillance System catchment area. Furthermore, we investigated the volume of provision of systemic antibiotics in 10 drug outlets. We held 16 in-depth interviews with randomly selected antibiotics dispensers. Interviews explored factors associated with antibiotic selling. Responses were transcribed, coded for themes, and summarized. We used ATLAS.ti 5.2 for conducting a thematic analysis. Results: A total of 301 antibiotic dispensers were identified, of whom 92% (n = 278) were private and 8% (n = 23) public. 52% (n = 155) operated informally (i.e. without legal authorization). In order to promote and survive in their business, dispensers sell antibiotics for a range of conditions without a qualified physician's prescription. Factors that facilitate these inappropriate sales include lack of access to healthcare in the rural community, inadequate doctor: population ratio, limited dispenser knowledge, poor pharmacovigilance concerning safety of self medication, lack of enforcement of policies, financial benefits for both customers and dispensers, and high dependency on pharmaceutical companies' information. Conclusion: Dispensers in rural Bangladesh sell antibiotics inappropriately by ignoring existing national regulations. They operate the antibiotic sales without facing any legal barriers and primarily with a view to sustain their business, resulting in inappropriate sales of antibiotics to the rural community. The influence of the drug industry needs to be replaced with evidence-based, not commercially driven information. Awareness programs for antibiotic providers that promote understanding of antibiotics and antibiotic resistance through tailored interventions may be helpful in changing current antibiotic sales practices. [ABSTRACT FROM AUTHOR]

Summary: Statistical methodology plays a crucial role in drug regulation. Decisions by the US Food and Drug Administration or European Medicines Agency are typically made based on multiple primary studies testing the same medical product, where the two‐trials rule is the standard requirement, despite shortcomings. A new approach is proposed for this task based on the harmonic mean of the squared study‐specific test statistics. Appropriate scaling ensures that, for any number of independent studies, the null distribution is a χ2‐distribution with 1 degree of freedom. This gives rise to a new method for combining one‐sided p‐values and calculating confidence intervals for the overall treatment effect. Further properties are discussed and a comparison with the two‐trials rule is made, as well as with alternative research synthesis methods. An attractive feature of the new approach is that a claim of success requires each study to be convincing on its own to a certain degree depending on the overall level of significance and the number of studies. The new approach is motivated by and applied to data from five clinical trials investigating the effect of carvedilol for the treatment of patients with moderate to severe heart failure. [ABSTRACT FROM AUTHOR]

Autophagy is an important component of the innate immune system in mammals. Low levels of basic autophagy are sustained in normal cells, to help with the clearance of aging organelles and misfolded proteins, thus maintaining their structural and functional stability. However, when cells are faced with challenges, such as starvation or pathogenic infection, their level of autophagy increases significantly. Salmonella is a facultative intracellular pathogen, which imposes an economic burden on the poultry farming industry and human public health. Previous studies have shown that Salmonella can induce the autophagy of cells following invasion, which to a certain extent helps to protect the cells from bacterial colonization. This review summarizes the latest research in the field of Salmonella -induced autophagy, including: (i) the autophagy induction and escape mechanisms employed by Salmonella during the infection of host cells; (ii) the effect of autophagy on intracellular Salmonella ; (iii) the important autophagy adaptors that recognize intracellular Salmonella in host cells; and (iv) the effect of autophagy-modulating drugs on Salmonella infection. [ABSTRACT FROM AUTHOR]

Purpose: To review the marketing authorization of biosimilars and provide a critical analysis of the pivotal trials supporting their approval by the European Medicines Agency (EMA). Methods: EMA website to identify the biosimilars approved up to July 2019 and the European Public Assessment Report for information on pivotal trial design, duration, intervention and control, primary outcome, data on immunogenicity, and comparability margins. Results: The EMA has approved 55 biosimilars (62% in 2017–2019) of 16 biologic products, used in several clinical indications. Some biosimilars were licensed as multiple products, with different commercial names, by the same or different companies. The comparability exercise and subsequent approval of 49/55 (89%) biosimilars were based on one or more pivotal phase III trials testing their clinical efficacy. In all, biosimilars were approved on the basis of 55 trials, mostly phase III (42/55, 76%) assessing clinical efficacy; these were mainly equivalence trials (31/55, 56%). The pivotal phase III trials assessed surrogate measures of clinical effect, and 71% reported immunogenicity data. Conclusion: Analysis of the approval of biosimilars in Europe depicts a complex and heterogeneous scenario. The requirement for showing similarity in terms of clinical efficacy and safety provides a robust demonstration of comparable clinical outcomes but lays a burden on biosimilar manufacturers and may delay the introduction of the drugs. The development, licensing, and monitoring of biosimilars would benefit from new strategies to accelerate access to these drugs while reducing uncertainties about their use in practice. [ABSTRACT FROM AUTHOR]

Aims: Regulatory risk communications are important to ensure medication safety, but their impact is poorly understood. The aim was to quantify the impact of UK risk communications on medication use and other outcomes. Methods: We conducted a systematic review of studies reporting prescribing/health outcome data relevant to UK regulatory risk communication. Data were reanalysed using interrupted time series regression 12 months after each regulatory intervention. Mean changes were pooled using random‐effects generic inverse variance examining the following subgroups: drug withdrawals; restrictions/changes in indications; be aware messages without specific recommendations for action; communication via direct healthcare practitioner communications; communication via drug bulletins. Results: Of 11 466 articles screened, 40 studies examining 25 UK regulatory risk communications were included. Product withdrawals, restriction in indications and be aware communications were associated with relative mean changes of −78% (95% confidence interval [CI] −60 to −96%), −34% (95% confidence interval [CI] −12 to −55%) and −11% (95%CI −8 to −15%) in targeted drug prescribing respectively. Direct healthcare professional communications were associated with relative mean changes of −47% (95%CI −27 to −68%) compared to −13% (95%CI −6 to −20%) for drug bulletins. Of 7 studies examining unique health outcomes related to the safety concern, risk communications were associated with a mean −10% (95%CI −3 to −16%) decrease in intended and a 7% (95%CI 4 to 10%) increase in unintended health outcomes. Discussion: UK regulatory risk communications were associated with significant changes in targeted prescribing and potential changes in clinical outcomes. Further research is needed to systematically study the impact of regulatory interventions. [ABSTRACT FROM AUTHOR]

Globally, cancer is the second leading cause of death, with numbers greatly exceeding those for human immunodeficiency virus/acquired immunodeficiency syndrome, tuberculosis, and malaria combined. Limited access to timely diagnosis, to affordable, effective treatment, and to high-quality care are just some of the factors that lead to disparities in cancer survival between countries and within countries. In this article, the authors consider various factors that prevent access to cancer medicines (particularly access to essential cancer medicines). Even if an essential cancer medicine is included on a national medicines list, cost might preclude its use, it might be prescribed or used inappropriately, weak infrastructure might prevent it being accessed by those who could benefit, or quality might not be guaranteed. Potential strategies to address the access problems are discussed, including universal health coverage for essential cancer medicines, fairer methods for pricing cancer medicines, reducing development costs, optimizing regulation, and improving reliability in the global supply chain. Optimizing schedules for cancer therapy could reduce not only costs, but also adverse events, and improve access. More and better biomarkers are required to target patients who are most likely to benefit from cancer medicines. The optimum use of cancer medicines depends on the effective delivery of several services allied to oncology (including laboratory, imaging, surgery, and radiotherapy). Investment is necessary in all aspects of cancer care, from these supportive services to technologies, and the training of health care workers and other staff. [ABSTRACT FROM AUTHOR]

The Food and Drug Administration (FDA) and European Medicines Agency (EMA) now have expedited review procedures for new drugs. We compared the review times of medicines licensed by the 2 agencies and explored differences in the evidence submitted. In 2015–2017 the FDA licensed 113 drugs, 66 of which reached Europe. The median review time was longer at the EMA than FDA and was shorter for drugs undergoing FDA‐expedited programmes compared to the same drugs approved by the EMA through the standard procedure. We identified differences regarding the evidence submitted to the 2 regulators for 7 drugs. The greater use of expedited programmes by the FDA and administrative time at the European Commission mainly explain the later access of new drugs to the European market. The additional evidence submitted to the EMA is generally scant and limited to a few drugs. [ABSTRACT FROM AUTHOR]

Drugs are used in veterinary medicine to prevent or treat animal diseases. When rationally administered to livestock following Good Veterinary Practices (GVP), they greatly contribute to improving the production of food of animal origin. Since humans can be exposed chronically to veterinary drugs through the diet, residues in food are evaluated for effects following chronic exposures. Parameters such as an acceptable daily intake (ADI), the no-observed-adverse-effect level (NOAEL), maximum residue limits (MRLs), and the withdrawal periods (WPs) are determined for each drug used in livestock. Drug residues in food exceeding the MRLs usually appear when failing the GVP application. Different factors related either to the treated animal or to the type of drug administration, and even the type of cooking can affect the level of residues in edible tissues. Residues above the MRLs can have a diverse negative impact, mainly on the consumer’s health, and favor antimicrobial resistance (AMR). Drug residue monitoring programmes are crucial to ensure that prohibited or authorized substances do not exceed MRLs. This comprehensive review article addresses different aspects of drug residues in edible tissues produced as food for human consumption and provides relevant information contributing to rational pharmacotherapy in food-producing animals.

Despite the increasingly strict legislation on medicinal products, the „off-label use“ or „use of medicinal product outside the approved summary of product characteristics (SmPC)“ is a weak point of today’s drug regulation and raises many questions about the risk, ethics, and legality of this type of practice. In recent years, through guidance and legal changes in some countries were defined the conditions and responsibilities, but in the most European countries still lack rules for off-label prescribing. The purpose of this study was to identify and analyse different approaches to regulation, adopted by some member states as well as to summarize the efforts in demand of common harmonized approach to solve this problem within the European Union. In the study, we used the available regulatory information in different electronic resources associated with the off-label drug use in selected European countries without limited time range. The results show that decisions taken to regulate the issue have significant differences and specific approach, while none of them is enough satisfactory and comprehensive. In conclusion, it can be claimed that the existing regulatory rules in various countries require significant improvement and update.

Aim: The aim of this study was to describe content and procedures in some selected Swedish health care quality registries (QRs) of relevance to regulatory decision-making. Methods: A workshop was organized with participation of seven Swedish QRs which subsequently answered a questionnaire regarding registry content on drug treatments and outcomes. Patient populations, coverage, data handling and quality control, as well as legal and ethical aspects are presented. Scientific publications from the QRs are used as a complementary measure of quality and scientific relevance. Results: The registries under study collect clinical data of high relevance to regulatory and health technology agencies. Five out of seven registries provide information on the drug of interest. When applying external quality criteria, we found a high degree of fulfillment, although information on medication was not sufficient to answer all questions of regulatory interest. A notable strength is the option for linkage to the Prescribed Drug Registry and to information on education and socioeconomic status. Data on drugs used during hospitalization were also collected to some extent. Outcome measures collected resemble those used in relevant clinical trials. All registries collected patient-reported outcome measures. The number of publications from the registries was substantial, with studies of appropriate design, including randomized registry trials. Conclusions: Quality registries may provide a valuable source of post-marketing data on drug effectiveness, safety, and cost-effectiveness. Closer collaboration between registries and regulators to improve quality and usefulness of registry data could benefit both regulatory utility and value for health care providers.

Traditional Chinese medicines (TCMs) represent one form of complementary and alternative medicine. The popularity and complexity in production make them attractive and vulnerable to adulteration in stages ranging from planting to production. Adulteration refers to the addition of extraneous, improper, or inferior ingredients that should not be present in TCMs. To detect and combat adulterated TCMs, supplementary testing methods (STMs), which expand the capability of routine testing standards, have been applied in China since 2003. From 2003 to 2017, a total of 184 STMs for TCMs were approved by the Chinese national drug regulatory authority. By assessing these STMs, this research intends to identify those TCMs vulnerable to adulteration, to list common adulterants, and to characterize the techniques of analysis. The results show that adulteration of TCMs can be classified into three main categories: the addition of undeclared drugs/chemical substances, substitution with non-drug components, and the addition of foreign non-drug materials. The top five therapeutic areas of TCMs vulnerable to adulteration are diabetes, calm and sleep, sexual dysfunction, pain relief, and rheumatism. A total of 166 adulterants were detected in the adulterated TCM preparations and herbal products studied here, with 158 adulterants in TCM preparations and 43 in herbal products, with 35 adulterants in common. Each STM consists of different pharmaceutical analysis techniques, including tests for physical-chemical properties, chromatography, spectroscopic techniques, and mass spectrometry. The analytical methodology of STMs relies on the combination of these techniques, with HPLC ranking the highest percentage (76.1%) and physical-chemical techniques the lowest percentage (11.4%). This research shows that STMs have played a crucial role in combating adulterated TCMs. However, STMs represent merely a product testing-centered regulatory strategy. The inspection of cultivation and manufacturing processes should also be strengthened. More importantly, the awareness and self-discipline of TCM manufacturers in implementing good manufacturing practices and regulating the planting and cultivation of raw materials should be improved.

Drug regulation is a system to support and protect public health. Drugs with market access must be effective, safe and of high quality. Therefore, drug regulatory decision-making by the competent authorities is made on a scientific basis. Real-world evidence (RWE) from real-world data (RWD) has so far predominantly been taken into account in a supportive manner in drug regulatory decision-making with regard to drug safety after marketing authorisation. The extensive potential of RWE for regulatory decision-making processes along the entire product life cycle has been increasingly used and further examined in recent years.This article provides an overview of current applications of RWE in drug regulatory decision-making processes. The potentials of RWE along with the hurdles to be addressed are described and examples of current projects on RWE research for drug regulation are given. The work is based on current international literature as well as examples from international and European initiatives and regulatory practice, which aim to support an increased use of RWD/RWE in regulatory decision-making processes. In order to be able to utilise the potential of RWE even more in the future, it is important to make relevant RWD sources more readily available through research projects and initiatives, to further develop evaluative methods and to establish the significance of RWE., (© 2024. The Author(s).)

Nitrofurantoin has shown exceptional durability against resistance over 70 years of use. This longevity stems from factors such as rapid achievement of therapeutic concentrations, multiple physiological targets against bacteria, low risk of horizontal gene transfer, and the need to acquire multiple mutations to achieve resistance. These combined features limit resistance emergence and spread of nitrofurantoin resistance. We propose nitrofurantoin as an exemplar for developing other durable treatments., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2024.)

Modeling and simulation (M&S), including in silico (clinical) trials, helps accelerate drug research and development and reduce costs and have coined the term "model-informed drug development (MIDD)." Data-driven, inferential approaches are now becoming increasingly complemented by emerging complex physiologically and knowledge-based disease (and drug) models, but differ in setup, bottlenecks, data requirements, and applications (also reminiscent of the different scientific communities they arose from). At the same time, and within the MIDD landscape, regulators and drug developers start to embrace in silico trials as a potential tool to refine, reduce, and ultimately replace clinical trials. Effectively, silos between the historically distinct modeling approaches start to break down. Widespread adoption of in silico trials still needs more collaboration between different stakeholders and established precedence use cases in key applications, which is currently impeded by a shattered collection of tools and practices. In order to address these key challenges, efforts to establish best practice workflows need to be undertaken and new collaborative M&S tools devised, and an attempt to provide a coherent set of solutions is provided in this chapter. First, a dedicated workflow for in silico clinical trial (development) life cycle is provided, which takes up general ideas from the systems biology and quantitative systems pharmacology space and which implements specific steps toward regulatory qualification. Then, key characteristics of an in silico trial software platform implementation are given on the example of jinkō.ai (nova's end-to-end in silico clinical trial platform). Considering these enabling scientific and technological advances, future applications of in silico trials to refine, reduce, and replace clinical research are indicated, ranging from synthetic control strategies and digital twins, which overall shows promise to begin a new era of more efficient drug development., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Traditional Chinese medicines (TCMs) represent one form of complementary and alternative medicine. The popularity and complexity in production make them attractive and vulnerable to adulteration in stages ranging from planting to production. Adulteration refers to the addition of extraneous, improper, or inferior ingredients that should not be present in TCMs. To detect and combat adulterated TCMs, supplementary testing methods (STMs), which expand the capability of routine testing standards, have been applied in China since 2003. From 2003 to 2017, a total of 184 STMs for TCMs were approved by the Chinese national drug regulatory authority. By assessing these STMs, this research intends to identify those TCMs vulnerable to adulteration, to list common adulterants, and to characterize the techniques of analysis. The results show that adulteration of TCMs can be classified into three main categories: the addition of undeclared drugs/chemical substances, substitution with non-drug components, and the addition of foreign non-drug materials. The top five therapeutic areas of TCMs vulnerable to adulteration are diabetes, calm and sleep, sexual dysfunction, pain relief, and rheumatism. A total of 166 adulterants were detected in the adulterated TCM preparations and herbal products studied here, with 158 adulterants in TCM preparations and 43 in herbal products, with 35 adulterants in common. Each STM consists of different pharmaceutical analysis techniques, including tests for physical-chemical properties, chromatography, spectroscopic techniques, and mass spectrometry. The analytical methodology of STMs relies on the combination of these techniques, with HPLC ranking the highest percentage (76.1%) and physical-chemical techniques the lowest percentage (11.4%). This research shows that STMs have played a crucial role in combating adulterated TCMs. However, STMs represent merely a product testing-centered regulatory strategy. The inspection of cultivation and manufacturing processes should also be strengthened. More importantly, the awareness and self-discipline of TCM manufacturers in implementing good manufacturing practices and regulating the planting and cultivation of raw materials should be improved. [ABSTRACT FROM AUTHOR]

Focusing on the controversial birth control pills Yaz and Yasmin, this article explores how debates about the safety of these drugs have materialized in risk evaluations and the management of technological risk. Drawing on in-depth interviews with stakeholders and content analysis of legal, medical, and regulatory documents, I highlight how professional contraceptive risk assessment is characterized by systemic uncertainty and doubt, resulting in increased responsibility for users themselves to manage the drugs' potentially increased risks of venous thromboembolism. The analysis centers on three key areas in the assessment process that denote disagreement: risk measurement in postmarket surveillance data, the distinctiveness of the drugs' benefits when compared to other contraceptive technologies, and the weighing of the risks and benefits against each other. While professionals negotiate uncertainty both in epidemiological research and in clinical practice, users are constructed as agents who should manage risk individually. Such processes are underlined by a diffusion of responsibility in the systemic management of contraceptive risk. This article suggests, more broadly, that medical technologies can be conceptualized as artifacts that are instrumental in the dispersion of risks. [ABSTRACT FROM AUTHOR]

Background: Active management of third stage of labor is the most indispensable intervention to avert post-partum hemorrhage which is one of the typical causes of maternal morbidity and mortality. Therefore, the aim of the study was to assess practice and factors associated with active management of third stage of labor among obstetric care providers in referral hospitals. Methods: Institution based cross-sectional study design was conducted from April 1–30, 2018. Simple random sampling technique was used to select a total of 356 obstetric care providers. Data were collected using pretested, structured and self-administered questionnaires. Data were entered to Epi data version 3.1 statistical software and exported to SPSS 23 for analysis. Bivariate and multivariate logistic regression analyses were performed to identify associated factors. P value <0.05 with 95% confidence level were used to declare statistical significance. Result: This study revealed that practice of active management of third stage of labor was 61.2%. Age group of 20–30 years [AOR = 1.95 (95%CI;1.13–3.38)], Being male obstetric care provider [AOR = 1.74 (95%CI;1.03–2.94)], having work experience ≥2 years [AOR = 1.95(95%CI;1.13–3.38)], availability of oxytocin [AOR = 5.46 (95%CI; 2.41–12.3)], having exposure to manage third stage of labor [AOR = 2.91(95%CI; 1.55–5.48)], and having good knowledge [AOR = 2.67 (95%CI; 1.46–4.90)], were the factors associated with practice. Conclusion: This study showed that practice of active management of third stage of labor was high. Age group between 20–30 years, being a male obstetric care provider, having ≥2years work experience, availability of oxytocin, exposure to third stage management and having good knowledge were factors associated with practice. Therefore, all referral hospitals and concerned bodies need efforts to focus on providing training to increase health care provider’s knowledge so as to sustain good practice through appropriate interventions. [ABSTRACT FROM AUTHOR]