Search

Despite regulatory changes designed to stimulate investment in therapies for rare diseases, many of these conditions lack government-approved treatments. Advanced regenerative medicines, which are therapies and clinical interventions aimed at healing or replacing damaged or defective human cells, tissues, and organs, offer great promise for addressing many rare diseases. A major challenge facing advanced regenerative medicines for rare diseases is securing financial support to assist in bringing a therapy to market. This paper describes the factors cited by pharmaceutical industry players globally for sponsoring the development of advanced regenerative medicines for rare diseases. The paper examines the motivations of 53 sponsors that meet the latter criteria. The motivations behind investments were broadly similar amongst sponsors and map closely onto regulatory requirements for clinical development and marketing authorization of advanced therapeutic products, including the presence of accelerated or attenuated pathways for regulatory approval, use for indications with high unmet medical needs, and/or that have advantages over existing therapies, and robust preclinical data. Other factors include availability of investment incentives and opportunities for off-label use in the post-approval stages. [ABSTRACT FROM AUTHOR]

Since the United States Food and Drug Administration (FDA) approved the first chimeric antigen receptor T-cell (CAR-T) therapy in 2017, it has marked a major breakthrough in cancer treatment, leading to a surge in global research and applications in this field. In recent years, China has made rapid progress, quickly catching up through heavy investment in CAR-T construction, preparation processes, and treatment strategies. China's CAR-T therapy market is driven by substantial pharmaceutical investment targeting its vast population, yet high therapy costs remain uncovered by basic medical insurance. In November 2023, FDA issued a warning about the risk of secondary cancers in patients undergoing CAR-T therapy, sparking global concern. In fact, the China National Medical Products Administration (NMPA) preemptively implemented a series of measures to address the safety concerns of CAR-T therapy, emphasizing the risk of secondary cancers and advising lifelong monitoring as part of the approval process for CAR-T products. Nevertheless, additional regulatory measures are needed to address emerging risks, particularly the threat of secondary cancers. The authors believe that raising the standards for Investigational New Drug (IND) approval and establishing a dynamic reporting and feedback system based on real-world data will strengthen regulatory oversight and support the sustainable growth of the CAR-T industry in China. [ABSTRACT FROM AUTHOR]

Medicine shortages are increasingly common and disruptive to the optimal delivery of health care. They are caused by a variety of factors, including manufacturing and supply-chain issues, regulatory and trade issues, and fluctuations in demand. Prescribers and pharmacists in Australia can manage a shortage by switching to another brand, strength or dosage form of the same medicine, switching to a different registered medicine, or accessing an unregistered medicine that has been made available via section 19A of the Therapeutic Goods Act 1989 or through the Special Access Scheme. There are a range of resources and tools that can assist clinicians with identifying and managing medicine shortages in Australia. Shortages are managed most effectively when prescribers, pharmacists and nurses work together, in collaboration with patients, to develop, implement and monitor strategies to manage the shortage. [ABSTRACT FROM AUTHOR]

Abstract Since the United States Food and Drug Administration (FDA) approved the first chimeric antigen receptor T-cell (CAR-T) therapy in 2017, it has marked a major breakthrough in cancer treatment, leading to a surge in global research and applications in this field. In recent years, China has made rapid progress, quickly catching up through heavy investment in CAR-T construction, preparation processes, and treatment strategies. China’s CAR-T therapy market is driven by substantial pharmaceutical investment targeting its vast population, yet high therapy costs remain uncovered by basic medical insurance. In November 2023, FDA issued a warning about the risk of secondary cancers in patients undergoing CAR-T therapy, sparking global concern. In fact, the China National Medical Products Administration (NMPA) preemptively implemented a series of measures to address the safety concerns of CAR-T therapy, emphasizing the risk of secondary cancers and advising lifelong monitoring as part of the approval process for CAR-T products. Nevertheless, additional regulatory measures are needed to address emerging risks, particularly the threat of secondary cancers. The authors believe that raising the standards for Investigational New Drug (IND) approval and establishing a dynamic reporting and feedback system based on real-world data will strengthen regulatory oversight and support the sustainable growth of the CAR-T industry in China.

Alkyl nitrites (“poppers”) are a diverse class of volatile chemical compounds with a varied legal and medical history. Though once commonly prescribed to treat angina, popper use is now almost exclusively recreational. Currently, poppers are widely available and sold legally under labels like “solvent cleaner”, despite marketing suggesting they are meant to be consumed. As a result, there is little incentive for producers to implement robust quality controls to protect users. In this study, nine common popper brands were analyzed using hydrogen-1 and carbon-13 nuclear magnetic resonance spectroscopy to assess the presence of impurities. Physical labels on all nine samples indicated the contents were “pure” isobutyl nitrite, despite contradictory online marketing in several cases. Spectral results showed isobutyl nitrite was present in all popper samples. However, there was evidence that various unlabeled compounds were also present in all samples. The identity and concentration of these contaminants were not clear, but the seemingly ubiquitous presence of impurities and lack of consistency in the tested samples are concerning and may represent a threat to users’ health. We hope the results of this study draw attention to the potential dangers of recreational popper use and the need to reassess how these compounds are regulated.

Alkyl nitrites ("poppers") are a diverse class of volatile chemical compounds with a varied legal and medical history. Though once commonly prescribed to treat angina, popper use is now almost exclusively recreational. Currently, poppers are widely available and sold legally under labels like "solvent cleaner", despite marketing suggesting they are meant to be consumed. As a result, there is little incentive for producers to implement robust quality controls to protect users. In this study, nine common popper brands were analyzed using hydrogen-1 and carbon-13 nuclear magnetic resonance spectroscopy to assess the presence of impurities. Physical labels on all nine samples indicated the contents were "pure" isobutyl nitrite, despite contradictory online marketing in several cases. Spectral results showed isobutyl nitrite was present in all popper samples. However, there was evidence that various unlabeled compounds were also present in all samples. The identity and concentration of these contaminants were not clear, but the seemingly ubiquitous presence of impurities and lack of consistency in the tested samples are concerning and may represent a threat to users' health. We hope the results of this study draw attention to the potential dangers of recreational popper use and the need to reassess how these compounds are regulated. [ABSTRACT FROM AUTHOR]

We sought to quantify exposure to and financial impacts of poly (adenosine diphosphate ribose) polymerase inhibitor (PARPi) treatments for eventually withdrawn ovarian cancer indications. We identified in Optum's deidentified Clinformatics® Data Mart database 1695 patients with ovarian cancer diagnoses who received olaparib, rucaparib, or niraparib between January 2015 and September 2021. We describe PARPi use and out-of-pocket, total healthcare, and PARPi spending among patients with ovarian cancer with 3 or more previous lines of therapy. Of the 1695 patients who received PARPi, 254 were estimated to have been heavily pretreated and exposed to eventually withdrawn indications. Cumulative total medical and pharmacy costs for these patients were $53 392 184; PARPi costs accounted for 34%. Median PARPi cost per patient was $43 347. Cumulative out-of-pocket costs totaled $533 281. Potential patient harm, including financial toxicity, might have been mitigated through more stringent drug approval requirements. • Starting in 2014, 3 poly (adenosine diphosphate ribose) polymerase inhibitors were approved without evidence of overall survival benefit for ovarian cancer treatment of heavily pretreated patients with recurrent disease. Ovarian cancer treatment indications were withdrawn in 2022, after trials demonstrating shorter survival among heavily pretreated patients with recurrent disease. • In addition to potential patient harm from drug exposure, conservative estimates of the number of patients treated with poly (adenosine diphosphate ribose) polymerase inhibitor for the withdrawn indications demonstrated significant financial impact for patients and the healthcare system. • Financial toxicity of Food and Drug Administration cancer drug approvals without evidence of clinical benefit must be considered. [ABSTRACT FROM AUTHOR]

The aim of this paper is to shed light on and critically evaluate the potential impact of evidential pluralism in the realm of pharmaceutical regulation. In the complex landscape of drug evaluation and approval, the role of evidence is pivotal. Firstly, we delve into the role of evidence of mechanisms within drug regulation, with a particular focus on the Accelerated Approval pathway administered by the US Food and Drug Administration. Our analysis reveals that this program, in practice, closely resembles a pluralistic approach to evidence. Secondly, we undertake a thorough examination of the reliability of evidential pluralism within the context of drug regulation. We dissect and discuss the open-cases approach recently put forth by Sung and Holman. While acknowledging its potential merits, we also identify and articulate significant limitations inherent in this approach. Finally, we propose an alternative empirical approach that centres on the real-world outcomes of regulatory programs. [ABSTRACT FROM AUTHOR]

PARP inhibitors in ovarian cancer have been a breakthrough therapy of the past decade, driven by positive trial results, and supported by an original pharmacological rationale. However, with mature data, detrimental survival results led to the withdrawals, in 2022, of all approved PARP inhibitors in the most advanced settings' indication (as monotherapy in third or subsequent lines) by the US Food and Drug Administration (FDA). Two other indications, as maintenance after relapse, were also restricted. In this work, based on pooled meta-analysis in each setting, we question a unique situation in oncology: a survival benefit is seen in front-line settings, with, at the same time, a survival decrement in later lines. Either this original feature is explained by the unique biological action of PARP inhibitors-through synthetic lethality-in patients with ovarian cancer and homologous repair deficiency. Another explanation may be trial design: decrement in later lines could partly explain why beneficial results were seen in early settings, simply by avoiding late exposure to PARP inhibitors in the experimental arm in those trials. High crossover rates seen in some trials further support this alternate hypothesis. We contend our analysis and recent survival results of PARP inhibitors warrant a whole reassessment of the place of these compounds in the landscape of ovarian cancer treatments.

BackgroundSuboptimal treatment upon progression may affect overall survival (OS) results in oncology randomized controlled trials (RCTs). We aim to assess the proportion of trials reporting post-progression treatment.MethodsThis cross-sectional analysis included two concurrent analyses. The first one examined all published RCTs of anti-cancer drugs in six high impact medical/oncology journals between January 2018 and December 2020. The second studied all US Food and Drug Administration (FDA) approved anti-cancer drugs during the same period. Included trials needed to study an anti-cancer drug in the advanced or metastatic setting. Data abstracted included the tumor type, characteristics of trials, and reporting and assessment of post-progression treatment.ResultsThere were 275 published trials and 77 US FDA registration trials meeting inclusion criteria. Assessable post-progression data were reported in 100/275 publications (36.4%) and 37/77 approvals (48.1%). Treatment was considered substandard in 55 publications (n = 55/100, 55.0%) and 28 approvals (n = 28/37, 75.7%). Among trials with assessable post-progression data and positive OS results, a subgroup analysis identified substandard post-progression treatment in 29 publications (n = 29/42, 69.0%) and 20 approvals (n = 20/26, 76.9%). Overall, 16.4% of publications (45/275) and 11.7% of registration trials (9/77) had available post-progression data assessed as appropriate.ConclusionWe found that most anti-cancer RCTs do not report assessable post-progression treatment. When reported, post-progression treatment was substandard in most trials. In trials reporting positive OS results and with assessable post-progression data, the proportion of trials with subpar post-progression treatment was even higher. Discrepancies between post-progression therapy in trials and the standard of care can limit RCT results' applicability. Regulatory rules should enforce higher requirements regarding post-progression treatment access and reporting.

BackgroundIn 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.MethodsThe 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.ResultsThe 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.ConclusionThese 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.

Summary: 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.

Copyright of Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz is the property of Springer Nature 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.)

Aims: To describe characteristics of applicant, tool, outcomes, regulatory responses and general learnings from European Medicines Agency (EMA) Qualification Procedures on patient‐reported outcomes (PROs), observer‐reported outcomes (ObsROs) and performance outcomes (PerfOs) finalized between January 2013 and December 2018. Methods: Descriptive analysis, and qualitative review of the regulatory outcomes of the study procedures. Results: Seventeen qualification programmes for PROs, 6 for ObsRO tools and 11 for PerfO tools were submitted by consortia, large and small/medium companies. Gastroenterology and neurology were the most frequent therapeutic areas. There was a high level of regulators' partial agreement (above 70%) with applicant's approaches with constructive input; EMA published Letters of Support for PRO (6), ObsRO (2) and PerfO (4) tools, and Qualification Opinions on PROs (2) and PerfOs (1). General issues related to Qualification Procedures on PROs raised by EU regulatorsincluded: population, appropriate studies to demonstrate ability to detect change, tool validation in interventional trials, anchoring, identification of the minimally important difference, item selection, weighting, and multiple domains. In addition, specific issues for ObsROs and PerfO tools validation are identified. Conclusions: Regulators discussed principles and challenges of validation tailored to specific setting in tool development, providing constructive feedback. Regulatory outputs supportive of further development were published in over one‐third of programs. We encourage applicants intending to use or develop novel PRO, ObsRO and PerfO tools that will generate evidence for regulatory submissions on medicines to consider Qualification procedures for novel methods to seek feedback on the development and validation of these tools. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration's controversial decision to grant accelerated approval to aducanumab (Aduhelm), a therapy for Alzheimer's disease, has motivated multiple policy reforms. Drawing a case series of other drugs granted accelerated approval and interviews of senior FDA officials, I argue that reform should be informed but not defined by aducanumab. Rather, structural reforms are needed to reshape FDA's core priorities and restore the regulatory system's commitment to scientific rigor. [ABSTRACT FROM AUTHOR]

In "Missing the Forest for the Trees: Aduhelm, Accelerated Approvals & the Agency," Dr. Matthew Herder argues that agency capture and politicized discretion drive delays in confirmatory trials of accelerated approval drugs amongst other concerns at US Food and Drug Administration (FDA). In highlighting this important problem and offering nuanced insight into agency workings based in part on interviews with twenty-three unnamed FDA officials and a three-drug case study, Dr. Herder suggests two innovative solutions. However, amidst broader debates balancing agency expertise, data, and delegation, these proposed policy solutions would benefit from more corroborative evidence and consideration of institutional advantages within constitutional limits. [ABSTRACT FROM AUTHOR]

Abstract Background Suboptimal treatment upon progression may affect overall survival (OS) results in oncology randomized controlled trials (RCTs). We aim to assess the proportion of trials reporting post-progression treatment. Methods This cross-sectional analysis included two concurrent analyses. The first one examined all published RCTs of anti-cancer drugs in six high impact medical/oncology journals between January 2018 and December 2020. The second studied all US Food and Drug Administration (FDA) approved anti-cancer drugs during the same period. Included trials needed to study an anti-cancer drug in the advanced or metastatic setting. Data abstracted included the tumor type, characteristics of trials, and reporting and assessment of post-progression treatment. Results There were 275 published trials and 77 US FDA registration trials meeting inclusion criteria. Assessable post-progression data were reported in 100/275 publications (36.4%) and 37/77 approvals (48.1%). Treatment was considered substandard in 55 publications (n = 55/100, 55.0%) and 28 approvals (n = 28/37, 75.7%). Among trials with assessable post-progression data and positive OS results, a subgroup analysis identified substandard post-progression treatment in 29 publications (n = 29/42, 69.0%) and 20 approvals (n = 20/26, 76.9%). Overall, 16.4% of publications (45/275) and 11.7% of registration trials (9/77) had available post-progression data assessed as appropriate. Conclusion We found that most anti-cancer RCTs do not report assessable post-progression treatment. When reported, post-progression treatment was substandard in most trials. In trials reporting positive OS results and with assessable post-progression data, the proportion of trials with subpar post-progression treatment was even higher. Discrepancies between post-progression therapy in trials and the standard of care can limit RCT results’ applicability. Regulatory rules should enforce higher requirements regarding post-progression treatment access and reporting.

BackgroundThis study examined multiple aspects about the approval of new drugs: the characteristics of the drugs, the quality and quantity of information that Health Canada discloses about the demographics of patients enrolled in clinical trials, the characteristics of the trial, and the type of review that it uses. It examines whether there have been changes in these measures between 1 September 2012 and 31 March 2022.MethodsA list of all new drugs approved, type of review used, and drug characteristics was generated from Health Canada annual reports. Therapeutic categories were identified from the World Health Organization Collaborating Center for Drugs Statistics Methodology. The Summary Basis of Decision documents of Health Canada were used to identify patient demographics in clinical trials and clinical trial characteristics.ResultsHealth Canada approved 326 new drugs for 407 indications. The percent of orphan drugs approved increased from 35.6 to 51.3%. The number of indications per drug decreased (p = 0.0817) as did the number of pivotal trials per drug (p = 0.0091). The percent of Phase 3 trials dropped from 76.3% in 2012–2015 to 64.8% in 2019–2022 (p = 0.005). There was also a statistically significant decrease in the percent of trials that were randomized, controlled, and blinded. The clinical trial characteristics of orphan drugs and the type of review used were both significantly different compared with non-orphan drugs. The percent of trials which had information about the number of patients enrolled, the percent of trials that provided the age of the patients, and the sex breakdown all significantly increased.ConclusionThe results show that there has been a change in regulatory standards that may be due to them becoming less rigorous, because of an adaptation to the number of orphan drugs being submitted or a combination of both reasons. At the same time, there has been some improvement in the transparency of data. Health Canada has recently embarked on a series of reforms in drug regulation and clinical trial management. These changes need to be closely evaluated to be sure that they enhance the efficacy and safety of new drugs.

Drugs addressing unmet medical needs can change the lives of millions. Developing and validating new drugs can, however, take many years. To streamline the assessment of new drugs, regulatory agencies have long established shortened review pathways. Among these programs, Accelerated Approval (AA) has recently come under scrutiny due to the U.S. Food and Drug Administration's decision to authorize Aducanumab, the first Alzheimer's disease drug. This decision attracted fierce criticism due to the allegedly insufficient evidence about the safety and efficacy of the drug. While considerable scholarly attention has been devoted to this case, the ethical aspects of the AA regulatory pathway have so far remained relatively unexplored. In this paper, we set out to fill this gap. We illustrate six conditions that should be met for AA to be ethically acceptable: moral solicitude, evidence, risk mitigation, impartiality, sustainability, and transparency. We discuss such conditions and suggest practical steps to implement them in regulatory and oversight processes. Taken together, our six conditions represent a benchmark for assessing the ethical validity of AA processes and decisions. [ABSTRACT FROM AUTHOR]

Aims: In 2017, two distinct interventions were implemented in Ireland and England to reduce prescribing of lidocaine medicated plasters. In Ireland, restrictions on reimbursement were introduced through implementation of an application system for reimbursement. In England, updated guidance on items which should not be routinely prescribed in primary care, including lidocaine plasters, was published. This study aims to compare how the interventions impacted prescribing of lidocaine plasters in these countries. Methods: We conducted an interrupted time‐series study using general practice data. For Ireland, monthly dispensing data (2015–2019) from the means‐tested General Medical Services (GMS) scheme was used. For England, data covered all patients. Outcomes were the rate of dispensings, quantity and costs of lidocaine plasters, and we modelled level and trend changes from the first full month of the policy/guidance change. Results: Ireland had higher rates of lidocaine dispensings compared to England throughout the study period; this was 15.22/1000 population immediately pre‐intervention, and there was equivalent to a 97.2% immediate reduction following the intervention. In England, the immediate pre‐intervention dispensing rate was 0.36/1000, with an immediate reduction of 0.0251/1000 (a 5.8% decrease), followed by a small but significant decrease in the monthly trend relative to the pre‐intervention trend of 0.0057 per month. Conclusions: Among two different interventions aiming to decrease low‐value lidocaine plaster prescribing, there was a substantially larger impact in Ireland of reimbursement restriction compared to issuing guidance in England. However, this is in the context of much higher baseline rates of use in Ireland compared to England. [ABSTRACT FROM AUTHOR]

Hypotonic intravenous (IV) fluids are associated with an increased risk of hospital-acquired hyponatraemia, eventually leading to brain injury and death. We evaluated the effectiveness of a treatment guide to improve prescribing practices of IV fluids. We conducted a before-and-after cross-sectional survey among physicians working at Danish emergency departments. The primary outcome was prescribing practices of IV fluids. Participants were asked which IV fluid they would select in four clinical scenarios. We applied multivariate logistic regression models to estimate the odds ratio of selecting hypotonic fluids. Secondary outcomes included knowledge about IV fluids and hyponatraemia, and the receipt, reading, and usefulness of the treatment guide. After the intervention, about a third (47/154) reported that they would use hypotonic fluids in patients with increased intracranial pressure, and a quarter (39/154) would use hypotonic maintenance fluids in children, both of which are against guideline recommendations. A total of 46% selected the correct fluid, a 3% hypertonic saline solution for a patient with hyponatraemia and severe neurological symptoms. None of the knowledge questions met the predefined criteria of success of 80% correct answers. Of the respondents, 22% had received the treatment guide. Since the implementation failed, we recommend improving distribution by applying methods from implementation science. [ABSTRACT FROM AUTHOR]

The U.S. Food and Drug Administration's (FDA) 2013 decision to lower recommended Ambien dosing for women has been widely cited as a hallmark example of the importance of sex differences in biomedicine. Using regulatory documents, scientific publications, and media coverage, this article analyzes the making of this highly influential and mobile 'sex-difference fact'. As we show, the FDA's decision was a contingent outcome of the drug approval process. Attending to how a contested sex-difference fact came to anchor elite women's health advocacy, this article excavates the role of regulatory processes, advocacy groups, and the media in producing perceptions of scientific agreement while foreclosing ongoing debate, ultimately enabling the stabilization of a binary, biological sex-difference fact and the distancing of this fact from its conditions of construction. [ABSTRACT FROM AUTHOR]

COVID-19 vaccines were developed and approved rapidly in response to the urgency created by the pandemic. No specific regulations existed at the time they were marketed. The regulatory agencies therefore adapted them as a matter of urgency. Now that the pandemic emergency has passed, it is time to consider the safety issues associated with this rapid approval. The mode of action of COVID-19 mRNA vaccines should classify them as gene therapy products (GTPs), but they have been excluded by regulatory agencies. Some of the tests they have undergone as vaccines have produced non-compliant results in terms of purity, quality and batch homogeneity. The wide and persistent biodistribution of mRNAs and their protein products, incompletely studied due to their classification as vaccines, raises safety issues. Post-marketing studies have shown that mRNA passes into breast milk and could have adverse effects on breast-fed babies. Long-term expression, integration into the genome, transmission to the germline, passage into sperm, embryo/fetal and perinatal toxicity, genotoxicity and tumorigenicity should be studied in light of the adverse events reported in pharmacovigilance databases. The potential horizontal transmission (i.e., shedding) should also have been assessed. In-depth vaccinovigilance should be carried out. We would expect these controls to be required for future mRNA vaccines developed outside the context of a pandemic. [ABSTRACT FROM AUTHOR]

Copyright of Saúde e Sociedade is the property of Universidade de Sao Paulo, Faculdade de Saude Publica 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.)

"The Regulation of Drugs in Plato's Laws". In the standard manuscript of the Laws --the Parisinus Graecus 1807 of the 9th Century AD-- this dialogue is placed between the Minos and the Epinomis. While in the Minos the pupil refers to the diversity of rites and traditions that can be observed amongst different peoples, the Epinomis stresses the unity of the law. The regulation of symposia, the access to drugs, to intoxicating drinks and to medicine is a fundamental theme of the Laws. This is evident already from the composition of the dialogue, since this theme is discussed in its first books. The art of regulating communal life is shown as a technique that can be perfected through dialogue. Communal drinking can be beneficial, says the anonymous Athenian foreigner, since wine encourages citizens to sing, and through the confrontation with pleasure citizens are able to exercise temperance. Since the consumption of wine may also produce excesses and loss of constraint, its consumption should be regulated. The Athenian proposes a minimal age limit for wine drinking: 18 years old (Laws, 2.666a-e). The position of the Athenian foreigner concerning the regulation of drugs is a message that might be called "antiprohibitionist", although not in the contemporary sense (individualist and liberal), but in the sense that an absolute prohibition of drug consumption for the citizens is not defended: the proposal is to allow its consumption, but under a legal and communitarian regulation. [ABSTRACT FROM AUTHOR]

Aims: Chirality of drugs might be associated with safety issues through pharmacokinetic or pharmacodynamic variations, interactions, or direct toxicological responses. We aimed to compare chiral status of the available drugs to that of drugs withdrawn due to adverse drug reactions (ADRs). Methods: We searched the literature regarding withdrawn drugs due to safety‐related issues (n = 391) to compare them with all available small‐molecule drugs (n = 1633). We examined their chiral status and assigned as achiral compound, chiral mixture or pure enantiomer. We compared the mean survival (i.e., nonwithdrawal) time and withdrawal rates of drugs by their chirality, with further stratification by the launch year, ATC‐1 (Anatomical Therapeutic Chemical) level and ADR. Results: We identified higher withdrawal rate in achiral drugs (hazard ratio 2.1, 95% CI: 1.6–2.7) and chiral mixtures (hazard ratio 2.6, 95% CI: 1.9–3.5) compared to that in pure enantiomers. Pure enantiomers had the longest mean survival time (62.4 ± 0.8 years), followed by achiral drugs (55.4 ± 0.9 years, P <.01) and chiral mixtures (52.4 ± 1.4 years, P <.01). Pure enantiomers had higher survival rates than chiral mixtures if launched before 1941 (P =.02), in 1961–1980 (P <.001) or 1981–2000 (P <.001). Pure enantiomers had lower withdrawal rate (18.2%) vs. chiral mixtures (35.1%, P =.02) in nervous system drugs. Pure enantiomers had lower withdrawal rate than chiral mixtures in hepatotoxic (P <.01) and cardiovascular ADRs (P <.01). Conclusion: Our study showed lower likelihood of withdrawal for pure enantiomers compared to that in chiral mixtures and achiral drugs, which was more remarkable for those launched in certain time periods and several ADRs, including hepatotoxicity and cardiovascular toxicity. [ABSTRACT FROM AUTHOR]

Innovative health technologies are not well regulated under current pathways, leading regulators to adopt contextual, life-cycle regulatory models, which authorize drugs based on earlier clinical evidence subject to the conduct of post-market trials that confirm clinical benefit and safety. In this paper, we evaluate all drugs authorized in Canada under the Notice of Compliance with conditions (NOC/c) policy from 1998 to 2021 to analyze its function, identify challenges and areas for improvement, and make recommendations to inform Health Canada's regulatory reforms. We analyzed a sample of 148 drugs authorized between 1998 and 2021, including characteristics about the pre- and post-market clinical trials, finding that most NOC/c authorizations are based on one, single-arm clinical trial using a surrogate endpoint. Post-market trials are more likely to be randomized, Phase III trials but mostly use surrogate endpoints. Based on our findings, we recommend increasing decision-making transparency throughout the regulatory process, developing comprehensive eligibility criteria for selecting appropriate health technologies, modernizing pre-market evidence requirements, adopting a more active role in designing post-market trials, and utilizing automatic expiry, stronger penalties, and ongoing disclosure of the status of post-market trials to promote compliance. [ABSTRACT FROM AUTHOR]

Drugs are increasingly authorized based on less mature evidence, leaving payors faced with significant clinical and cost-effectiveness uncertainties. As a result, payors must often choose between reimbursing a drug that may not turn out to be cost-effective (or may even be unsafe) or delaying the reimbursement of a drug that is cost-effective and offers clinical benefit to patients. Novel reimbursement decision models and frameworks, such as managed access agreements (MAAs), may address this decision challenge. Here, we provide a comprehensive overview of the legal limitations, considerations, and implications for adopting MAAs in Canadian jurisdictions. We begin with an overview of current drug reimbursement processes in Canada, terminology and definitions of the different types of MAAs, and select international experiences with MAAs. We discuss the legal barriers to MAA governance frameworks, design and implementation considerations, and legal and policy implications of MAAs. Finally, we provide recommendations to guide policy development for implementing MAAs in Canada, based on existing literature, international experience, and our legal analysis. We conclude that legal and policy barriers likely prevent the adoption of a pan-Canadian MAA governance framework. More feasible is a quasi-federal or provincial approach, building on existing infrastructure. [ABSTRACT FROM AUTHOR]

This article challenges drug prohibition advocated by UN conventions as the prevailing regulatory model for psychoactive substances, highlighting its ineffectiveness, harmfulness and outdated nature. At the same time, the conventions exclude some psychoactive substances from international regulation, leaving control to individual countries. Presenting an innovative approach, this article outlines an approach to the legal regulation of psychomodulatory substances (psychoactive substances with low health and societal risk) in non-medical contexts. Acknowledging the potential benefits of such psychoactive substances and balancing them with potential harms, it suggests stringent rules for marketing, safety, and preventing sales to minors. This approach aims to quell illicit markets, safeguard vulnerable populations, and encourage controlled use. Through a case study of the Czech Republicʼs introduction of a new category of psychomodulatory substances, this article showcases a paradigm shift from the prevailing repressive approach to drug regulation. This adaptive model effectively navigates the regulatory void, offering a viable alternative to the UNʼs prohibition framework. [ABSTRACT FROM AUTHOR]

The U.S. Food and Drug Administration (FDA) Division of Applied Regulatory Science (DARS) moves new science into the drug review process and addresses emergent regulatory and public health questions for the Agency. By forming interdisciplinary teams, DARS conducts mission-critical research to provide answers to scientific questions and solutions to regulatory challenges. Staffed by experts across the translational research spectrum, DARS forms synergies by pulling together scientists and experts from diverse backgrounds to collaborate in tackling some of the most complex challenges facing FDA. This includes (but is not limited to) assessing the systemic absorption of sunscreens, evaluating whether certain drugs can convert to carcinogens in people, studying drug interactions with opioids, optimizing opioid antagonist dosing in community settings, removing barriers to biosimilar and generic drug development, and advancing therapeutic development for rare diseases. FDA tasks DARS with wide ranging issues that encompass regulatory science; DARS, in turn, helps the Agency solve these challenges. The impact of DARS research is felt by patients, the pharmaceutical industry, and fellow regulators. This article reviews applied research projects and initiatives led by DARS and conducts a deeper dive into select examples illustrating the impactful work of the Division.

Direct‐acting oral anticoagulants (DOACs) are licensed for the prevention of thromboembolism in non‐valvular atrial fibrillation, amongst other indications. Prescribers use information derived from the summary of product characteristics which is based on the key trials supporting the DOAC's market authorisation. However, prescribers may not be aware of the limitations within these trials regarding underrepresentation of patient populations commonly encountered in clinical practice and how this may adversely impact them. This review highlights the gaps in the licensing evidence using four clinical vignettes that explore prescribing challenges in older adults, female patients, patients with obesity and patients from non‐Europid ethnic backgrounds. [ABSTRACT FROM AUTHOR]

Copyright of Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz is the property of Springer Nature 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.)

The development of specific drug therapy for children was a paradigm‐changing event that transformed paediatric medical practice. However, a series of tragedies involving drug treatment for children resulted in a gap developing between drug regulation and practice, with the majority of drugs used in child healthcare being used off‐label, rendering children therapeutic orphans. Over the past two decades changes in drug regulation led by the US Food and Drug Administration and followed by the European Union's European Medicines Agency have led to substantial changes in how new drugs with potential use in children are studied and labelled. While these changes have substantially improved labelling for new drugs, there has been much less progress with older drugs. Although the unique challenges of conducting clinical research in children have been addressed by novel clinical trial designs, many of these innovations have not been translated into approaches accepted for the drug approval process. The regulations applying to the need for paediatric studies currently are only applicable in the United States and the European Union, and there is less impetus for paediatric labelling in other jurisdictions. This impacts on a number of issues beyond labelling, including the availability of child‐friendly formulations. Finally, the impact of Brexit on paediatric drug studies in the UK remains unclear and is subject to ongoing negotiations between the UK government and the European Union. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) is the main storage site of Zn2+, and Zn2+ plays an important role in regulating ER homeostasis. Therefore, we designed and synthesized a ratiometric fluorescent Zn2+ probe ER-Zn targeting ER stress. The probe displayed a specific Zn2+ induced blue shift at the spectral maximum values of excitation (80 nm) and emission (30 nm). The ratio imaging capability of Zn2+ under dual excitation mode can be applied not only to quantitative and reversible detection of exogenous Zn2+, but also the observation of the Zn2+ level change under ER stress, elucidating the different behaviors of Zn2+ release in ER stimulated by tunicamycin and thapsigargin. Additionally, the NIR imaging capability of ER-Zn provides an important basis for further research on animal models and is expected to realize the visualization and treatment of ER stress-related diseases through the regulation of ER stress by Zn2+. We envision that this probe can be applied to screen drugs for diseases related to ER stress regulation. [ABSTRACT FROM AUTHOR]

Patients with rare diseases often have limited or no options for approved treatments or participation in clinical trials. In such cases, expanded access (or "compassionate use") provides a potential means of accessing unapproved investigational medicines. It is also possible to capture and analyze clinical data from such use, but doing so is controversial. In this perspective, we offer examples of evidence derived from expanded access programs for rare diseases to illustrate its potential value to the decision-making of regulators and payers in the European Union and the United States. We discuss ethical and regulatory aspects to the use of expanded access data, with a focus on rare disease medicines. The heterogeneous approach to expanded access among countries within the European Union leaves uncertainties to what extent data can be collected and analyzed. We recommend the issuance of new guidance on data collection during expanded access, harmonization of European pathways, and an update of existing European compassionate use guidance. We hereby aim to clarify the supportive role of expanded access in evidence generation. Harmonization across Europe of expanded access regulations could reduce manufacturer burdens, improve patient access, and yield better data. These changes would better balance the need to generate quality evidence with the desire for pre-approval access to investigational medicine. [ABSTRACT FROM AUTHOR]

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

Background: To "limit the risk of abuse and misuse" and "encourage correct usage", the French drug regulatory authority stated that—from April 2017—zolpidem prescription must be performed on a secured prescription pad. This national study aims to evaluate the perception of general practitioners (GPs) towards this new regulation and its link with prescription strategies. Methods: We conducted structured interviews of GPs. Data were collected about GPs' perception of the measure and therapeutic strategies towards zolpidem. The primary outcome was the description of the GPs' strategy of prescription, based on the perception towards the new regulation for zolpidem. Results: For 206 GPs, the new regulation was mainly perceived as helpful (61%) and as a difficulty (55%). Other perceptions were the awareness of the risks of zolpidem (18%), awareness of the risks of hypnotics (13%), and nothing changed (5%). Four clusters of GPs were identified. In the clusters with the perception as a difficulty (only or associated with helpful), the GPs who applied the strategy "no modification" for >50% of their patients were more frequently compared to awareness and helpful only clusters (60.8%; 42.9%; 20.4%; 26.7%) (p < 0.001). Conclusions: We highlighted an association between the perception of the new regulation of zolpidem prescription by GPs and a strategy of prescription. [ABSTRACT FROM AUTHOR]

Older people are often affected by impaired organ and bodily functions resulting in multimorbidity and polypharmacy, turning them into the main user group of many medicines. Very often, medicines have not specifically been developed for older people, causing practical medication problems for them like limited availability of easy to swallow formulations, easy to open packaging and dosing instructions for enteral administration. In 2020, the European Medicines Agency (EMA) published a reflection paper 'Pharmaceutical development of medicines for use in the older population', which discusses how the emerging needs of an ageing European population can be addressed by medicines regulation. The paper intends to help industry to better consider the needs of older people during pharmaceutical/clinical medicines development by summarising data on the most relevant topics, providing early suggestions on how to move forward and prompting expert discussions and studies into knowledge gaps. Topics include patient acceptability, (dis)advantages of an administration route, formulation, dosage form, packaging, dosing device and user instruction. While the paper is directed at older people and the pharmaceutical industry, the reflections are also relevant to younger patients with similar disease‐related needs and of value to other stakeholders parties, e.g., healthcare professionals, academics, patients and caregivers, as the paper makes clear what can be expected from industry and where collaborative work is needed. This commentary provides an overview of the different steps in the development of the reflection paper, discusses points considered most controversial and/or subject to (multidisciplinary) expert discussions and indicates their value for real world clinical practice. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

The endoplasmic reticulum (ER) is the main storage site of Zn2+, and Zn2+ plays an important role in regulating ER homeostasis. Therefore, we designed and synthesized a ratiometric fluorescent Zn2+ probe ER-Zn targeting ER stress. The probe displayed a specific Zn2+ induced blue shift at the spectral maximum values of excitation (80 nm) and emission (30 nm). The ratio imaging capability of Zn2+ under dual excitation mode can be applied not only to quantitative and reversible detection of exogenous Zn2+, but also the observation of the Zn2+ level change under ER stress, elucidating the different behaviors of Zn2+ release in ER stimulated by tunicamycin and thapsigargin. Additionally, the NIR imaging capability of ER-Zn provides an important basis for further research on animal models and is expected to realize the visualization and treatment of ER stress-related diseases through the regulation of ER stress by Zn2+. We envision that this probe can be applied to screen drugs for diseases related to ER stress regulation.

Patients with rare diseases often have limited or no options for approved treatments or participation in clinical trials. In such cases, expanded access (or “compassionate use”) provides a potential means of accessing unapproved investigational medicines. It is also possible to capture and analyze clinical data from such use, but doing so is controversial. In this perspective, we offer examples of evidence derived from expanded access programs for rare diseases to illustrate its potential value to the decision-making of regulators and payers in the European Union and the United States. We discuss ethical and regulatory aspects to the use of expanded access data, with a focus on rare disease medicines. The heterogeneous approach to expanded access among countries within the European Union leaves uncertainties to what extent data can be collected and analyzed. We recommend the issuance of new guidance on data collection during expanded access, harmonization of European pathways, and an update of existing European compassionate use guidance. We hereby aim to clarify the supportive role of expanded access in evidence generation. Harmonization across Europe of expanded access regulations could reduce manufacturer burdens, improve patient access, and yield better data. These changes would better balance the need to generate quality evidence with the desire for pre-approval access to investigational medicine.

Proactive and objective regulatory risk management of ongoing clinical trials is limited, especially when it involves the safety of the trial. We seek to prospectively evaluate the risk of facing adverse outcomes from standardized and routinely collected protocol data. We conducted a retrospective cohort study of 2860 Phase 2 and Phase 3 trials that were started and completed between 1993 and 2017 and documented in ClinicalTrials.gov. Adverse outcomes considered in our work include Serious or Non-Serious as per the ClinicalTrials.gov definition. Random-forest-based prediction models were created to determine a trial's risk of adverse outcomes based on protocol data that is available before the start of a trial enrollment. A trial's risk is defined by dichotomic (classification) and continuous (log-odds) risk scores. The classification-based prediction models had an area under the curve (AUC) ranging from 0.865 to 0.971 and the continuous-score based models indicate a rank correlation of 0.6–0.66 (with p-values < 0.001), thereby demonstrating improved identification of risk of adverse outcomes. Whereas related frameworks highlight the prediction benefits of incorporating data that is highly context-specific, our results indicate that Adverse Event (AE) risks can be reliably predicted through a framework of mild data requirements. We propose three potential applications in leading regulatory remits, highlighting opportunities to support regulatory oversight and informed consent decisions. [ABSTRACT FROM AUTHOR]

Background: Regulatory assessment of anthroposophic medicinal products (AMPs) can be challenging due to their specific features. Objective: The aim of this paper is therefore to provide adequate scientific information on AMPs for regulatory purposes. Methods: A literature review was executed with database searches in PubMed, Cinahl, Merkurstab, Anthromedics, and https://iaap-pharma.org/. Search terms were: anthroposophic medicinal products, anthroposophic medicines, anthroposophic pharmacy. There was no language restriction; searches were executed from onset until June 11, 2020. In addition, experts were invited to suggest relevant literature. Results: Eighty-seven of 660 identified publications were included. The system of anthroposophic medicine (AM) with its conceptual background and various aspects of AMPs was described: definition, pharmaceutical properties, an example of AMP development, use in clinical practice, similarities with and differences to conventional medicinal products, societal aspects, scientific and regulatory assessment. Conclusion: AMPs are part of the integrative whole medical system of AM. AMPs are manufactured according to Good Manufacturing Practice and national drug regulations and have an excellent safety status; the limited available evidence suggests clinical benefits. Current drug regulation of AMPs in the EU and most European countries does not take the special properties of AMPs into account. Future research should focus on appropriate methodologies for the evaluation of effects of AMPs as part of the AM whole medical system, the scientific quality of its non-atomistic holistic ontological position, and the integration of AM and conventional medicine in clinical practice. Future policies should focus on appropriate ways of addressing regulatory challenges to AMPs. [ABSTRACT FROM AUTHOR]