Drug Regulation Research Articles

Simultaneous Global Drug Development and Multiregional Clinical Trials (MRCT): 5 Years After Implementation of ICH E17 Guidelines.

The ICH E17 guidelines (2014-2017) on Multiregional Clinical Trials (MRCT) was a joint effort by the regulators and industry to facilitate simultaneous global drug development and registration through taking a strategic approach for clinical trials. In other words, the objective was to reduce the time it takes to bringing medications to patients around the world through minimizing unnecessary duplication of local or regional studies, which may add the regulatory burden to cost and time of bringing new therapies to patients. Under the auspices of ICH, training materials were created and provided to various stakeholders. Despite the successful promotion of the benefits of ICH E17 MRCT guidelines across the different regions, the uptake of some concepts (e.g., pooling strategy) in the ICH E17 guidelines has been slow. This paper describes various factors which could affect the conduct of MRCT at a global level, including ambiguity in definition of "region" (in MRCT), new regulatory requirements to enroll a diverse patient population, the use of decentralized clinical trials, use of data sources other than randomized clinical trials (e.g., use of Real Word Data), and the impact of the COVID-19 pandemic on the conduct of MRCT.

Merging the Worlds of Pets and Pills: Development and Evaluation of an Interprofessional Activity Linking Pharmacy and Veterinary Medicine

AbstractInterprofessional education (IPE) is noticeably lacking between pharmacy and veterinary medicine students despite the two health professions overlapping in practice. To address this, an asynchronous IPE activity was developed together with practicing pharmacists and veterinarians. Students worked in groups across two campuses to discuss clinical cases, specifically requiring input from both professions. Students reported they learned more about the two professions’ interconnection, felt prepared to interact with the other professionals in the future, and found value in learning from each other. Overall, the results of this study outline a successful pilot IPE activity between veterinary medicine and pharmacy students.

Revolutionizing Cardiovascular Frontiers: A Dive Into Cutting-Edge Innovations in Coronary Stent Technology.

Plain balloon angioplasty was the initial method used to enlarge the intracoronary lumen size. However, it was linked to acute coronary closure due to early vessel recoil. This led to the invention of coronary stents, which offer mechanical support to open and maintain the vascular lumen. Nevertheless, the metallic scaffold introduced other issues, such as thrombosis and restenosis caused by neointimal proliferation. To address these concerns, polymers were employed to cover the scaffold, acting as drug reservoirs and regulators for controlled drug release. The use of polymers prevents direct contact between blood and metallic scaffolds. Drugs within the stent were incorporated to inhibit proliferation and expedite endothelialization in the healing process. Despite these advancements, adverse effects still arise due to the inflammatory reaction caused by the polymer material. Consequently, resorbable polymers and scaffolds were later discovered, but they have limitations and are not universally applicable. Various scaffold designs, thicknesses, materials, polymer components, and drugs have their own advantages and complications. Each stent generation has been designed to address the shortcomings of the preceding generation, yet new challenges continue to emerge. Conflicting data regarding the long-term safety and efficacy of coronary stents, especially in the extended follow-up, further complicates the assessment.

Cripistemologies of Drug Use Against Transinstitutional Carceral Ableism

Across Canada, thousands of drug users are dying from a toxic illicit drug supply resulting from oppressive drug policies and regulations that reinforce the prohibition and criminalization of drug use and the pathologization and rehabilitation of drug users. Bringing together critical drug studies and critical disability studies, the article contributes cripistemologies of drug use to unpack some of the ways transinstitutional carceral ableism conjoins control strategies of punishment-therapy-abandonment to unite both medical and carceral approaches to disability and drug use that have debilitating and deadly consequences. Against transinstitutional carceral ableism, the article mobilizes cripistemologies of drug use to trouble and reject the disposability of non-rehabilitated drug users central to medical and carceral approaches and instead favour consensual and pleasurable drug use via care practices grounded in interdependence, mutual aid, and solidarity.

Status and trends of legislative and regulatory regulation of off-label use of drugs: A review

The off-label use of drugs is a common practice worldwide. The legal basis for off-label medical use varies from country to country. Regulatory control of the pharmaceutical market in the off-label preventive and therapeutic practice at the international and national levels has become a breakthrough with the emergence of the coronavirus pandemic. The prospects for off-label use in the context of innovations in the legislation of public health in the Russian Federation are crucial. Professionally significant aspects of the use of medicinal products outside the Summary of Product Characteristics and the off-label use have been introduced by supranational regulatory authorities for the common market of medicinal products of the Eurasian Economic Union. Special attention should be paid to the regulatory control of the use of extemporaneous medicines as part of improving the government regulation of drug compounding in pharmacies. The active development of pharmacy activities in drug compounding within the framework of improving regulatory practice determines the relevance of actual off-label prescriptions and the use of extemporaneous formulations. Aim – to perform a systematic analysis of national, transnational legislative and regulatory documents regulating off-label use of medicinal products, determine the main conceptual components of the current regulatory pool and directions for future development in this area. Systematic analysis of the national legislative and regulatory pool of documents and the regulatory framework of the common market of medicinal products of the Eurasian Economic Union on the regulation of various aspects of the off-label use of medicinal products. Study of the components and identification of the main trends in the regulatory practice of prescriptions outside the Summary of Product Characteristics and the off-label use. An analytical search was carried out in the reference legal systems "ConsultantPlus" and "Garant" on the official websites of the Ministry of Health of Russia, the Eurasian Economic Union, the RusMed information resource of the National Library resource of Russia in medicine and pharmacy "Central Scientific Medical Library" was used. A logical generalization of the results on the current state of the legal framework and the development of conceptual proposals on the key directions of the prospective development of regulation, control, and supervisory activities of the pharmaceutical off-label use of medicinal products was made.

Qualitative transformations of street-seized ecstasy over a decade: A case study in Rio de Janeiro (Brazil).

The illegal drug market is constantly evolving, with new drugs being created and existing ones being modified. Adulterants are often added to the mix, and the primary substance may be secretly replaced by a new one. Once-known tablets can now be vastly different from what they are sold as, all due to the pursuit of profit and evasion of current drug regulations. These alterations in drug composition pose a threat to society, as their effects are still not well understood. Therefore, it is crucial for police intelligence and public health development to obtain the chemical profiles of illicit drugs. This study presents the chemical fingerprinting of ecstasy tablets seized in the state of Rio de Janeiro (Brazil) between 2012 and 2021. The tablet samples were weighed, extracted, diluted with methanol, and acidified before analysis using gas chromatography high-resolution mass spectrometry and attenuated total reflection Fourier transform infrared spectroscopy. The major constituents found were MDMA and clobenzorex, with fewer occurrences of MDA, MDEA, and 2C-B. The results also indicate that the occurrence of mega-events in the study location impacted the chemical fingerprints of ecstasy. A total of 27 combinations of cutting agents, including caffeine, ephedrine, and anesthetics, were identified. Samples composed of clobenzorex were observed throughout the evaluated period in areas near highways, suggesting that this product is mainly used by truck drivers. These findings can help police intelligence units anticipate the behavior of the illicit market during major events, identify traffic routes, and support public health initiatives.

A Network Enhancement Method to Identify Spurious Drug-Drug Interactions.

As medical safety and drug regulation gain heightened attention, the detection of spurious drug-drug interactions (DDI) has become key in healthcare. Although current research using graph neural networks (GNNs) to predict DDI has shown impressive results, it often fails to account for false DDI in the constructed DDI networks. Such inaccuracies caused by data errors, false alarms, or incorrect drug details can skew the network's structure and hinder the accuracy of GNN-based predictions. To tackle this challenge, we propose ANSM, a network-enhancement method specifically designed to identify and attenuate spurious links between drugs for ensuring the accuracy of DDI networks. ANSM integrates three key components: the feature extractor, the network optimizer, and the discriminative classifier. The feature extractor captures local structural features from drug node pairs, while the network optimizer leverages network information to improve feature extraction and reduce the impact of spurious DDI links. The discriminative classifier then identifies potential spurious links. Experimental results demonstrate that ANSM outperforms state-of-the-art methods in identifying spurious DDI.

ICH S1 prospective evaluation study: weight of evidence approach to predict outcome and value of 2-year rat carcinogenicity studies. A report from the regulatory authorities subgroup.

Introduction: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) initiated a process in 2012 to revise the S1B Guideline "Testing for Carcinogenicity of Pharmaceuticals". Previous retrospective analysis indicated the importance of histopathological risk factors in chronic toxicity studies, evidence of endocrine perturbation, and positive genetic toxicology results as potentially predictive indicators of carcinogenic risk. In addition, a relationship between pharmacodynamic activity and carcinogenicity outcome in long-term rodent studies has been reported. It was postulated that these factors could be evaluated in a Weight-of-Evidence (WoE) approach to predict the outcome of a 2-year rat study. Methods: The ICH S1B(R1) Expert Working Group (EWG) conducted a Prospective Evaluation Study (PES) to determine the regulatory feasibility of this WoE approach. Drug Regulatory Authorities (DRAs) evaluated 49 Carcinogenicity Assessment Documents (CADs), which describe the WoE for submitted pharmaceutical compounds. Each compound was categorized into a carcinogenic risk category including a statement of the value of the 2-year rat study. The outcome of the completed 2-year rat studies was evaluated in relation to the prospective CAD to determine the accuracy of predictions. Results: Based on the results of the PES, the EWG concluded that the evaluation process for assessing human carcinogenic risk of pharmaceuticals described in ICH S1B could be expanded to include a WoE approach. Approximately 27% of 2-year rat studies could be avoided in cases where DRAs and sponsors unanimously agreed that such a study would not add value. Discussion: Key factors supporting a WoE assessment were identified: data that inform carcinogenic potential based on drug target biology and the primary pharmacologic mechanism of the parent compound and major human metabolites; results from secondary pharmacology screens for this compound and major human metabolites that inform carcinogenic risk; histopathology data from repeated-dose toxicity studies; evidence for hormonal perturbation; genotoxicity data; and evidence of immune modulation. The outcome of the PES indicates that a WoE approach can be used in place of conducting a 2-year rat study for some pharmaceuticals. These data were used by the ICH S1B(R1) EWG to write the R1 Addendum to the S1B Guideline published in August 2022.

Patient Experiences of Community Pharmacy Medication Supply and Medicines Reconciliation at Hospital Discharge: A Pilot Qualitative Study.

(1) Background: As part of the Scottish Government's five-year recovery plan to address the backlog in NHS care following the COVID-19 pandemic, community pharmacies in Scotland are planned to provide a Hospital Discharge Medicines Supply and Medicines Reconciliation Service. We aimed to qualitatively explore patients' experiences with this new service. (2) Method: Adult patients (≥18 years age) who consented to participate in the Community Pharmacy Hospital Discharge and Medicines Reconciliation Service were invited for an interview within 21 days of discharge from hospital. Qualitative, one-to-one, semi-structured patient interviews were conducted by telephone and audio-recorded using Microsoft Teams®. The interview audio recordings were transcribed verbatim and underwent thematic analysis. (3) Results: Twelve patients were interviewed, evenly split by sex and with a median age of 62 years (range 36 to 88 years). Our analysis generated main five themes: patient engagement, stakeholder communication, practical factors, human factors, and comparative experiences. Many of these were interdependent. (4) Conclusions: Patients appreciated that the service ensured a quicker discharge from hospital. Good stakeholder communication, practical factors (including choice, location, and the realities of obtaining their medication from the community pharmacy), and a pre-existing and trusted relationship in their usual community pharmacy were the key factors that regulated the patient experience. Generally, patients were positive about the introduction of this new service. However, the lack of a previous relationship or trust with a community pharmacy, and previous experiences with medication supply problems were factors which had the potential to negatively impact patient experiences.

Low-dose colchicine for atherosclerosis: long-term safety.

Low-dose colchicine (0.5 mg daily) is now FDA-approved for secondary prevention in patients with coronary disease and will be increasingly prescribed in clinical practice. In this State-of-the-Art Review, data were collated from contemporary systemic reviews of case reports, drug registries, and placebo-controlled trials that assessed specific issues of safety related to the continuous use of colchicine in a range of clinical settings to inform physicians, pharmacists, and patients of the absolute risks of continuous use of low-dose colchicine, including among individuals taking statin therapy. Based upon these collective data, it is concluded that aside mild diarrhoea on initiation of colchicine that typically subsides in the vast majority of patients within a week of therapy, continuous use of low-dose colchicine is well tolerated and very safe. It does not affect renal, liver, or cognitive function, has no adverse effects on bleeding, wound healing, fertility, or pregnancy, and does not increase risks of cancer, serious infection, or cause-specific mortality. When appropriately prescribed to patients without significant renal or hepatic impairment, reports of myelosuppression, myotoxicity, and serious drug-drug interactions are rare and no more frequent than placebo, including in patients taking statin therapy. Physicians, pharmacists, and patients can be reassured that in the absence of significant renal or hepatic impairment continuous use of low-dose colchicine can be used safely in patients with atherosclerosis for the purpose of reducing cardiovascular risk.

Academia-pharmaceutical industry linkage: An academic perspective.

The pharmaceutical sector in Pakistan has grown over a period, however, there are several barriers in the framework governing the growth of the country's pharmaceuticals. The lack of academia-industry linkage (AIL) is among the critical barriers; hence the focus of the study is to find out the reasons for the lack in the above collaboration. Understanding barriers may help their redressal. This qualitative phenomenology-based study has been conducted in the most prominent pharmacy institutes, located in Lahore, Islamabad, Peshawar, Sargodha, and Quetta. Academic participants, with a minimum experience of 10 years and designation of assistant professor or above were recruited with a two-stage selection process, purposive sampling and snowball sampling. The data were collected using semi-structured interviews with academic experts. Thematic content analysis was employed to conclude the data. Analysis of data yielded 8 themes with 18 codes. The main reasons for neglected AIL were explained by a partial or complete lack of industrial research and development activities. Other key factors for the scarcity of AILs were the lack of positive attitude from both industry and academia, applied research in academics, and the research and development of the new molecules in the pharmaceutical industry. Support by the government and the drug regulatory authority of Pakistan in terms of regulatory and academic policies was also perceived to be absent. New horizons in research and development could be opened by providing applied research to industry, including but not limited to new molecule development. Academia-industry linkage could be boosted with government-backed funded projects and policies. Academia should focus on the industrial-demanded applied research.

Musculoskeletal Health Systematic Review: Clinical and Pharmacological, Organizational and Legal, Administration and Pharmaceutical Management Aspects

This article examines current aspects of musculoskeletal health and pharmacotherapy of disorders of the human musculoskeletal system. An objective review of disorders of the musculoskeletal system was conducted in the areas of administration, clinical and pharmacological, organizational and legal, pharmaceutical management. The results of the systematic review show that the availability of diagnoses in the section "Orthopedics and traumatology" on the platform of the state expert center of the Ministry of Health of Ukraine is limited. It is necessary and urgent to expand the scientific base for practicing doctors. The study confirmed the importance of using new clinical protocols in medical and pharmaceutical practice for the implementation of evidence-based medicine and evidence-based pharmacy in Ukraine. Gradual improvement of medical and pharmaceutical practice allows to increase the quality, efficiency, safety, availability of pharmacotherapy for patients with disorders of the musculoskeletal system. The paper examines guidelines developed on the basis of health evidence provided by Duodecim Medical Publications. The study shows the availability of a wide range of treatment methods and helps to determine optimal therapy strategies in the field of orthopedics. It was found that non-steroidal anti-inflammatory drugs and analgesics are more often prescribed for the pharmacotherapy of disorders of the musculoskeletal system, which emphasizes the perspective of further clinical and pharmacological, organizational and legal researches in the pharmaceutical development and management of new drugs.

MODELLING AND SIMULATION OF NONLINEAR DYNAMIC FLOW FIELD AND TEMPERATURE FIELD OF DEPYROGENATION TUNNEL

Nonlinear dynamics plays a crucial role particularly in equipment validation of preparation production, validation results of which will significantly influence the results and period of drug registration in drug production processes. In this research, the flow field and temperature field simulation, calculation and analysis are creatively carried out in terms of depyrogenation tunnel, a very popular preparation drying-sterilization equipment in pharmaceutical processes with strong dynamic characteristics. After construction of 3D model of this equipment using Catia and mesh generation applying ANSYS, the computational fluid dynamic (CFD) method and verification of irrelevance method are carried out regarding 6.05 million of meshes to identify the flow velocity model and heat transfer model inside the equipment, to further provide methodology for pharmaceutical process validation and to further optimize the design of control methods. After calculation and simulation, the low-velocity vortices of different sizes inside the hood and the drying chamber are identified, which could cause vials to fall down; meanwhile, vials that are farther away from the outlet receives less heat exchange effect, which would shrink the effective sterilization area, indicating an inadequate validation methodology in pharmaceutical processes.

An empirical analysis of overall survival in drug approvals by the US FDA (2006-2023).

The US Food and Drug Administration (FDA) has expanded the use of surrogate markers in drugs approved for oncology/hematology indications. This has likely resulted in a greater number of approvals and possibly drugs coming to market faster, but it is unknown whether these drugs also improve overall survival (OS) for patients taking them. We sought to estimate the percentage of oncology drugs that have shown to improve OS in a cross-sectional analysis of US FDA oncology drug approvals (2006-2023). We searched for OS data in registration trials and the peer-reviewed literature. We found 392 oncology drug approvals. Eighty-seven (22%) drug approvals were based on OS, 147 drug approvals were later tested for OS benefit (38% of all approvals and 48% of drugs approved on a surrogate), and 130 (33%) have yet to be tested for OS benefit. Of the 147 drug approvals later tested for OS, 109 (28% of all approvals and 74% of drugs later tested for OS) have yet to show OS benefit, whereas 38 (10% of all approvals and 26% of drugs later tested for OS benefit) were later shown to have OS benefit. In total, 125 out of 392 (32%) drugs approved for any indication have been shown to improve OS benefit at some point, and 267 (68%) have yet to show approval. About 32% of all oncology drug approvals have evidence for an improvement in OS. Higher standards are needed in drug regulation to ensure that approved drugs are delivering better patient outcomes, specifically in regards to survival.

The Increasing Incidence of Rapes Caused by Illicit Use of Skunchies and Rohypnol Among Youths in Nigeria

The ugly rise in rape cases in Nigeria caused by persistent use of stimulants commonly referred to as ‘skunchies and Rohypnol posed a great challenge for health professionals and drug regulatory authorities. We report two cases of illicit use of controlled or banned substances in the preparation of ‘zobo’ artisanal beverages in some parts of Nigeria and consumed by some youths to be ‘high’. In this case, dried or fresh leaves of marijuana (Cannabis sativa) are soaked in water for 48 hours, and the resulting filtrate will be mixed with cracked cocaine and ethanol. This mixture will then be added to prepared artisanal ‘zobo’ (Hibiscus sabdariffa) beverages and sold to some youths for consumption to be ‘high’. In case two, instead of adding the abovementioned substances to the ‘zobo’ beverages, Rohypnol (Flunitrazepam) a CNS depressant was added. The consequences of using these two preparations by some youths aged between 18 and 40 years are elevated rape cases in Nigeria (with many rape cases unreported). Most of the consumers of these preparations are currently in rehabilitation health centres across the country due to various degrees of CNS imbalance.

Could the medicalization of psychedelics lead to the next generation of antidepressants?

A major part of the counterculture that emerged in western societies in the 1960s centred around the use of mind-altering psychedelic drugs such as lysergic acid diethylamide (LSD). Humans had, however, been consuming hallucinogenic substances since prehistoric times and often incorporated them into their religious rituals. Concerns over the effects of potent psychedelics like LSD led to them being outlawed in many jurisdictions around the world via the UN Convention on Psychotropic Substances in 1971. During the intervening decades, the scientific investigation of psychedelics and their potential for legitimate therapeutic use has consequently been limited. In recent years, hints that psychedelics may be effective against certain treatment-resistant depressive states like post-traumatic stress disorder (PSTD) have led to more concerted efforts to obtain reliable clinical data that could convince drug regulators to approve them as legitimate medical treatments.

Diabetes Technology Meeting 2023.

Diabetes Technology Society hosted its annual Diabetes Technology Meeting from November 1 to November 4, 2023. Meeting topics included digital health; metrics of glycemia; the integration of glucose and insulin data into the electronic health record; technologies for insulin pumps, blood glucose monitors, and continuous glucose monitors; diabetes drugs and analytes; skin physiology; regulation of diabetes devices and drugs; and data science, artificial intelligence, and machine learning. A live demonstration of a personalized carbohydrate dispenser for people with diabetes was presented.

Role of ICH in Harmonising Drug Regulation

Role of ICH in Harmonising Drug Regulation

Neurologijos srityje vartojamų vaistinių preparatų klinikinių tyrimų tendencijos Lietuvoje ir Europoje

Background. As the global burden of neurological diseases has been increasing, clinical trials have become more important. Yet, no systematic analysis of clinical trials of neurological medicinal products has been done in Europe and, specifically, in Lithuania. The aim of this study is to evaluate the tendencies of characteristics and registration dynamics of clinical trials of neurological medicines in Europe and Lithuania.Materials and methods. Analysis of data from the clinical trials register of the European Union drug regulatory authorities (EudraCT) has been performed. Applications of clinical trials of neurological medicines included in the register during the period between 2012–2021 have been reviewed. The following aspects have been evaluated: the phase of the trial, the sponsor status, the neurological condition (indication), the expected sample size of the trial, the trial design, and the number of member countries.Results. 2,242 clinical trials of neurological medicines have been registered in Europe during the period of 2012–2021, and they comprised 6.49% of all clinical trials registered in Europe. The annual registration rates did not change significantly during the period of 2012–2021 (R² = 0.039; p = 0.606). The majority of the trials (72.18%) were sponsored by commercial pharmaceutical companies. Most trials (31.73%) were registered as phase I trials. The majority of the trials (363 (17.20%)) were clinical trials for Alzheimer’s disease and other dementias. During the period of 2012–2021, there was a significant decrease in the annual registration rate of clinical trials for Alzheimer’s disease and other dementias (R² = 0.751, p = 0.001) and an increase of clinical trials for myoneural junction and muscle diseases and motor neuron disease (R² = 0.582, p = 0.010 and R² = 0.635, p = 0.006, accordingly). Commercial trials had a higher planned number of subjects (p = 0.014). Multiple member states participated in commercial trials more frequently (p < 0.001). Fifty-five clinical trials of neurological medicines were registered in Lithuania during the period of 2012–2021, and they comprised 8.08% of all clinical trials registered in Lithuania. The annual registration rate has decreased significantly (R² = 0.401, p = 0.049). Almost all trials in Lithuania (53 out of 55) were sponsored by commercial companies. The majority of trials (23 (42%)) were trials for demyelinating diseases of the CNS.Conclusions. The annual registration rates of trials of neurological medicines remain stable in Europe while decreasing in Lithuania. Commercial clinical trials have more participants, and are more commonly conducted in multiple member states.

Exploring the Versatility of Topical Gels: - An Overview

Topical gels represent semi-solid formulations characterized by a phase of matter existence that is fluid encased within A three-dimensional structure made of polymers, typically consisting of synthetic or natural gums with substantial cross-linking, achieved either chemically or physically. Their unique composition enables diverse applications owing to their intermediate state between liquid and solid phases. In recent times, topical gels have garnered significant interest across various sectors, including industry, research, education, drug regulation, and professional fields. Special emphasis is placed on the utilization of gels in drug delivery systems; the discussion serves to provide insights into the versatility and involving landscape of topical gels, catering to the interests and needs of professionals and researchers in diverse domains.