Assessing the risk of a clinically significant infection from a Microneedle Array Patch (MAP) product

While the controversy over compounding for animals is contemporary, the practice of compounding for animals is not. Pharmaceutical compounding is an ancient art and science. Compounding has been an integral part of the practice of veterinary medicine since the first cures were blended together to help an animal patient. Skilled healers have utilized compounds for both human and animal patients for thousands of years. With hundreds of species requiring treatment and dozens of new diseases emerging, the half-life of truth in veterinary medicine is particularly short. As a result of a complex and lengthy approval process, the veterinary pharmaceutical industry can never be expected to adequately supply labeled products to treat every disease encountered in every species. Consequently, in order to provide state-of-the-art veterinary therapy, the veterinarian must frequently alter commercially available dosage forms to meet needs for individual patients. This activity is defined as compounding by the major veterinary drug regulatory agencies in North America, the Canadian Bureau for Veterinary Drugs (BVD) and the United States (US) Food and Drug Administration Center for Veterinary Medicine (FDACVM). In some cases, as with potassium bromide and cisapride, there are no commercially available products for any species, and these life-saving therapies must be compounded from raw chemicals. Often, the safety of the caregiver also depends on the ability to get medications into the animal in the least invasive, most palatable manner possible. Compliance is paramount in achieving successful therapeutic outcomes, but many owners will not administer unpalatable or invasive therapies if they perceive that their pet will “hate” them as a result. Compounding based on individual patient need is an ageless solution for all of these problems.

Scientists have been looking at the role the immune system may play in fighting cancer for decades, but it is only recently that this knowledge has been translated into immuno-oncology therapies that provide the promise of long-term quality survival to patients [1–3]. Agents are now available to patients with advanced melanoma [1] and castration resistant prostate cancer, [3] and many more agents are expected to become available in the next few years, including in some of most common (e.g. breast and lung) and most difficult-to-treat cancers [1–5]. What makes these new therapies unique is that they confer long-lasting memory to the immune system, enabling it to adapt itself to fight against cancer cells even after remission. Side-effects also tend to be manageable compared to many other cancer therapies. But as with all new treatments, providing fast access to immuno-oncology therapies to appropriate patients will be increasingly challenging in our resource-constrained health care systems. In addition, the science of immuno-oncology is rapidly evolving, and we are still learning how to use these agents to achieve the best possible response in patients [4]. We still lack a clear understanding of what biological factors make a given immuno-oncology therapy work in a particular patient [6]. Also, the clinical development pathways traditionally used in oncology were typically developed for conventional cytotoxic therapies and may be poorly suited to reflect the effects seen with immunooncology therapies [7]. With these challenges in mind, the European Expert Group on Immuno-Oncology was established in early 2014 as an independent network of patients, oncology healthcare professionals, scientists, industry and politicians to help improve overall understanding of what immuno-oncology therapies are and what they may mean for cancer patients. A first goal of the Expert Group was to help policymakers identify what policy adaptations were needed to enable rapid access to immunooncology therapies in appropriate patients across Europe. The resulting Policy Action Framework [8] was launched at the European Parliament in November 2014 along with a guide for patients on immuno-oncology [9]. The Action Framework proposes five priority areas, as shown in Figure 1. Figure 1. Key recommendations for policymakers on immuno-oncology [8]. Promoting a greater understanding of immuno-oncology among policymakers, regulatory and Health Technology Assessment (HTA) agencies, health professionals and patients is key. Informed policymakers are more likely to integrate new therapies into cancer plans and policies, and ensure that appropriate resources and funding are put in place to deliver on these plans at the local level. Professional training across the entire care team is essential for treatments to be used as appropriately as possible in patients who are most likely to benefit, and to monitor the long-term effects, including toxicity, of this new group of agents. And patients need continuous information and support in order to engage fully in treatment decisions. Long-term quality survival is the ultimate goal of cancer therapy [10], however obtaining this evidence may take several years. Therefore, it is important to identify validated intermediary endpoints that are predictive of long-term survival [11]. Integrating appropriate measures of quality of life into clinical trials and clinical practice is also critical to assess the impact of new therapies on patients both during and after treatment. Also, HTA agencies and subsequent funding decisions should be based on what matters most to patients and their families, and take account of the full societal benefits of new therapies, for example individuals’ ability to return to work and lead a ‘normal’ life with long-term survival. Greater flexibility is also needed in existing regulatory frameworks to allow for an appropriate balance between the need for safety and efficacy data and rapid access to promising therapies [12]. For example, the European Medicines Agency is currently exploring more flexible frameworks which allow regulatory decisions to be based on an evolving set of data for selected therapies [13, 14] Early collaboration between drug developers, patient organisations, regulatory agencies and HTA agencies is instrumental for the success of such schemes, as they need to agree to a comprehensive development and licensing plan early on, matched with adaptive frameworks for reimbursement and HTA decisions as well. Collaborative, multidisciplinary research platforms in the form of public-private partnerships (PPPs) also have a huge role to play in immuno-oncology. For example, the Innovative Medicines Initiative is Europe’s largest PPP aimed at speeding up the development of, and patient access to, innovative medicines, particularly in areas where there is high unmet patient need [15]. PPPs may also help provide access to immuno-oncology therapies in poorer-resourced countries as part of compassionate use programmes. Collaborations between the research community and pharmaceutical companies may also allow the creation of large databases that combine data from several clinical trials. These data may help identify which patient characteristics make individuals more likely to respond to different immuno-oncology therapies and develop suitable biomarkers and other patient selection tools as a result. Finally, mechanisms need to be put in place to make sure that the most effective new therapies are included in local care pathways and supported by appropriate funding streams, particularly in heavily decentralised health care systems. For example, the Melanoma Taskforce in the UK developed a national toolkit for local commissioners responsible for funding care to ensure equitable, timely and appropriate access to the full range of approved treatments for people with advanced melanoma across all localities. Long-term alternative financing mechanisms that address payer concerns and maximize and accelerate patient access will also be critical.

The existence of 3D printing (3DP) ways back to 1992, and its sound presence in the pharmaceutical industry was made in 2015 by the launch of 1st 3D printed drug, Spritam was manufactured by Aprecia Pharmaceuticals. Implementation of 3DP is escalating in the number of industries, including the pharmaceutical industry. The purpose of this review paper is to briefly discuss types of 3DP and their role in formulating novel dosage forms. Binder jet printing, VAT polymerization, powder bed fusion, and material extrusion are briefly explained along with an example of their implementation in the formulation of the dosage form. A few novel dosage forms which can bypass the first-pass metabolism and how 3D printing is useful in formulating them as been discussed. It also includes a comparison of the process of 3D printed tablets and conventional methods of manufacturing. The significance of 3D printing in novel dosage form and augmenting 3DP with hot-melt extrusion (HME) method is discussed. The regulatory concerns in adopting this technology on a large-scale are addressed. 3DP technology could rapidly print transdermal needles, buccal patches, and different shapes of vaginal rings and proved it can be a versatile tool in formulation technology. As the pharmaceutical industry involves stringent regulations, certain aspects need to be considered by regulatory authorities before implementing this tool into commercialscale manufacturing.

Off-label use is the use of pharmaceutical drugs for an indication, age group, dosage, or route of administration that is not approved by the regulatory agencies and is not mentioned in the prescribing information for the drug. A regulatory agency (e.g., Drugs Controller General of India, United States Food and Drug Administration [USFDA]) approves a drug for a particular indication, in a particular dose, dosage formulation and route of administration based on data from clinical trials that have been submitted to and scrutinised by the regulatory agency. Thus, fentanyl is approved as an analgesic for intravenous use, but not for intrathecal or epidural use, making epidural analgesia with fentanyl an off-label use.[1] It is important to understand that off-label use is not illegal. Off-label use is considered as legal unless it violates ethical guidelines or other safety regulations. It is ethical and justifiable to use drugs in an off-label fashion provided such use is based on sound data and evidence. Several prescription drugs and over-the-counter drugs are used in off-label ways to good effect. Off-label prescribing is not necessarily bad. It can be beneficial, especially when patients have exhausted all other approved options. Chemotherapy drugs for cancer are often used off-label, because a drug approved for one type of cancer may actually target many other types of tumours. Off-label use of a drug or combination of drugs often represents the standard of care.[2] The use of β-blockers for heart failure is a standard of care, but was an off-label use for many years. They were initially approved by the USFDA for the treatment of hypertension, before some β-blockers were formally approved to treat heart failure. Thus, it is possible for off-label uses to eventually get approved by the USFDA. The prescribing of drugs for off-label use is entirely proper since the decision regarding how to use a drug is based on what is considered "good medical practice" regardless of whether or not it conforms to the package insert. Drug labelling per se is not intended to set a standard for good medical practice. Although some off-label therapies can be beneficial and even lifesaving for some patients, in many cases, off-label use can be problematic, especially if there is inadequate data regarding drug safety and effectiveness for the off-label use. The combined use of fenfluramine hydrochloride and phentermine hydrochloride (Fen-Phen) is one of the best examples of off-label use with a poor outcome.[2] Individually, they are approved by the USFDA as short-term treatments for obesity. They were prescribed in combination after reports of dramatic weight loss effects of the combination appeared in medical journals. However, its prolonged use lead to severe, and potentially fatal, heart valve damage,[3] and Fen-Phen was withdrawn from the market.[4] Thus, we emphasise that off-label prescribing has its place in medical practice; however, we also emphasise that off-label use must be backed by strong medical rationale and scientific evidence. Use of off-label drugs in the perioperative setting is not uncommon. In fact, it is imperative. For instance, small-dose droperidol for prevention of postoperative nausea and vomiting is an off-label use which was widely accepted at a time when ondansetron was very expensive until USFDA placed a "black-box" warning. Ondansetron itself is used mostly off-label for anti-emetic prophylaxis because studies have shown greater efficacy when it is administered near the end of surgery as against the label which states that it should be administered prior to induction of anaesthesia.[5] The study by Patil et al. is an audit of off-label use of perioperative medications in the surgical wards of a teaching hospital.[6] Approximately, one-fifth of drugs prescribed were off-label indications. Inappropriate dose was the most common off-label use followed by inappropriate indication. The authors observed that off-label drug use was practiced with questionable clinical justification in many instances since underdosage can lead to suboptimal treatment. However, anaesthesiologists often adjust doses of induction agents or muscle relaxants based on the patient's condition and patient response. This may result in doses administered that are outside those mentioned in the drug package insert or formulary. The authors also observed a 1.6-fold higher incidence of adverse events in patients in whom drugs were used off-label. However, they did not perform a systematic severity assessment or a causality assessment of adverse events and a thorough risk-benefit assessment. Thus, the impact of off-label use is not very clear in this study. While off-label use may be associated with a greater number of side effects, the benefits may outweigh the risks. Again, off-label practices based solely on intuition are unlikely to be effective as against off-label use supported by clinical evidence. Therefore, future audits of off-label practices should include these metrics in the overall assessment of the utility of such practices. Despite some of these limitations, this is an important study that provides a critical view of some of our practices. The regulatory agencies do not regulate the practice of medicine, and therefore, they do not regulate the prescribing of drugs for off-label uses. However, some agencies including the USFDA have the authority to regulate the manufacturer's promotion of off-label uses of approved drugs. The recent USFDA guidelines allow "safe harbours" for disseminating information.[7] For instance, pharmaceutical company representatives may circulate peer-reviewed information from high-quality medical journals on the off-label use of drugs and devices amongst doctors, facilitating the practice of evidence-based medicine rather than "limiting" their practice to the information provided in the manufacturer's package insert. On the other hand, promoting off-label uses through mass media such as the internet is not permitted and subject to more regulation. The Indian Medical Association is also extremely tolerant towards off-label drug use and has left such practices to the discretion of the physician.[8] Ideally, the use of drugs in clinical practice should be based on rational scientific theory, expert medical opinion and well-controlled clinical trials (i.e., evidence-based) rather than the package insert. While the package insert can be a useful source of information about a drug, it is not meant to determine medical practice and is no substitute for sound medical judgement.[9]

Extemporaneously compounded products are designed for an individual patient based on a licensed physician’s prescription in response to an identified need. Compounding provides medications for unique medical needs for which commercially manufactured products are unavailable. Compounding practice includes activities such as formulating, mixing, or repacking products. Extemporaneous preparations are not licensed by Drug Regulatory Authorities and hence, are not evaluated for quality, efficacy, and stability. Also, adverse event reporting is not mandatory for these products. The need for extemporaneous preparations is precipitated by a lack of commercially available products for all the medicines and dosage forms that are required by patients. Products intended for topical and pediatric use are the majority. Extemporaneous preparations are generally considered as high-risk products. Common risks of compounded products include calculation errors, microbial contamination, therapeutic failure, and adverse reactions. To reduce the risks, Drug Regulatory Authorities havedeveloped guidelines that describe the minimum standards to be followed when preparing for extemporaneous compounding to ensure product quality and fitness. A comprehensive assessment is performed to justify the need for these products. The preparation process should comply with all the Good Manufacturing Practices including design of compounding areas. Pharmacists performing compounding activities require appropriate knowledge, skills, and competence to undertake the task. The ingredients used in compounding are subject to pharmacopeial quality standards and should be sourced from approved vendors. The final compounded product in some countries is controlled as stipulated in the components standard. Extemporaneous compounding remains an important part of pharmacy practice. Comprehensive risk assessment, adherence to the prescribed manufacturing practices, and use of national formularies are necessary for quality assurance of these preparations.

BackgroundInnovative statistical methodologies have been proposed to improve Alzheimer’s clinical trial efficiency: (i) Models leveraging data across multiple post‐baseline visits might provide greater power compared to traditional MMRM approaches which focus on mean changes at the last visit. (ii) Machine learning techniques, such as those incorporating prognostic covariates or regression trees with fused leaves, may improve precision in treatment effect estimation. (iii) Alternative analyses such as time‐to‐event or ranking‐based approaches are becoming relevant as AD clinical trials increasingly focus on prevention and asymptomatic participants. This session seeks to stimulate a collaborative dialogue among regulatory agencies, Alzheimer’s associations, industry, and academia to evaluate the feasibility, benefits, and limitations of these methodologies in the context of AD clinical trials.MethodsThis presentation will review the methodologies introduced by five speakers, formulating discussion questions around their statistical validity, challenges, and limitations in application and interpretability.ResultsThe session discussions are expected to deepen understanding of how innovative statistical approaches address the unique challenges of AD clinical trials. Insights gained may inform pathways for integrating novel methods into trial designs and analyses.ConclusionsAdvances in our understanding of AD disease progression and treatment effects provide a opportunity to explore some innovative statistical methodologies. Rigorous evaluation and open dialogue are essential to utilize these methods effectively, ensuring they enhance trial efficiency and maintain the rigor required for regulatory decision‐making.

Health claims for probiotics are evaluated by the Panel on Dietetic Products, Nutrition and Allergies of the European Food Safety Authority. Despite a substantial amount of basic and clinical research on the beneficial effects of probiotics, all of the evaluated claim applications thus far have received a negative opinion. With the restrictions on the use of clinical endpoints, validated biomarkers for gut health and immune health in relation to reduction in disease risk are needed. Clear-cut criteria for design as well as evaluation of future studies are needed. An open dialogue between basic and clinical scientists, regulatory authorities, food and nutrition industry, and consumers could bridge the gap between science and marketing of probiotics.

PurposeThe therapeutic index (TI) is the range of doses at which a medication is effective without unacceptable adverse events. Drugs with a narrow TI (NTIDs) have a narrow window between their effective doses and those at which they produce adverse toxic effects. Generic drugs may be substituted for brand-name drugs provided that they meet the recommended bioequivalence (BE) limits. However, an appropriate range of BE for NTIDs is essential to define due to the potential for ineffectiveness or adverse events. Flecainide is an antiarrhythmic agent that has the potential to be considered an NTID. This review aims to evaluate the literature surrounding guidelines on generic substitution for NTIDs and to evaluate the evidence for flecainide to be considered an NTID.MethodsA review of recommendations from various regulatory authorities regarding BE and NTIDs, and publications regarding the NTID characteristics of flecainide, was carried out.ResultsRegulatory authorities generally recommend reduced BE limits for NTIDs. Some, but not all, regulatory authorities specify flecainide as an NTID. The literature review demonstrated that flecainide displays NTID characteristics including a steep drug dose–response relationship for safety and efficacy, a need for therapeutic drug monitoring of pharmacokinetic (PK) or pharmacodynamics measures and intra-subject variability in its PK properties.ConclusionsThere is much evidence for flecainide to be considered an NTID based on both preclinical and clinical data. A clear understanding of the potential of proarrhythmic effects or lack of efficacy, careful patient selection and regular monitoring are essential for the safe and rational administration of flecainide.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-015-1832-0) contains supplementary material, which is available to authorized users.

The therapeutic doses of beta-stimulants in the treatment of bronchial asthma show wide variation among the drugs. In the present study, we tried to construct a system for prediction of the optimum clinical dose of beta-stimulants as oral dosage forms and aerosols using the data from preclinical pharmacological studies and pharmacokinetic data in humans. Values of EC50 (drug concentration that gives the half-maximum bronchodilator effect) in the in vitro studies based on isolated trachea of guinea pigs were collected from the literature. The ratios of the EC50 value of each drug to that of isoproterenol were used as the indicator of in vitro pharmacological activity. There were significant correlations between the EC50 ratios and the oral dose or the maximum plasma concentration after single oral administration, but the correlation coefficients were relatively small (r < .9). On the other hand, a linear log-log relationship was observed between the EC50 ratio and the maximum plasma unbound concentration (Cu(max)) (slope = 0.907, r = .955, p < 0.001). In the case of aerosols, a good correlation was observed between the EC50 ratio and the dose (slope = 0.770, r = .900, p < 0.01). The predicted concentration of beta-stimulants in the lung after aerosol administration tended to be higher than the Cu(max) after oral administration, suggesting the contribution of nonspecific binding in the lung tissue. These findings indicate the possibility of predicting the appropriate dose of beta-stimulants based on the preclinical pharmacological data and the pharmacokinetic data in humans.

Globally, oyster reef restoration is on the rise. In many instances, restoration is occurring alongside established oyster aquaculture industries that grew to prominence following oyster reef demise. This paper examines the potential positive and negative interactions between the two industries and identifies key factors that may promote positive interactions. Interactions between the two industries result from shared resource requirements (e.g., space, clean water, brood-stock, breeding programs), shared knowledge requirements (e.g. around threats and their mitigation, factors optimizing growth/survival) and biological interactions (e.g. over-catch, disease spill-over, competition for resources). Many of these interactions are reciprocated, and can shift from positive to negative depending on environmental, biological and socio-economic conditions. From our examination, three key factors emerge as shaping the strength and direction (positive or negative) of interactions: (1) whether the focal species is common or different between the two industries; (2) the physicochemical and socio-economic environment in which the two industries are occurring; and (3) whether there is open dialogue and consultation between the two industries and relevant stakeholders. Positive interactions can be maximized where the two industries are able to co-invest in and share infrastructure (e.g. hatcheries, breeding programs), resources (e.g. spat, broodstock, shell) and knowledge (e.g. optimal conditions of growth) – an easier task where the target oyster species is in common. Positive interactions may also be maximized by utilizing marine spatial planning tools, such as suitability modelling, to inform optimal siting of the two industries. As the two industries continue to grow, open and inclusive dialogue between these and key stakeholders will be essential for mitigating risk and maximising positive synergies.

Stent fracture is a recognized complication following percutaneous coronary intervention, with incidence influenced by stent design, vessel anatomy, and patient-specific factors. Despite advances in stent technology, this condition remains clinically important due to its association with restenosis, thrombosis, and major adverse cardiovascular events. Key mechanistic contributors include stent-related factors such as material properties, design, and deployment technique, as well as vessel-related factors like angulation, calcification, and mechanical stress. Clinical presentation varies from asymptomatic to acute coronary syndromes, often necessitating high-resolution imaging such as stent enhancement or intracoronary imaging for diagnosis. Preventive strategies focus on optimal lesion preparation, potential use of drug-coated balloons and tailored stent selection. Management should be individualized based on fracture severity and clinical context. This article reviews the incidence, pathogenesis, clinical presentation, prevention, diagnosis, and management of stent fracture, and proposes a practical, algorithm to guide diagnosis and intervention, aiming to improve patient outcomes and reduce long-term complications.

Comparative safety profiles of bispecific T-cell engagers and CAR-T therapies: Real-world insights from the FDA adverse event reporting system database

Background The Model for Dementia Palliative Care Project will develop a service delivery model for community-based dementia palliative care in Ireland. This responds to palliative care now being recognised as a priority in care for people with dementia. Various dementia palliative care services exist internationally, however little is known about what the service providers would deem to be the most important aspects of service provision. The aim of this study was to identify what key stakeholders consider to be essential components of a model of dementia palliative care. Methods A web-based survey was developed, piloted (n=5), and revised. It was distributed electronically within five healthcare jurisdictions, in the Republic of Ireland, Northern Ireland, England, Scotland, and Wales. The target population was healthcare professionals, policy-makers, and academics, with an interest in dementia and palliative care. Content analysis of open ended questions was used to identify common themes within the data. Results Complete surveys were received from 112 stakeholders. The majority of respondents were female (86%). Identified key principles of care incorporated the philosophies of palliative care and good dementia care, with many describing ‘holistic’ and ‘person-centred care’ as core. Important individual components were identified, including support for carers, advanced care planning, information, education and training, activities for ‘meaningful living’, comprehensive disease management, coordinated case management, and linking in with community health services and social activities. Barriers to the model were identified at three levels: ‘(mis)understanding of dementia palliative care’, ‘application of dementia palliative care’ and ‘wider service organisation’. Conclusion Numerous components of a ‘good’ model were identified, along with possible barriers to implementation of the model. This study, as part of the larger project, will inform a model of dementia palliative care for the Irish Healthcare system with the potential to improve the experiences of people with dementia and their families.

Current off-label bisphosphonate treatment for osteogenesis imperfecta (OI) does not induce healthy bone formation. Therefore, novel strategies to stimulate osteogenesis and reduce fractures are needed to meet the medical needs of these patients. Preclinical data and case studies show that multiple intravenous (IV) administrations of mesenchymal stem cells (MSCs) provide promising outcomes in the treatment of OI. In the Boost to Brittle Bones (BOOST2B) trial, we aim to assess the safety and tolerability of multiple IV and intraosseous (IO) administrations of foetal liver-derived MSCs in children aged one to five years diagnosed with severe OI. A total of 15 children will receive four doses of foetal MSCs IV (3 × 106 cells per kg of body weight) and IO (0.1 × 106 cells per kg of body weight per long bone) at four-month intervals. As a secondary endpoint, the therapeutic effect of the four MSC doses will be assessed based on the annual fracture rate, time to first fracture, bone mineral density, growth, clinical status of OI, and biochemical bone turnover in peripheral blood. Exploratory parameters include quality of life and donor cell engraftment. The BOOST2B trial has been approved by the regulatory agencies in India and is ongoing. It is the first clinical trial designed to evaluate IO administration of MSCs as a potential therapy for OI. Here, we describe the BOOST2B clinical trial protocol. The long-term data on safety and efficacy will be reported once completed.

Almost a decade after Argentina began privatizing its railways, resolution of conflicts between regulators, users, and operators continues to take longer, and to be more difficult, than expected. The authors contend that many of these conflicts arose because there are no rules for interactions between the key stakeholders: government, regulators, users, unions, and the media. One result of inexperience in setting up concession agreement has been that the agreements did not clearly define the information needed for oversight and regulation. Argentine rail concession contracts were supposed to be specific about the way tariffs, quality, investment, exclusivity, and so on, would change over time. And the newly created regulatory bodies were given some discretion about adjusting the contracts in the face of unforeseen developments. However, initial privatization were carried out in such a way that there was no time to refine terms, so many loopholes remained. Those unforeseen events have happened, and the regulatory agency, the National Commission for Transport Regulation (CNRT), has had to adapt its procedures and decisions to available information. In some cases, alleged modifications of the operating environment have led to renegotiations. Changes have been introduced in the approach to furnishing information to the government for oversight and regulatory accounting. The changes center on clearer definitions in connection with four major issues: a) The measurement of efficiency; b) access prices; and c) the financial model. Circumstances in the Argentine rail industry early in 2001 did not favor dramatic changes, but current renegotiations could be used to adjust information requirements to reflect what has been learned through six yearsof experience.