Machine Learning and Artificial Intelligence in Pharmaceutical Research and Development: a Review.

Over the past decade, artificial intelligence (AI) and machine learning (ML) have become the breakthrough technology most anticipated to have a transformative effect on pharmaceutical research and development (R&D). This is partially driven by revolutionary advances in computational technology and the parallel dissipation of previous constraints to the collection/processing of large volumes of data. Meanwhile, the cost of bringing new drugs to market and to patients has become prohibitively expensive. Recognizing these headwinds, AI/ML techniques are appealing to the pharmaceutical industry due to their automated nature, predictive capabilities, and the consequent expected increase in efficiency. ML approaches have been used in drug discovery over the past 15-20 years with increasing sophistication. The most recent aspect of drug development where positive disruption from AI/ML is starting to occur, is in clinical trial design, conduct, and analysis. The COVID-19 pandemic may further accelerate utilization of AI/ML in clinical trials due to an increased reliance on digital technology in clinical trial conduct. As we move towards a world where there is a growing integration of AI/ML into R&D, it is critical to get past the related buzz-words and noise. It is equally important to recognize that the scientific method is not obsolete when making inferences about data. Doing so will help in separating hope from hype and lead to informed decision-making on the optimal use of AI/ML in drug development. This manuscript aims to demystify key concepts, present use-cases and finally offer insights and a balanced view on the optimal use of AI/ML methods in R&D.

Research and Education Needs for Complex Generics.

Complex generics are generic versions of drug products that generally have complex active ingredients, complex formulations, complex routes of delivery, complex dosage forms, are complex drug-device combination products, or have other characteristics that can make it complex to demonstrate bioequivalence or to develop as generics. These complex products (i.e. complex generics) are an important element of the United States (U.S.) Food and Drug Administration's (FDA's) Generic Drug User Fee Amendments (GDUFA) II Commitment Letter. The Center for Research on Complex Generics (CRCG) was formed by a grant from the FDA to address challenges associated with the development of complex generics. To understand these challenges, the CRCG conducted a "Survey of Scientific Challenges in the Development of Complex Generics". The three main areas of questioning were directed toward which (types of) complex products, which methods of analysis to support a demonstration of bioequivalence, and which educational topics the CRCG should prioritize. The survey was open to the public on a website maintained by the CRCG. Regarding complex products, the top three selections were complex injectables, formulations, and nanomaterials; drug-device combination products; and inhalation and nasal products. Regarding methods of analysis, the top three selections were locally-acting physiologically-based pharmacokinetic modeling; oral absorption models and bioequivalence; and data analytics and machine learning. Regarding educational topics, the top three selections were complex injectables, formulations, and nanomaterials; drug-device combination products; and data analytics, including quantitative methods and modeling & simulation. These survey results will help prioritize the CRCG's initial research and educational initiatives.

Oral biopharmaceutics tools: recent progress from partnership through the Pharmaceutical Education and Research with Regulatory Links collaboration.

OBJECTIVES: To summarise key contributions of the Pharmaceutical Education and Research with Regulatory Links (PEARRL) project (2016-2020) to the optimisation of existing and the development of new biopharmaceutics tools for evaluating the in vivo performance of oral drug products during the development of new drugs and at the regulatory level. KEY FINDINGS: Optimised biopharmaceutics tools: Based on new clinical data, the composition of biorelevant media for simulating the fed state conditions in the stomach was simplified. Strategies on how to incorporate biorelevant in vitro data of bio-enabling drug products into physiologically based pharmacokinetic (PBPK) modelling were proposed. Novel in vitro biopharmaceutics tools: Small-scale two-stage biphasic dissolution and dissolution-permeation setups were developed to facilitate understanding of the supersaturation effects and precipitation risks of orally administered drugs. A porcine fasted state simulated intestinal fluid was developed to improve predictions and interpretation of preclinical results using in vitro dissolution studies. Based on new clinical data, recommendations on the design of in vitro methodologies for evaluating the GI drug transfer process in the fed state were suggested. The optimized design of in vivo studies for investigating food effects: A food effect study protocol in the pig model was established which successfully predicted the food-dependent bioavailability of two model compounds. The effect of simulated infant fed state conditions in healthy adults on the oral absorption of model drugs was evaluated versus the fasted state and the fed state conditions, as defined by regulatory agencies for adults. Using PBPK modelling, the extrapolated fasted and infant fed conditions data appeared to be more useful to describe early drug exposure in infants, while extrapolation of data collected under fed state conditions, as defined by regulators for adults, failed to capture in vivo infant drug absorption. SUMMARY: Substantial progress has been made in developing an advanced suite of biopharmaceutics tools for streamlining drug formulation screening and supporting regulatory applications. These advances in biopharmaceutics were achieved through networking opportunities and research collaborations provided under the H2020 funded PEARRL project.

Grand Challenges in Pharmaceutical Research Series: Ridding the Cold Chain for Biologics.

Biologics are complex pharmaceuticals that include formulated proteins, plasma products, vaccines, cell and gene therapy products, and biological tissues. These products are fragile and typically require cold chain for their delivery and storage. Delivering biologics, while maintaining the cold chain, whether standard (2°C to 8°C) or deepfreeze (as cold as -70°C), requires extensive infrastructure that is expensive to build and maintain. This poses a huge challenge to equitable healthcare delivery, especially during a global pandemic. Even when the infrastructure is in place, breaches of the cold chain are common. Such breaches may damage the product, making therapeutics and vaccines ineffective or even harmful. Rather than strengthening the cold chain through building more infrastructure and imposing more stringent guidelines, we suggest that money and effort are best spent on making the cold chain unnecessary for biologics delivery and storage. To meet this grand challenge in pharmaceutical research, we highlight areas where innovations are needed in the design, formulation and biomanufacturing of biologics, including point-of-care manufacturing and inspection. These technological innovations would rely on fundamental advances in our understanding of biomolecules and cells.

Encuesta Nacional de la SEFH-2019: cartera de servicios, actividad asistencial, docencia e investigación en los Servicios de Farmacia Hospitalaria en España / 2019 SEFH National Survey: service portfolio, care activities, education and research in Spain's hospital pharmacy departments

OBJETIVO: Dar a conocer los resultados referentes a la cartera de servicios y actividad asistencial, docente e investigación de la encuesta nacional de la Sociedad de Farmacia Hospitalaria (SEFH) 2019 en los Servicios de Farmacia Hospitalaria españoles. MÉTODO: En marzo de 2019 se elaboró y envió un cuestionario con 77 preguntas agrupadas en ocho dimensiones a los 368 Servicios de Farmacia Hospitalaria registrados en la SEFH, con un bloque adicional sobre actividad desarrollada en 2017 y 2018. RESULTADOS: La tasa global de respuesta fue 54,3%. El 69% de los hospitales eran públicos y el 75% generales. El 88,6% de los Servicios de Farmacia Hospitalaria realizaban atención farmacéutica en pacientes ingresados, y el 77,5% y el 65% en pacientes externos y ambulantes, respectivamente. Se elaboraban preparados estériles en el 70,6% de los Servicios de Farmacia Hospitalaria. Se determinaban niveles de medicamentos en el 12% y se efectuaban informes farmacocinéticos en el 76,9% de los hospitales con ≥ 1.000 camas. Los Servicios de Farmacia Hospitalaria atendieron en 2018 a una media de 929 pacientes al mes y 2.680 al año. El número de elaboraciones estériles y no estériles fue de 10.394.492, representando las estériles el 62,6%. La media de ensayos clínicos gestionados en los hospitales con más de 500 y 1.000 camas fue de 186,2 y 421,8, respectivamente. La mediana de convenios docentes de pregrado entre universidades y Servicios de Farmacia Hospitalaria era de 1 (rango intercuartílico: 0-2). El 21,5% de los Servicios de Farmacia Hospitalaria no tenía ningún convenio. La media de alumnos de grado de farmacia en los Servicios de Farmacia Hospitalaria fue 4,12 (desviación estándar: 8,26). Un total de 290 farmacéuticos eran profesores asociados en la universidad. El 15% de los farmacéuticos disponía de una certificación Board of Pharmacy Specialities, siendo el 55,3% de oncología. Los Servicios de Farmacia Hospitalaria contaban con una media de 1,31 (desviación estándar: 2,23) doctores. De los Servicios de Farmacia Hospitalaria que refirieron el factor de impacto acumulado de sus publicaciones, en un 60% era cero, y en el 19,6% ≥ 10. CONCLUSIONES: La atención a pacientes no ingresados y la elaboración de medicamentos continúan avanzando en los Servicios de Farmacia Hospitalaria españoles, mientras que existe un importante margen de mejora en farmacocinética clínica. Se refleja un compromiso con la docencia, mientras que la producción científica es todavía limitada, a pesar del incremento de doctores en los servicios

OBJECTIVE: To report on the results obtained from the 2019 SEFH National Survey regarding the service portfolio, care activities, training programs and research work of Spanish hospital pharmacy departments. METHOD: In March 2019, SEFH designed and distributed a questionnaire containing 77 questions grouped into 8 domains to its 368 affiliated hospital pharmacy departments. The questionnaire included an additional section on the activities carried out in 2017 and 2018. RESULTS: The overall response rate was 54.3%. Sixty-nine percent of hospitals were public and 75% were general hospitals. A total of 88.6% of hospital pharmacy departments provided pharmaceutical care to inpatients, whereas 77.5% and 65% treated outpatients and ambulatory patients, respectively. Sterile formulations were prepared by 70.6% of pharmacy departments, while 12% measured drug levels in bodily fluids; 76.9% of hospitals with more than 1,000 beds prepared pharmacokinetic reports. In 2018, hospital pharmacies provided for a mean of 929 patients a month and 2,680 a year. The amount of formulations (sterile and non-sterile) prepared was 10,394,492, sterile formulations accounting for 62.6%. The average amount of clinical trials managed in hospitals with ≥ 500 and ≥ 1000 beds was of 186.2 and 421.8, respectively. The median of number of undergraduate tuition agreements between pharmacy departments and universities was 1 (IQR: 0-2); 21.5% of pharmacy departments had no agreements with any university. The mean number of undergraduate pharmacy students per hospital pharmacy was 4.12 (SD: 8,26). A total of 290 pharmacists were associate professors at some university. Fifteen percent of pharmacists held a certification from the Board of Pharmacy Specialties, 55.3% of them in the specialty of oncology. Hospital pharmacy departments employed a mean of 1.31(SD: 2,23) PhD holders. From those which reported the impact factor of their publications, 60% had an impact factor of zero while in 19.6% the impact factor was ≥ 10. CONCLUSIONS: Care of out-patients and medication compounding are increasingly the main activities performed in Spanish hospital pharmacies, while there is still considerable room for improvement in the area of clinical pharmacokinetics. Pharmacy departments are generally committed to training as a key activity, while scientific output is still limited despite the increase in the number of PhD pharmacist

Evaluating and evolving a screening library in academia: the St Jude approach.

The quality of lead compounds is a key factor for determining the success of chemical probe and drug discovery programs. Given that high-throughput screening (HTS) continues to be a dominant lead generation paradigm, access to high-quality screening libraries is crucial for such efforts in both industry and academia. Here, we discuss the strategy implemented a decade ago to build from scratch one of the largest compound collections in academia, containing ∼575 000 carefully annotated small molecules, and a recent multidisciplinary effort designed to further enhance the collection to meet our research demands for the next decade.

Lo evidente ante nosotros / The obvious before us

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[Progress in pharmaceutical research for cerebral resuscitation after cardiac arrest].

OBJECTIVE: With the popularization of cardiopulmonary resuscitation (CPR) technology, the success rate of restoration of spontaneous circulation (ROSC) is gradually improved, and the survival rate and neurological outcome of patients with cardiac arrest are improved. Currently, therapeutic methods for cerebral resuscitation after cardiac arrest are limited. In addition to mild hypothermia for clinical application, the majority of drugs remain in the animal experimental stage. Finding effective brain protection drugs has become a hot spot in the field of brain resuscitation research. This article will review the pharmaceutical progress of research for cerebral resuscitation after cardiac arrest, so that we can study the brain protection mechanism of these drugs better and more targeted.

Design of Experiments in metabolomics-related studies: An overview.

Nowadays, Design of Experiments (DoE) approach is a very popular methodology of planning and conducting experiments, where the effect of each tested factor on the studied responses is systematically examined and documented. The results obtained in such manner represent the design space more precisely than in the case of One-Variable-At-Time (OVAT) approach, leading to reliable and comprehensive results, while saving time and resources. Despite such a large increase of interest in this approach recently, its implementation in metabolomics research seems to be limited. Therefore, in this short overview, apart from summarizing some basic concepts of DoE, we wanted to provide a guideline for those who are about to plan metabolomics-related experiments. This overview is divided into four sections. In addition to the first section, which will introduce the history and basics of DoE, second part will provide concise description of the most popular experimental designs. Furthermore, third section will describe examples of DoE application in metabolomics and related studies. We will conclude with fourth section, providing you briefly with opportunities and trends in metabolomics research utilizing experimental design.

Applications of proteomics in pharmaceutical research and development.

The significance of proteomics in the pharmaceutical industry has increased since overcoming initial difficulties. This review discusses recent proteomics publications from pharmaceutical companies to identify new trends in proteomics applications to research and development. Applications of proteomics such as chemical proteomics, protein expression profiling, targeted protein quantitation, analysis of protein-protein interactions and post-translational modification are widely used by various sections of the industry. Technological advancements in proteomics will further accelerate pharmaceutical research and development.

El papel del farmacéutico / No disponible

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Nanotechnology Inclusion in Pharmaceutical Sciences Education in Portugal.

Objective. To analyze the inclusion of nanotechnology in the curricula of Integrated Master's in Pharmaceutical Sciences programs in Portugal. Methods. Information regarding curricula (general notice and curricular unit description, objectives and syllabus) from national institutions was collected from their official websites or requested by e-mail, and analyzed for the occurrence of nanotechnology and related terms. A nanotechnology inclusion in curriculum (NIC) index was developed and used to rank each institution. Results. All institutions with available data (eight out of nine) offered nanotechnology in their curricula. Both basic and applied nanotechnology-related education were offered to students but mostly from a theoretical perspective. The NIC index provided a standardized tool for comparing the institutions' programs and highlighted differences according to the relative importance of the presence of nanotechnology and related terms in curricula. Conclusion. Portuguese institutions offering integrated master's programs in pharmaceutical sciences are including nanotechnology in their curricula. However, its implementation across all institutions remains weak and requires further strengthening to meet the requirements of this emerging field in health care practice.

Progress in Inherited Retinal Disease Drug Discovery and Development: A Foundation's Perspective.

Ophthalmic drug discovery and development has enjoyed a recent renaissance, with a major shift away from reformulating old systemic drugs for ocular use to de novo discovery of drugs for specific ocular disease targets. This shift, coupled with a revolution in molecular biology and genetic sequencing, has uncovered an unprecedented number and variety of novel targets for therapeutic intervention in eye disease. With such a treasure chest of new science to pursue, it also creates a new challenge for translating the lab-based discoveries through the translational "valley of death" into full scale industry-led development of new, approved therapeutics to treat eye disease. This is in fact a daunting task, as the cost of drug development continues to increase and many of the new therapeutic targets are based on smaller, orphan diseases with very high unmet medical needs. This perspective focuses on the role of a nonprofit foundation, The Foundation Fighting Blindness, in fueling and supporting the advancement of new therapies for blinding inherited retinal degenerative diseases into approved therapeutics. The new collaborative model is changing the way breakthrough drugs are coming to market for patients, and innovative funding models are required to match the innovative science.

Research trends in flavonoids and health.

Herein we describe, based on some bibliometric data, how the field of research on flavonoids has evolved over the last 25 years. The number of papers on flavonoids has risen in an exponential manner over these years, much faster than other fields on food constituents. This increase appears to be related to the contemporary explosion of interest in healthy foods, supplements and nutraceuticals. It was also probably triggered by large epidemiological studies on fruits and vegetables, and particularly on flavonoids, consumption and incidence of cancer, stroke and coronary heart disease. The widely distributed flavonols constitute the flavonoid subgroup upon which the greatest interest has been focused, followed by flavanols and more recently by anthocyanidins and other related polyphenols such as resveratrol. Research on isoflavones rapidly emerged in the 1990s but plateaued in the 2000s. In the 1990s flavonoids were mainly considered as the active components of medicinal plants, while from 2000 onward, they switched to be mainly regarded as bioactive food ingredients. We envision a continuation in the growth of research for the coming decade focused on clearly demonstrating the importance of flavonoids for human health.

Nine years of comparative effectiveness research education and training: initiative supported by the PhRMA Foundation.

The term comparative effectiveness research (CER) took center stage with passage of the American Recovery and Reinvestment Act (2009). The companion US$1.1 billion in funding prompted the launch of initiatives to train the scientific workforce capable of conducting and using CER. Passage of the Patient Protection and Affordable Care Act (2010) focused these initiatives on patients, coining the term 'patient-centered outcomes research' (PCOR). Educational and training initiatives were soon launched. This report describes the initiative of the Pharmaceutical Research and Manufacturers Association of America (PhRMA) Foundation. Through provision of grant funding to six academic Centers of Excellence, to spearheading and sponsoring three national conferences, the PhRMA Foundation has made significant contributions to creation of the scientific workforce that conducts and uses CER/PCOR.