Methods in safety pharmacology in focus

This focused issue of the Journal of Pharmacological and Toxicological Methods is the fifth to highlight Methods in Safety Pharmacology and includes a number of articles from the 7th Annual Safety Pharmacology Society (SPS) meeting that was held in Edinburgh, Scotland, September 19-21, 2007. However, unlike issues of the past, in which content predominantly focused on cardiovascular issues (specifically QT interval prolongation, QT-HR correction methods and validation of non-clinical cardiovascular models) this issue is composed of a number of non-cardiovascular methods papers and review articles. Of particular interest to readers will be articles related to CNS studies, in particular neurobehavioral assessments in non-human primates and the effects of drugs in juvenile and adult rats (an article that may be relevant in light of recent EU/US pediatric legislation). While cardiovascular function may not dominate there are several useful methodological papers including an assessment of cardiovascular sensitivity of drugs in conscious and anesthetized non-human primates, and a mathematical model (fractal analysis) applied to canine heartbeat dynamics. A first for the journal is a paper by Vargas et al., (2008-this issue) in which members of the SPS formed a working group in order to assess and review safety pharmacology testing of biological therapeutic agents (specifically monoclonal antibodies, mAbs). The group provides recommendations that will likely shape regulatory strategy and discussions in the yet to be fully discussed area of biological safety testing. In the tradition of obtaining a perspective on industry safety pharmacology program practices Lindgren et al., (2008-this issue) provide the results of a recent SPS survey that examines ICH S7A and S7B trends, aspects of early 'frontloading' safety studies, abuse and dependence liability and Contract Research Organization (CRO) tests/assays used in safety assessment of core battery and supplementary organ systems. In keeping with the translation track aspect of the 2007 meeting is an overview of the Distinguished Service Award lecture to Dr. T. Hammond that discusses many aspects of safety pharmacology including its evolution, impact, value and translation of non-clinical findings to humans. Finally, perspectives are presented on the use of the zebrafish as an early safety pharmacology-screening assay.     

Exploratory Safety Pharmacology: a new safety paradigm to de-risk drug candidates prior to selection for regulatory science investigations

The primary objective of Safety Pharmacology is to ensure the safety of medicines on physiological functions in order to protect humans against adverse drug reactions. Safety Pharmacology became a major non-clinical discipline in 2000 when the International Conference on Harmonization approved the S7A guideline. This regulatory document requires pharmaceutical companies to undertake Safety Pharmacology assessment under Good Laboratory Practice (GLP) in order to guarantee the absence of unmanageable risks on vital organ function for compounds to be tested on humans. These regulatory studies often reveal liabilities impacting on the smooth transition of drug candidates from the discovery phase into the clinical arena. However, if these safety issues were uncovered prior to regulatory science assessment, the chemistry of poorly safe molecules could be modified during the lead optimisation phase for preventing later occurring attrition accidents. This article proposes the establishment of a spin-off specialty of Regulatory Safety Pharmacology, for which the name ‘Exploratory Safety Pharmacology’ is proposed. The objective of this discipline would be to conduct early safety investigations on potential drug candidates by applying, outside the constraints of GLP, in silico, in vitro, ex vivo and in vivo platforms translating clinical liabilities into simple, fast and cost-effective screening assays. This approach should result in early hazard detection with rapid turnaround of the data, enabling medicinal chemists to mitigate the safety liabilities of new compounds in an iterative manner. Hence, the ultimate aim of Exploratory Safety Pharmacology activities is to transform Regulatory Safety Pharmacology investigations into risk-known exercises.     

Origins, practices and future of safety pharmacology

The origins of safety pharmacology are grounded upon observations that organ functions (like organ structures) can be toxicological targets in humans exposed to novel therapeutic agents, and that drug effects on organ functions (unlike organ structures) are not readily detected by standard toxicological testing. Safety pharmacology is " em leader those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relationship to exposure in the therapeutic range and above em leader " [International Conference on Harmonization (ICH) S7A guidelines; Safety Pharmacology Studies for Human Pharmaceuticals]. This publication provides a comprehensive review of the history of safety pharmacology, international regulatory guidelines that govern the practices of this important field, and the scientific challenges that are being faced by its rapid emergence in pharmaceutical development. The criticality of identifying undesired adverse effects of new drugs in nonclinical models, which reflect the overall human condition, is reflected in the importance of generating an integrated and accurate assessment of possible human risk. The conundrum posed by the challenge of formulating a reliable risk assessment is the importance of improving and enhancing the safe progression of new drugs to the marketplace, while preventing unnecessary delays (or discontinuances), based on nonclinical findings that are not relevant or interpretable in terms of clinical response or human risk.     

Status of safety pharmacology in the pharmaceutical industry—1995

Safety pharmacology contributes to the pharmacological characterization, risk assessment, and registration of new drugs; however, safety pharmacology strategies and study designs for new drugs vary widely across the pharmaceutical industry. We surveyed 26 pharmaceutical companies for how and why they conduct safety pharmacology studies. All conduct/contract safety pharmacology studies; 19 have safety pharmacology units, seven do not; ten locate responsibility for safety pharmacology in development, 16 in discovery (or research). Total staff range from two to 16 full-time equivalents (fte)/unit. Most companies conduct evaluations of cardiovascular and CNS functions, less evaluate respiratory, gastrointestinal and renal functions; a few conduct a ligand-binding/activity panel as part of their pharmacological profiling. Resources to complete a company's standard safety pharmacology program are ～1–4 fte/compound. One-third of companies use a maximum tolerated dose (MTD) for safety pharmacology studies, two-thirds use multiples of pharmacological or therapeutic doses. Approximately half conduct safety pharmacology studies to Good Laboratory Practices (GLPs) and use the 1992 Japanese guidelines only as a guide or outline. Company clinicians are most often cited as the “primary customer” for whom Safety Pharmacology studies are done, followed by research and development scientists, and then regulatory authorities. The results suggest that most companies conduct safety pharmacology for its contribution to risk assessment and critical care management. © 1995 Wiley-Liss, Inc.     

Safety pharmacology in 2010 and beyond: survey of significant events of the past 10 years and a roadmap to the immediate-, intermediate- and long-term future in recognition of the tenth anniversary of the Safety Pharmacology Society

In recognition of the tenth anniversary of the Safety Pharmacology Society (SPS), this review summarizes the significant events of the past 10years that have led to the birth, growth and evolution the SPS and presents a roadmap to the immediate-, intermediate- and long-term future of the SPS. The review discusses (i) the rationale for an optimal non-clinical Safety Pharmacology testing, (ii) the evolution of Safety Pharmacology over the last decade, (iii) its impact on drug discovery and development, (iv) the merits of adopting an integrated risk assessment approach, (v) the translation of non-clinical findings to humans and finally (vi) the future challenges and opportunities facing this discipline. Such challenges include the emergence of new molecular targets and new approaches to treat diseases, the rapid development of science and technologies, the growing regulatory concerns and associated number of guidance documents, and the need to train and educate the next generation of safety pharmacologist.     

2011 Annual Meeting of the Safety Pharmacology Society: an overview

The keynote address of 2011 Annual Meeting of the Safety Pharmacology Society examined the known and the still to be known on drug-induced nephrotoxicity. The nominee of the Distinguished Service Award Lecture gave an account of his career achievements particularly on the domain of chronically instrumented animals for assessing cardiovascular safety. The value of Safety Pharmacology resides in the benefits delivered to Pharma organizations, regulators, payers and patients. Meticulous due diligence concerning compliance of Safety Pharmacology studies to best practices is an effective means to ensure that equally stringent safety criteria are applied to both in-licensed and in-house compounds. Innovative technologies of great potential for Safety Pharmacology presented at the meeting are organs on chips (lung, heart, intestine) displaying mechanical and biochemical features of native organs, electrical field potential (MEA) or impedance (xCELLigence Cardio) measurements in human induced pluripotent stem cell-derived cardiomyocytes for unveiling cardiac electrophysiological and mechanical liabilities, functional human airway epithelium (MucilAir?) preparations with unique 1-year shelf-life for acute and chronic in vitro evaluation of drug efficacy and toxicity. Custom-designed in silico and in vitro assay platforms defining the receptorome space occupied by chemical entities facilitate, throughout the drug discovery phase, the selection of candidates with optimized safety profile on organ function. These approaches can now be complemented by advanced computational analysis allowing the identification of compounds with receptorome, or clinically adverse effect profiles, similar to those of the drug candidate under scrutiny for extending the safety assessment to potential liability targets not captured by classical approaches. Nonclinical data supporting safety can be quite reassuring for drugs with a discovered signal of risk. However, for marketing authorization this information should be complemented by a clear clinical proof of safety. The ongoing outsourcing process of Regulatory Safety Pharmacology activities from large Pharmas to contract research organizations should be taken as an opportunity to establish long-overdue in-house Exploratory Safety Pharmacology units fully dedicated to the optimization of clinical candidates on organ safety.     

How many ECG leads are required for in vivo studies in safety pharmacology?

This article explains the principles of electrocardiography, and explains how it is used by Safety Pharmacology, with a focus on the requirement for multiple leads in Safety Pharmacology assessment. Electrocardiography as used in different disciplines (e.g., medicine, anesthesiology, physiology, and pharmacology/toxicology/safety pharmacology) has different requirements for the number of electrodes applied. Electrodes may be placed at an infinite number of points on the body, and voltages (electrocardiograms) may be registered between/among them. However in safety pharmacology there is little evidence that more than 1--or at most 3--lead(s) is (are) required to provide all of the information that might be present using an infinite number. This is based upon (1) the biophysics of the heart as a generator of electrical potential/voltage, (2) the fact that most properties of electrophysiology affected adversely by drugs are expressed as changes in durations, and (3) experience. A single, unipolar lead (V(3)) recorded from the left sternal border at the 5th intercostal space possesses minimal artifact and large, stable deflections. This lead allows for accurate measurement of heart rate and rhythm, durations of component deflections (e.g., PQ, QRS, QT), and J-point deviation. A greater number of leads seldom or never yield additional information that detects liabilities. Commonly voltages recorded between the right thoracic and left pelvic limbs (lead II) provides information similar to lead V(3), and lead II is easier to apply, and produces voltages with less artifact and similar to those in lead V(3). A lead measuring the voltage between the left and right thoracic limbs (lead I) along with lead II allows for estimating orientation of vectors in the frontal plane, but knowledge of these vectors seldom or never indicates liability of a test article.     

2011 Annual Meeting of the Safety Pharmacology Society: an overview

The keynote address of 2011 Annual Meeting of the Safety Pharmacology Society examined the known and the still to be known on drug-induced nephrotoxicity. The nominee of the Distinguished Service Award Lecture gave an account of his career achievements particularly on the domain of chronically instrumented animals for assessing cardiovascular safety. The value of Safety Pharmacology resides in the benefits delivered to Pharma organizations, regulators, payers and patients. Meticulous due diligence concerning compliance of Safety Pharmacology studies to best practices is an effective means to ensure that equally stringent safety criteria are applied to both in-licensed and in-house compounds. Innovative technologies of great potential for Safety Pharmacology presented at the meeting are organs on chips (lung, heart, intestine) displaying mechanical and biochemical features of native organs, electrical field potential (MEA) or impedance (xCELLigence Cardio) measurements in human induced pluripotent stem cell-derived cardiomyocytes for unveiling cardiac electrophysiological and mechanical liabilities, functional human airway epithelium (MucilAir^?) preparations with unique 1-year shelf-life for acute and chronic in vitro evaluation of drug efficacy and toxicity. Custom-designed in silico and in vitro assay platforms defining the receptorome space occupied by chemical entities facilitate, throughout the drug discovery phase, the selection of candidates with optimized safety profile on organ function. These approaches can now be complemented by advanced computational analysis allowing the identification of compounds with receptorome, or clinically adverse effect profiles, similar to those of the drug candidate under scrutiny for extending the safety assessment to potential liability targets not captured by classical approaches. Nonclinical data supporting safety can be quite reassuring for drugs with a discovered signal of risk. However, for marketing authorization this information should be complemented by a clear clinical proof of safety. The ongoing outsourcing process of Regulatory Safety Pharmacology activities from large Pharmas to contract research organizations should be taken as an opportunity to establish long-overdue in-house Exploratory Safety Pharmacology units fully dedicated to the optimization of clinical candidates on organ safety.     

Safety pharmacology in focus: new methods developed in the light of the ICH S7B guidance document

'Safety' continues to be a growth area in 'Pharmacology'. This issue of Journal of Pharmacological and Toxicological Methods is the third to be focused on methods development in the safety pharmacology area. The unusual nature of safety pharmacology mandates that methods development be done with, not only scientific validation, but also, adherence to the mandates of legislation to the forefront. This focused issue draws on a broad range of global safety pharmacology experts, many of whom operate in the industrial milieu. They have reviewed and updated current models, validated modifications, and have also introduced novel methodology important to the conduct of non-clinical safety pharmacology studies. The contributors were all active participants at the 5th Annual Safety Pharmacology Society (SPS) meeting held in Mannheim, Germany September 25-28, 2005. The publications presented here describe in vitro and in vivo pharmacological methods development that has been informed by the S7A regulatory guidance document for pre-clinical safety testing of drugs. While S7A describes the 'core battery' of methods used to characterize the safety pharmacology profile of a compound, the most recent news in Safety Pharmacology involves ratification of the related S7B safety guidance document. Unlike the past, S7B heralds a new era for the pharmaceutical industry since it now sets out how to address safety concerns of a new chemical entity (NCE) in relation to adverse actions on ventricular repolarization, a topic that has vexed industry and regulatory authorities for many years. Unsurprisingly there are many papers in the present issue that address this specific aspect of safety pharmacology. These include results from the Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) initiative, in which non-clinical in vitro (hERG and Purkinje fiber) and in vivo (QT dog study) assays were found to be useful in the determination of drug-induced QT prolongation risk, and thus provide better characterization of a biomarker for the potential risk in humans for development of the torsades de pointes syndrome. However, safety methods development does not begin and end with ventricular repolarization. This focused issue also describes the re-evaluation and validation of a primate CNS model for evaluating orthostatic hypotension, and outlines a simple and rapid rodent object recognition task model that can be used to assess the amnesic potential of an NCE. Reviews of respiratory safety studies as well as both in vitro and in vivo aspects of cardiovascular function are also described. There are also papers that describe the pharmacology of vehicles and solvents used to solubilize study drugs and the applicability of voltage-sensitive dyes to optically record cardiac action potentials from single myocytes. Thus, this issue of the Journal of Pharmacological and Toxicological Methods remains a primary resource for industrial and academic pharmacologists interested in better understanding non-clinical safety pharmacology methods.     

The role of general pharmacological studies and pharmacokinetics in the evaluation of drugs (1): The role of general/safety pharmacology studies in the development of pharmaceuticals: international harmonization of guidelines

The working group for reevaluation of the Guideline for General Pharmacology Studies has completed a draft guideline for Safety Pharmacology studies and plan to recommend replacing the existing guideline with the revised one. This proposed guideline is now subject to domestic and international consultation. The basic principle of the revision is to harmonize the guideline with the international concepts. The working group decided to change the title of "General pharmacology" to "Safety pharmacology", because the objective of this guideline is to assess the safety of a test substance in humans by examining the pharmacodynamic properties of the substance. The proposed guideline includes studies on vital functions as essential studies that should be performed prior to human exposure. Studies are also required to be conducted when predictable or unexpected observed effects are concerned. The working group recommends a case-by-case approach to select the necessary test items in consideration of the variable information available.     

Safety Pharmacology Society: 5th Annual Meeting

This report summarises selected presentations delivered at the Safety Pharmacology Society annual meeting. Organ safety was covered, with cardiac QT liability being discussed most extensively. Of particular interest, was the lecture on beat-to-beat variability of cardiac repolarisation in anesthetised dogs with chronic atrioventricular block. This model, characterised by an electrophisyologically remodelled heart (replicating a human heart with reduced cardiac repolarisation reserve), was developed to assess the potential of drugs to cause unsafe QT prolongation that may spontaneously evolve into life-threatening arrhythmias. An interesting case study illustrated the apparent failure of safety pharmacology studies to accurately predict clinical QT liability due to an underestimated plasma concentration for therapeutic efficacy at early nonclinical stage. An emerging attractive new technology, presented as a means to minimise drug failure to reach marketing stage (attrition) dealt with biological fingerprinting which consists in placing drug candidates in the context of chemical, pharmacological, toxicological and clinical liability spaces available for marketed, withdrawn or failed drugs, as well as reference compounds. The meeting was an excellent occasion for sharing knowledge and technologies among members of this young society actively engaged in promoting safety pharmacology, a novel research activity which now plays a pivotal role in the drug development process.     

Safety Pharmacology Society: 5th annual meeting

This report summarises selected presentations delivered at the Safety Pharmacology Society annual meeting. Organ safety was covered, with cardiac QT liability being discussed most extensively. Of particular interest, was the lecture on beat-to-beat variability of cardiac repolarisation in anesthetised dogs with chronic atrioventricular block. This model, characterised by an electrophisyologically remodelled heart (replicating a human heart with reduced cardiac repolarisation reserve), was developed to assess the potential of drugs to cause unsafe QT prolongation that may spontaneously evolve into life-threatening arrhythmias. An interesting case study illustrated the apparent failure of safety pharmacology studies to accurately predict clinical QT liability due to an underestimated plasma concentration for therapeutic efficacy at early nonclinical stage. An emerging attractive new technology, presented as a means to minimise drug failure to reach marketing stage (attrition) dealt with biological fingerprinting which consists in placing drug candidates in the context of chemical, pharmacological, toxicological and clinical liability spaces available for marketed, withdrawn or failed drugs, as well as reference compounds. The meeting was an excellent occasion for sharing knowledge and technologies among members of this young society actively engaged in promoting safety pharmacology, a novel research activity which now plays a pivotal role in the drug development process.     

Challenges and lessons learned since implementation of the safety pharmacology guidance ICH S7A

The International Conference on Harmonization, Topic S7A guidance (ICH S7A) on safety pharmacology for human pharmaceuticals has been in effect for 3 years in Europe, the United States and Japan. Surveys of the pharmaceutical industry, regulatory agencies and the audience attending the 4th Annual Meeting of the Safety Pharmacology Society have helped identify and address areas of controversy, as well as those challenges that have emerged since implementation of the guidance worldwide. Overall, ICH S7A has been successfully implemented. The guidance provides for "Good Laboratory Practice" compliant "safety pharmacology core battery" of studies that are generally performed prior to first administration to humans. The approach is science-driven and specifies the use of robust and sophisticated in vitro and/or in vivo assays. There are, however, some areas that require further refinement/clarification such as the specifics of study design including the selection of dose/concentration, choice of species, modeling of the temporal pharmacodynamic changes in relation to pharmacokinetic profile of parent drug and major metabolites, use of an appropriate sample size, statistical power analysis as a means of demonstrating the sensitivity of the model system, testing of human-specific metabolites and demonstrating not only the model's sensitivity, but also its specificity for predicting adverse events in humans. There was also discussion of when these studies are needed in relation to the clinical development plan. Representatives from the pharmaceutical industry and regulatory agencies see the implementation of ICH S7A as a major step forward towards identifying the risk to Phase 1 and 2 volunteers and patients. It remains to be seen, however, whether and in what ways the ICH S7A-based strategy will contribute to the modification of the integrated risk assessment during the latter stages of clinical development or once drugs have been introduced to the marketplace.     

Safety and secondary pharmacology: successes, threats, challenges and opportunities

This review summarises the lecture of Dr Tim Hammond, recipient of the Distinguished Service Award of the Safety Pharmacology Society, given on 20 September 2007 in Edinburgh. The lecture discussed the rationale behind the need for optimal non-clinical Safety and Secondary Pharmacology testing; the evolution of Safety and Secondary Pharmacology over the last decade; its impact on drug discovery and development; the value of adopting an integrated risk assessment approach; the translation of non-clinical findings to humans and finally the future challenges and opportunities facing these disciplines.     

Assessment of biotechnology products for therapeutic use

Biotechnology products for therapeutic use include a very diverse range of products, including growth factors, cytokines, hormones, receptors, enzymes, clotting factors, monoclonal antibodies, vaccines, DNA vaccines, gene transfer products, cell therapies and tissue/organ grafts. While some of these products are regulated as medicinal products, the regulatory status of others such as some cell therapies and tissue/organ-based products differs globally and falls within the borderline between the practice of medicine, medical devices and medicinal products. The unclear regulatory status of some products can add to the complexity of the safety assessment of such products. Conventional non-clinical testing paradigms and guidelines for small molecule development are often not relevant for biotechnology products. Guidelines relating to the non-clinical safety evaluation of biotechnology products, gene transfer products and cell therapy products are available and represent a set of general guiding principals to be applied on a case-by-case basis. The quality, safety and efficacy of biotechnology products for therapeutic use are intricately linked, far more so than for conventional medicinal products, leading to the need for increased communication between those responsible for ensuring product quality and those responsible for non-clinical safety testing. Safety issues include microbiological safety (due to the use of biological materials either during the manufacturing process or as an integral part of the products), pharmacological/ biological toxicity (due to excessive primary pharmacology or undesirable secondary pharmacology), immunogenicity and potential tumourigenicity (for example, for growth factors, immunosuppressive monoclonal antibodies and cell therapy products). Genotoxicity and intrinsic chemical toxicity are less of a problem for biotechnology products.     

P30 The Pharmacology Teaching for Medical Students in Chinese College

Pharmacology is one major curriculum of medical students in China. It is an important bridge discipline which connects basic medical sciences and clinical sciences. Pharmacology teaching in Chinese medical colleges have developed rapidly recently. The popularization of modem teaching tools and the practice of bilingual teaching make pharmacology teaching developing by leaps and bounds. The aim of the article is to provide those who are interested in teaching of pharmacology to be acquainted with the teaching of pharmacology, including the teaching of both principles and practice, in China.     

A problem-oriented approach to safety issues in drug development and beyond.

Human safety issues arise throughout the life cycle of pharmaceutical products and relevant information comes from a multitude of sources. Assessment and management of risks to humans requires a problem-based analysis to bring together relevant information regardless of source. The Safety Evaluation Plan (SEP) is a tool to support problem-oriented safety analysis. Safety issues are specified and the evaluation and management of each problem is based on a status summary that integrates the most current information from all relevant sources. The status summary is updated regularly during the course of clinical development to reflect the results of new studies and new clinical trials. In the postmarketing period, relevant postmarketing data is incorporated. Recent regulatory initiatives emphasise early identification of product safety risks so that appropriate risk-management measures can be instituted at the time of approval. A problem-oriented approach supports growing regulatory expectations regarding risk assessment and risk management. The problem-oriented approach facilitates early identification of safety issues and an evidence-based approach to their evaluation. Proactive management of safety problems leads to prompt assessment of risks and timely and appropriate steps aimed at risk reduction. The SEP provides a single global assessment for each safety issue. Regulatory submissions for pharmaceutical and biological products are organised by type of information. International Conference of Harmonisation documents covering clinical safety issues structure and analyse information separately by type, for example, adverse events, serious adverse events, laboratory data, vital signs, etc. A problem-oriented analysis would need to find a place in the regulatory process. A problem-oriented approach to safety cuts across typical structures in the pharmaceutical industry where different groups handle preclinical, clinical and postmarketing safety information. The SEP can improve communication within the company and externally. Nonetheless, supporting structures need to be adapted to support such an interdisciplinary process. Overall, the problem-oriented approach, supported by a SEP, contributes to realistic expectations and sustained credibility when dealing with safety issues.