An Industry Survey With Focus on Cardiovascular Safety Pharmacology Study Design and Data Interpretation.

INTRODUCTION: The Safety Pharmacology Society (SPS) conducted a membership survey to examine industry practices related mainly to cardiovascular (CV) safety pharmacology (SP). METHODS: Questions addressed nonclinical study design, data analysis methods, drug-induced effects, and conventional and novel CV assays. RESULTS: The most frequent therapeutic area targeted by drugs developed by the companies/institutions that employ survey responders was oncology. The most frequently observed drug-mediated effects included an increased heart rate, increased arterial blood pressure, hERG (IKr) block, decreased arterial blood pressure, decreased heart rate, QTc prolongation, and changes in body temperature. Broadly implemented study practices included Latin square crossover study design with n = 4 for nonrodent CV studies, statistical analysis of data (eg, analysis of variance), use of arrhythmia detection software, and the inclusion of data from all study animals when integrating SP studies into toxicology studies. Most responders frequently used individual animal housing conditions. Responders commonly evaluated drug effects on multiple ion channels, but in silico modeling methods were used much less frequently. Most responders rarely measured the J-Tpeak interval in CV studies. Uncertainties relative to Standard for Exchange of Nonclinical Data applications for data derived from CV SP studies were common. Although available, the use of human induced pluripotent stem cell cardiomyocytes remains rare. The respiratory SP study was rarely involved with identifying drug-induced functional issues. Responders indicated that the study-derived no observed effect level was more frequently determined than the no observed adverse effect level in CV SP studies; however, a large proportion of survey responders used neither.

CNS Safety Screening Under ICH S7A Guidelines Requires Observations of Multiple Behavioral Units to Assess Motor Function.

In the adoption of behavior as a critical end point in safety pharmacology and neurotoxicity screening, federal regulatory agencies have shifted the predominating scientific perspective from pharmacology back to the experimental analysis of behavior (psychology). Nowhere is this more evident than in tier I safety assessment of the central nervous system (CNS). The CNS and peripheral nervous system have multiple behavioral units of general activity. A complete picture of the motor control neural pathways cannot be measured by any one single approach. The CNS safety protocols under International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use S7A are required to be conducted in accordance with Good Laboratory Practices by trained technical staff. The CNS safety assessments necessitate the inclusion of a thorough and detailed behavioral analysis of home cage activity, the response to handling, and transportation to and observations within an open-field apparatus with ancillary measures of basal muscle tone, muscle strength, and tremor in a functional observation battery, as well as quantitative measurements of 3-dimensional activity in an automated photobeam arena. Cost-cutting initiatives or a radical application of the "reduce use" principle of the 3 Rs only jeopardize the spirit, intent, and predictive validity of tier I safety testing assays dictated by current drug safety guidelines.

Preclinical Abuse Potential Assessment.

Although laboratories have been conducting scientific evaluations of the abused drugs for many years, preclinical evaluations of the abuse potential of new drugs have been an integral component of new drug applications more recently. The development of a unified testing approach is crucial prior to initiating individual studies to address abuse potential. The core preclinical studies that will be required include a dependence/withdrawal study, an assessment of the discriminative cue produced by the new drug, and an assessment of whether the drug will be self-administered. This discussion is focused on the requirements for drug scheduling recommendations from the FDA and how to conduct the evaluations that will be used to make those recommendations and how to select parameter details such as preclinical species, test doses, test conditions, route of drug administration, comparator compounds, and behavioral test designs recommended.

Withdrawal assessment following subchronic oral ketamine administration in Cynomolgus macaques.

Recently there is increased regulatory interest in the assessment of physical dependence and withdrawal as part of the safety assessment for novel therapeutic entities. Choosing appropriate and sensitive parameters to detect withdrawal syndromes, and relevant positive control comparator drugs that can be administered in the same manner as the test agent, are critical study design elements. Pilot studies to determine the effects of oral ketamine in cynomolgus monkeys during, and following cessation of treatment, were explored. Detailed behavioral observations (both remote and interactive), food consumption, and body weight and temperature, were assessed during the dose-ranging, repeat dose (5 or 14 days), and withdrawal phases (3 or 5 days). Doses explored during dose-ranging included 20, 40, 100, or 200 mg/kg ketamine; subsequent withdrawal assessments were conducted following repeat dosing of 150 mg/kg. In the 14-day dosing study, exposure to ketamine and norketamine was assessed following 8 days of dosing. Administration of 150 mg/kg ketamine produced decreased activity, loss of balance, ataxia, hunched posture, nystagmus, lateral recumbence, and changes in alertness levels during dosing phases. When ketamine was withdrawn, increased reactivity, increased activity, and stereotypic behaviors were demonstrated that were absent during baseline or the dosing phase of the studies.

Establishing performance characteristics for positive control article selection in drug self-administration studies.

The selection of a controlled substance (CS) for use as the positive control article in a nonclinical drug abuse liability (DAL) assessment study should be contemplated carefully and with full understanding of the stated intent of the study design. Any CS that can maintain day-to-day stable baseline responding of voluntary intravenous intakes in animals may be selected under the current guidelines. Schedule I - IV CNS stimulants, depressants, and sedative/hypnotics can serve as maintenance drugs in these protocols, but not all of these compounds will provide comparatively efficient, robust, and stable daily intakes. Each Sponsor is directed to select a positive control article and training dose that will provide the most balanced, predictive, and scientifically-sound comparison consistent with the mechanism of action or therapeutic target of the test article. The SA study design is not a "one-size-fits-all" assay. This is a discussion of the critical design factors to be considered in selecting the most appropriate positive control article to use for a SA study.

Current FDA regulatory guidance on the conduct of drug discrimination studies for NDA review: Does the scientific literature support recent recommendations?

BACKGROUND: The Controlled Substances Staff of the Center for Drug Evaluation and Research at the US Food and Drug Administration and the Pharmaceutical Research Manufacturers Association (PhRMA) conducted a series of open forum dialog sessions between 2006 and 2016. A Cross Company Abuse Liability Council (CCALC) was formed during the process of this unique collaborative effort between Industry and Federal Regulators whose goals were to establish the development of standards for the preclinical screening of new molecular entities for schedule control actions required as part of every New Drug Application process. The draft guidance document was published and disseminated in 2010, which allowed for alternative approaches to each study protocol requirement needed for NDA review, if the approach satisfied the requirements of the applicable statutes and regulations (i.e., the controlled substance act). In a series of recent pre-study protocol reviews requested by confidential Pharmaceutical Sponsors of MPI Research, the CSS staff appeared to change its policy and set forth to require all drug discrimination study data to be generated under "extinction" test sessions. MPI Research is a Contract Research Organization acting on behalf of pharmaceutical companies and bound under separate confidentiality agreements. PURPOSE: The purpose of this review is to highlight the data appearing in peer-reviewed scientific journals that do not support the regulatory administrative constraints on one specific testing methodology (extinction) to the exclusion of another (reinforced test sessions). CONCLUSION: This mind shift represents a restrictive administrative policy by the FDA that is not supported by the published data.

EEG in non-clinical drug safety assessments: Current and emerging considerations.

Electroencephalogram (EEG) data in nonclinical species can play a critical role in the successful evaluation of a compound during drug development, particularly in the evaluation of seizure potential and for monitoring changes in sleep. Yet, while non-invasive electrocardiogram (ECG) monitoring is commonly included in preclinical safety studies, pre-dose or post-dose EEG assessments are not. Industry practices as they relate to preclinical seizure liability and sleep assessments are not well characterized and the extent of preclinical EEG testing varies between organizations. In the current paper, we discuss the various aspects of preclinical EEG to characterize drug-induced seizure risk and sleep disturbances, as well as describe the use of these data in a regulatory context. An overview of EEG technology-its correct application and its limitations, as well as best practices for setting up the animal models is presented. Sleep and seizure detection are discussed in detail. A regulatory perspective on the use of EEG data is provided and, tying together the previous topics is a discussion of the translational aspects of EEG.

Safety pharmacology investigations on the nervous system: An industry survey.

The Safety Pharmacology Society (SPS) conducted an industry survey in 2015 to identify industry practices as they relate to central, peripheral and autonomic nervous system ('CNS') drug safety testing. One hundred fifty-eight (158) participants from Asia (16%), Europe (20%) and North America (56%) responded to the survey. 52% of participants were from pharmaceutical companies (>1000 employees). Oncology (67%) and neurology/psychiatry (66%) were the most frequent target indications pursued by companies followed by inflammation (48%), cardiovascular (43%), metabolic (39%), infectious (37%), orphan (32%) and respiratory (29%) diseases. Seizures (67% of participants), gait abnormalities (67%), tremors (65%), emesis (56%), sedation (52%) and salivation (47%) were the most commonly encountered CNS issues in pre-clinical drug development while headache (65%), emesis/nausea (60%), fatigue (51%) and dizziness (49%) were the most frequent issues encountered in Phase I clinical trials. 54% of respondents reported that a standard battery of tests applied to screen drug candidates was the approach most commonly used to address non-clinical CNS safety testing. A minority (14% of all participants) reported using electroencephalography (EEG) screening prior to animal inclusion on toxicology studies. The most frequent group size was n=8 for functional observation battery (FOB), polysomnography and seizure liability studies. FOB evaluations were conducted in a dedicated room (78%) by blinded personnel (66%) with control for circadian cycle (55%) effects (e.g., dosing at a standardized time; balancing time of day across treatment groups). The rat was reported as the most common species used for seizure liability, nerve conduction and drug-abuse liability testing.

Evaluation of the reinforcing effects of monoamine reuptake inhibitors under a concurrent schedule of food and i.v. drug delivery in rhesus monkeys.

Most medications prescribed for attention-deficit-hyperactivity disorder are psychomotor stimulants with reinforcing effects in laboratory animals (eg methylphenidate). The present studies were conducted to evaluate the reinforcing effects of the recently approved medication atomoxetine in monkeys trained to 'choose' between automated deliveries of either an i.v. injection or food. Rhesus monkeys were trained to lever-press under concurrent schedules of reinforcement; responses on one lever resulted in an injection of either saline or drug, and responses on the alternative lever resulted in food delivery. Data were collected on four measures: response rates, percentage of total responses occurring on the injection-lever (% ILR), number of injections earned, and number of food pellets earned. Dose-effect functions were determined for cocaine (0.003-0.3 mg/kg/inj), methylphenidate (0.003-0.1 mg/kg/inj), amphetamine (0.003-0.1 mg/kg/inj), atomoxetine (0.01-0.3 mg/kg/inj), and desipramine (0.03-1.0 mg/kg/inj) using a double alternation schedule of saline and drug availability. Results indicate that the distribution of behavior changed according to the drug and dose available for self-injection. Saline availability was typically associated with high rates of food-maintained responding. The % ILR increased from 3+/-1% when saline was available to >90% when >0.03 mg/kg/inj of cocaine, methylphenidate or d-amphetamine was available. However, no dose of atomoxetine or desipramine maintained self-administration behavior on the injection-lever. The number of food pellets earned per session decreased as the dose of each drug increased, indicative of behavioral activity with all five drugs. The reinforcing effects of cocaine, methylphenidate, and d-amphetamine in these studies are consistent with previous findings in nonhuman primates and with their documented abuse liability. The absence of reinforcing effects of atomoxetine support the view that, like desipramine, it has no evident abuse potential.

The Diplomate in Safety Pharmacology (DSP) certification scheme.

As with other professional disciplines there is a growing need from within industry as well as global regulatory authorities for implementation of a certification process in order to assure that appropriate expertise is developed and quality standards are identified for professionals involved in the practice of Safety Pharmacology (SP). In order to meet this need, the Safety Pharmacology Society (SPS) has developed the Diplomate in Safety Pharmacology (DSP) certification process. There are many benefits to certification including authentication of the discipline within the overall pharmaceutical community and with regulatory authorities. It also encourages participation in SPS activities by other professionals (toxicologists, clinicians, academics) who wish to broaden their professional expertise. It provides an opportunity for candidates to strengthen their fundamental scientific knowledge, and stimulates the sharing of data, methods and model development in the form of publications and presentations on relevant topics in SP. Accreditation in SP occurs after candidates successfully complete a written certification examination conducted at the annual SPS meeting. The DSP exam consists primarily of material pertinent to the conduct of SP vital function core battery studies (i.e., cardiovascular, respiratory and central nervous systems), supplemental SP studies (i.e., renal/urinary, gastrointestinal, immunology, and hematology), Regulatory Guidelines (ICH Guidelines) as well as relevant cross-functional knowledge (e.g., physiology, pharmacology, toxicology, biochemistry, pathology, pharmacokinetics, dosing formulation, analytical methods, and statistics). Maintenance of the DSP certification results from the accrual of credits which are gained from a range of educational and scientific contributions. Eligibility requirements include a combination of at least a bachelor degree in science and two years of relevant professional SP experience and one poster presentation on a SP topic as first author at a recognized major scientific meeting.

Benchmarking safety pharmacology regulatory packages and best practice.

INTRODUCTION: The objectives of this survey were to obtain a global information update regarding current industry perspectives that describe Safety Pharmacology programs as they relate to the ICH S7A and S7B regulatory guidelines but also to obtain a broader perspective of other practises practices in the field currently used by companies. Preliminary findings were presented at the 7th Annual Meeting of the Safety Pharmacology Society (SPS) (Edinburgh, Scotland, Sept 19-21, 2007). METHODS: The survey was distributed by the SPS to 125 pharmaceutical companies. Survey topics included (a) an update on ICH S7A and S7B practices, (b) frontloading Safety Pharmacology studies prior to selection of candidate drugs, (c) abuse and dependence-liability studies and (d) an extended evaluation of industry practises practices as assessed by Contract Research Organizations (CROs). RESULTS: Respondents (>94%) include GLP core battery (CV, CNS and respiratory) studies in the drug package submitted to regulatory agencies, and approximately 40% also submit studies on gastrointestinal and renal function. Respondents to the ICH S7B aspects indicate approximately 98% include the hERG assay and QT interval (in vivo) data in submissions, 63% include APD in vitro data and another 23% APD in vivo and other cardiac channel data (26%). SP frontloading is performed by 78% of all responding companies. Respondents indicate that 39% of these non-GLP CV studies are conducted before lead optimization (LO) and 85% during LO and before candidate drug selection. The hERG, CNS selectivity binding screens and rodent behavioral studies are frontloaded by 100%, 90% and 74% of respondents. Responding CROs (26) were surveyed on the services offered including Irwin or Functional Observational Battery (FOB) tests (70%), respiratory studies (85%), in vivo telemeterized dogs (69%) and in vitro CV studies (50%). Only 38% of SP studies are combined with toxicology studies at the CROs. DISCUSSION: The survey results indicate that ICH S7A core battery studies are implemented by most of the responding companies with a clear trend of an enhanced submission of renal and GI studies. The impact of ICH S7B is clear since, all respondents assess cardiac repolarization using cellular hERG (I(Kr)) and whole animal (QT interval) assays as a component of their safety assessment. Responses indicate a diversity of approaches for conducting abuse liability studies, which primarily use the methods of self-administration and drug discrimination. While early SP frontloading of studies seems to vary, the methods used appear to be generic to some extent and include in vitro 'off-target' evaluations and in vivo tests to determine the potential for CNS and cardiovascular issues.