De-risking in Tier I CNS safety assessments is the primary function of study design and technical training of laboratory staff observers.

Derisking is not a pharmaceutical industry strategy to reduce time, effort, or costs in drug development. Derisking strategies originated within the National Institutes of Health as a predicate to good science. There is a growing sentiment within drug development programs to diminish the importance of behavioral measures in toxicological studies and in the Tiered Safety assessment plans of the U.S. Regulatory Agencies and the International Commission on Harmonization. The validity and reliability of the Functional Observational Batter (FOB) is critically dependent on consistency and technical quality in each risk assessment plan. US Federal and International drug approval organizations have universally adopted the concept of principles of test construction rather than delineating specific behavioral assay endpoints for inclusion of the FOB in nonclinical safety protocols. The validity and reliability of behavioral observations in standardized neurotoxicity screening is critically dependent on the FOB developed by the Study Director with the Sponsor throughout all stages of testing.. The individual risk factors selected for observation to be included in the early Tier 1 safety program should be determined by the mechanism and mode of action of the test article. The results of Tier I testing are the basis for Tier II testing designs. Critical to the compliance with Good Laboratory Practices is the documentation of training of the operational staff scheduled to conduct all aspects of the established protocol.

Study design criteria for regulatory-based drug control action: Drug discrimination.

This "methods paper" focusses on one specific and limited aspect of drug safety evaluations required for all new drug entities that affect the central nervous system - the drug discrimination (DD) assay. We focus on three critical factors involved in experimental design and protocol development for the conduct of DD studies for abuse liability risk assessment that comply with the Good Laboratory Practice Guidelines (GLPs). The selection of 1) the reference drug(s) choice, 2) training dose selection, and 3) the selected route-of-administration will determine the applicability of the data to meet the regulatory expectations of the 8-factors determinative of schedule control recommendations. The study conduct and resulting data submission to the FDA are intended for drug scheduling review by the Controlled Substances Staff in the Center for Drug Evaluation and Research (CDER) at the US Food & Drug Administration (FDA). These animal studies are required to meet the statutory requirements of the Controlled Substances Act of 1970. The abuse liability study is conducted during Phase II and III of human clinical trials. Procedural or method-based errors this late in drug development can result in a significant economic and business threat to the program.

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.

FOB vs modified Irwin: What are we doing?

There is a general sentiment in the nonclinical safety assessment literature and the proponents of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), that the "Modified Irwin" and the Functional Observation Battery are distinct and unique assays for the nonclinical assessment of the central nervous system (CNS). We identify and defend the position that the Irwin screen was developed as an FOB and both terms refer to a single, unitary functional assay. In giving credit to one prominent contributor to any one significant discipline of science for a specific assay, orientation, or theory may have an exclusionary influence on the merits of other prominent contributors within the same research arena. Scientific organizations as well as journal and textbook editors have attempted to unify the nomenclature used within a scientific discipline to make the disciplines conform to non-attributional surname nomenclatures. For example, the Salk-Sabin immunization is simply referred to as the polio vaccine. The "Skinner box" is now the "operant chamber" and "Pavlovian conditioning" is now "respondent conditioning". In 1968, Samuel Irwin established an operational method of analysis used for measuring drug effects in purpose bred laboratory animals. We present and defend the view that the behavioral screening assay developed by Irwin is, for all intents and purposes, a functional observational battery (FOB). We take the position that in standardizing nomenclature without "surnames" the FOB is simply the contemporary name for the data collection system in use under the harmonized safety pharmacology guidelines.

"Not Everything That Shakes Is a Seizure": Making the Determination of Test Article-Induced Convulsions in Toxicology Studies.

Spontaneous unexpected events occasionally develop during the course of rodent preclinical toxicology studies. The presentation of serious adverse events on animal studies may require notification of these events to the Food and Drug Administration if the events are most likely the direct result of test article administration. Classical conditioning of emotional responses may occur over the course of a repeat-dose study and clinical observation calls of "convulsions" are reported to the study director and/or staff veterinarians. In the current heightened environment of most research laboratories related to general animal welfare issues, it is imperative to have an action plan that will help to elucidate the potential origins of these motor events. We provide 10 factors that should be considered to help the study director determine the most likely cause of these motor attacks as being organic or psychogenic in origin.

The gold-standard in preclinical abuse liability testing: It's all relative.

All new molecular entities (NMEs) with targeted or indirect effects on the central nervous system (CNS) must be evaluated for their abuse liability as a part of their nonclinical development plan. Inherently key in the drug control review is the term "relative abuse liability". The basis for determination of drug control is critically dependent on the nonclinical assessment of the reinforcing attributes of the NME in animals (rat is the regulatory preferred species) in a standard operant conditioning paradigm. Pharmaceutical representatives without a background in behavioral analysis or operant conditioning models must weigh through conceptually-intriguing language and constructs that accurately convey and communicate the relative potential for abuse to drug regulatory experts in the field. Effective statutory language in the preclinical assessment of relative abuse liabilities for schedule control status reviews must be 1) specific; 2) concise; 3) familiar to the regulators; 4) unambiguous; 5) constructive; and 6) formalized with respect to both international and national drug control policies. In this review we attempt to define and highlight the importance of the statutory language used to report self-administration study results to both parties engaged in NDA approval process.

A predictive index of biomarkers for ictogenesis from tier I safety pharmacology testing that may warrant tier II EEG studies.

Three significant contributions to the field of safety pharmacology were recently published detailing the use of electroencephalography (EEG) by telemetry in a critical role in the successful evaluation of a compound during drug development (1] Authier, Delatte, Kallman, Stevens & Markgraf; JPTM 2016; 81:274-285; 2] Accardi, Pugsley, Forster, Troncy, Huang & Authier; JPTM; 81: 47-59; 3] Bassett, Troncy, Pouliot, Paquette, Ascaha, & Authier; JPTM 2016; 70: 230-240). These authors present a convincing case for monitoring neocortical biopotential waveforms (EEG, ECoG, etc) during preclinical toxicology studies as an opportunity for early identification of a central nervous system (CNS) risk during Investigational New Drug (IND) Enabling Studies. This review is about "ictogenesis" not "epileptogenesis". It is intended to characterize overt behavioral and physiological changes suggestive of drug-induced neurotoxicity/ictogenesis in experimental animals during Tier 1 safety pharmacology testing, prior to first dose administration in man. It is the presence of these predictive or comorbid biomarkers expressed during the requisite conduct of daily clinical or cage side observations, and in early ICH S7A Tier I CNS, pulmonary and cardiovascular safety study designs that should initiate an early conversation regarding Tier II inclusion of EEG monitoring. We conclude that there is no single definitive clinical marker for seizure liability but plasma exposures might add to set proper safety margins when clinical convulsions are observed. Even the observation of a study-related full tonic-clonic convulsion does not establish solid ground to require the financial and temporal investment of a full EEG study under the current regulatory standards. PREFATORY NOTE: For purposes of this review, we have adopted the FDA term "sponsor" as it refers to any person who takes the responsibility for and initiates a nonclinical investigations of new molecular entities; FDA uses the term "sponsor" primarily in relation to investigational new drug application submissions.

The drug discrimination assay: Interpretative value of partial generalization for drug schedule control actions.

The U.S. Food & Drug Administration (FDA) has issued a final guidance document on the preclinical determination of abuse potential that must be conducted in animals for all new molecular entities (NMEs) submitted for a new drug application (NDA). Under statutory restrictions government guidance documents serve only as a guide or an expression of the agency's current thinking on the topic. Guidelines do not legally bind the agency or its registrants to any content in the guidance. There are no statutory (legal) descriptions of what study designs or methodology must be submitted to the Drug Enforcement Administration with respect to drug scheduling review. This paper describes the utility of an alternate method used, worldwide, to assess the internal subjective effects of drugs to predict the abuse liability that provides additional information to address the relative aspects of that liability.

Repeated "Day 1" FOB testing in ICH S7A safety assessment protocols: The influence of within- and between-session learning.

A large number of CNS safety assessment studies using the standard Functional Observational Battery (FOB) are conducted each year at Contract Research Organizations throughout the globe. Study design characteristics are as varied as the Sponsors for whom they are contracted. Gender inclusion, sample sizes, and timing of the FOBs are generally negotiated during protocol development. The ICH S7A guidelines describe a dose-effect study design for CNS safety assessment to be conducted prior to the first dose administration in man. Additionally, some Sponsors attempt to use the CNS safety FOB to establish both time- and dose-related acute behavioral effects of their compound in this single critical safety study. In this review, we highlight the confounding influences of multiple postdose FOBs (Day 1) versus the more standard, single FOB scheduled near systemic Cmax of the compound. Within- and between-session learning, combined with changes in vigilance/alertness/fatigue in both the animals and raters, can limit the generalizability of the FOB to accurately assess CNS effects under the current guidelines. Rationale is provided as to the tenuous nature of conducting simultaneous time- and dose-effect behavioral assessments as part of the core safety pharmacology programs.

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.