S7A safety pharmacological studies for pharamaceuticals.pptx

Safety pharmacology is a critical discipline that evaluates the potential adverse effects of new pharmaceutical compounds on vital physiological systems.
This comprehensive assessment ensures the safety and well-being of patients during clinical trials and post-approval drug use.
This presentation focused on the safety pharmacological studies mentioned in the ich guidelines along with the safety and toxicity guidelines and the difference between the ICH and OECD guidelines

1. Safety Pharmacological Studies for Pharmaceuticals औषध विज्ञान और विष विज्ञान विभाग / Department of Pharmacology and Toxicology Presented by : Dheeraj Ms. Pharm./2023-25/PT/14

2. Content Safety Introduction Factors influencing drug safety Toxicity Toxicity and assessing toxicity Adverse drug reactions Safety pharmacological studies (S7A) Conclusion OECD Guidelines and ICH Guidelines

3. Safety Safety : the condition of being safe from the conditions like hurt, or injuries. Safety is a paramount concern which encompasses the careful evaluation of a drug or pharmaceutical product's potential risks and benefits to ensure it can be used without causing harm to patients. This includes assessing factors like drug interactions, side effects, and optimal dosing to minimize the likelihood of adverse reactions.

4. Factors influencing Drug safety 1 Pharmacokinetics How the body absorbs, distributes, metabolizes and eliminates the drug. 2 Pharmacodynamics The drug’s mechanism of action and its effects on the body. 3 Genetic factors Individual differences in how people respond to and metabolize drugs 4 Patient characteristics Age, health status, and other medications the patient is taking 5 Manufacturing quality Ensuring consistent composition and purity of pharmaceutical products

5. Toxicology and assessing toxicity Toxicity : containing or being a poisonous material capable of causing death or serious debilitation Safety margin depends upon the therapeutic indication of the drug, the intended patient population, the competitive environment, and the present standard of care. Irreversible toxicity usually is unacceptable in human clinical trials as well as post-marketing surveillance. Theophylline (IV) : emergency room for acute bronchoconstriction in children

6. Adverse Drug Reaction An adverse drug reaction (event) (ADR) can be defined as any undesired, noxious, or unintended event occurring from a normal dosage (used for prophylaxis, diagnosis, or treatment) of the drug. The Federal Drug Administration regards any outcome leading to death, risk of death, hospitalization, disability, or required intervention to prevent permanent impairment or damage as adverse; these account for approximately 5% of all hospital admissions per year.

7. Toxicity assessment guidelines and safety Pharmacological studies OECD (Organization for Economic Co-operation and Development) toxicity assessment guidelines and ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) safety pharmacological studies are both crucial frameworks for evaluating the safety of chemicals and pharmaceuticals , but they differ in their focus and scope.

8. OECD toxicity assessment guidelines : Aim: assessing potential adverse effects of chemicals including pharmaceuticals on human health and the environment. Covers a wide range of endpoints Used by regulatory authorities to determine the safety of chemicals and pharmaceuticals before they are approved for commercial use . Different types of toxicity, including ocular inhalational, skin, cardiovascular, neurological, respiratory, carcinogenicity toxicity, etc. Range : including industrial chemicals, pesticides, food additives, and pharmaceuticals. They provide standardized methodologies for conducting toxicity studies, enhancing consistency and comparability of results across different substances. ICH safety pharmacological studies : Aim: focus specifically on assessing the potential adverse effects of pharmaceuticals on physiological functions in humans. Covers the limited number of endpoints. Helping to identify potential safety concerns early on and guiding decision-making regarding further development and clinical trials . Focuses mostly on CNS, CVS, Respiratory, renal, GI Range: This integrated approach ensures a comprehensive evaluation of the safety profile of pharmaceuticals across different human physiological systems. These studies provide critical data for regulatory submissions, helping to demonstrate the safety profile of pharmaceuticals and inform risk-benefit assessments.

9. Safety Pharmacology: Introduction Safety pharmacology is a critical discipline that evaluates the potential adverse effects of new pharmaceutical compounds on vital physiological systems. This comprehensive assessment ensures the safety and well-being of patients during clinical trials and post-approval drug use. Adopted in 2000 by the ICH S7A Categories include Primary pharmacodynamics Secondary pharmacodynamics Safety pharmacology studies

10. Objective : Help to protect clinical trial participants. Avoiding unnecessary use of animals and other resources. Background : Non-clinical evaluation of Pharmaceuticals for human use. First appeared in the timing of non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals (S6). Support the use of therapeutics in humans. Scope: Applies to new chemical entities and biotechnology-derived products for human use. Applied to marketed pharmaceuticals when appropriate (e.g., When adverse clinical events, a new patient population, or a new route of administration raises concerns not previously addressed). General Principles The specific studies that should be conducted and their design will vary based on the individual properties and intended uses of the pharmaceuticals. Internationally recognized methods Safety pharmacology endpoints can be incorporated in the design of toxicology, kinetic, clinical studies, etc., While in other cases these endpoints should be evaluated in specific safety pharmacology studies. Safety Pharmacological Studies : Introduction 1 2 3 4

11. Guidelines Objective To identify undesirable pharmacodynamic properties of a substance that may have relevance to its human safety. To evaluate adverse pharmacodynamic and/or pathophysiological effects of a substance observed in toxicology and/or clinical studies; To investigate the mechanism of the adverse pharmacodynamic effects observed and/or suspected. The investigational plan to meet these objectives should be identified and delineated

12. Selection and design of safety Pharmacology Studies Studies must follow Good Laboratory Practice (GLP) standards to ensure high-quality, reliable data for regulatory submissions.

13. Dose levels or concentrations of test substance In vivo studies Dose response relationship Time course investigation Dose comparison with primary pharmacodynamic effect in the test species. Pharmacodynamic sensitivity species difference Toxic range parameters and test In vitro studies Concentration effect relationship Concentration limits Range justification Duration of studies Performed by single-dose administration Treatment duration Disease duration Repeat dose non–clinical studies Studies on metabolites, isomers, and finished products Absent or low concentration in animals Adequately assessed metabolites Individual isomers Pharmacological screening of formulation

14. Safety Pharmacological Core Battery Purpose : Investigate the effects of the test substances on vital functions . Central nervous system: Evaluation of motor activity, behavioural changes, coordination, sensory/motor reflex responses and body temperature, learning and memory, electrophysiology. Example: NORT Cardiovascular system: Evaluation of blood pressure, heart rate, electrocardiogram, conductance abnormalities, cardiac output, vascular resistance, and ventricular contractility. Respiratory system: Evaluation of respiratory rate, tidal volume, haemoglobin oxygen saturation, airway resistance, compliance, blood gases, blood pH

15. Follow - up and Supplemental Safety Pharmacological Studies Purpose: These studies explore the adverse drug effects that raise concerns for human safety based on the pharmacological properties or chemical class of the test substance. For safety pharmacology core battery Provide greater depth of understanding Provided by the core battery on vital functions. Evaluate potential adverse pharmacodynamic effect on the vital organs. Central nervous system, cardiovascular system, respiratory system. Supplement Safety Pharmacology studies Renal: urinary volume, specific gravity, osmolarity, pH, fluid/electrolyte balance, proteins, cytology, and blood chemistry determinations. Autonomic nervous system: functional responses to agonists or antagonists, biding to receptors relevant to the autonomic nervous system, direct stimulation of autonomic nerves and measurement of cardiovascular responses, baroreflex testing, and heart rate variability Gastrointestinal system: gastric secretion, gastrointestinal injury, bile secretion, transit time in vivo, ileal contraction in vivo, gastric pH,

16. Conditions under which studies are not necessary Locally applied agents Cytotoxic agents for the treatment of end-stage cancer patients. Biotechnology-derived products that achieve highly specific receptor targeting. In the case of new salt having similar pharmacokinetics and pharmacodynamics. Timing of safety pharmacology studies about clinical development Studies before first administration in humans: functions listed in the safety pharmacology core battery Information from toxicology studies adequately designed and conducted to address safety pharmacology endpoints can result in the reduction or elimination of separate safety pharmacology studies.

17. Conclusion 1 Comprehensive Regulatory Guidance Regulatory bodies like the FDA and EMA provide detailed, comprehensive guidelines for conducting robust safety pharmacology studies to thoroughly evaluate the potential risks of new drug candidates. 2 Systematic Evaluation of Vital Systems Safety pharmacology studies assess the effects of new drugs on the cardiovascular, central nervous, respiratory, renal, and gastrointestinal systems to identify any adverse impacts on critical physiological functions. 3 Rigorous Study Design and Analysis Researchers utilize specialized in vivo and in vitro experimental methods, adhering to GLP standards, to gather high-quality data, which is then analyzed using advanced statistical techniques to interpret the safety profile. 4 Ensuring Patient Safety The comprehensive safety pharmacology assessment helps identify potential risks early in the drug development process, enabling informed decisions to protect patient health during clinical trials and post-approval use.

18. References: Andrade J. Safety pharmacology. In: Wexler P, editor. Encyclopedia of Toxicology (Fourth Edition). Oxford: Academic Press; 2024. p. 397-402. Guideline, I. C. H. (2001). Safety pharmacology studies for human pharmaceuticals S7A.  Fed. Regist ,  66 , 36791-36792. Luft, J., & Bode, G. (2002). Integration of safety pharmacology endpoints into toxicology studies.  Fundamental & clinical pharmacology ,  16 (2), 91-103. Pugsley, M. K., & Curtis, M. J. (Eds.). (2015).  Principles of safety pharmacology  (Vol. 229). Springer. Kenakin TP. Chapter 10 - Safety Pharmacology. In: Kenakin TP, editor. Pharmacology in Drug Discovery and Development (Second Edition): Academic Press; 2017. p. 251-73. Kenakin TP. Chapter 11 - Safety pharmacology. In: Kenakin TP, editor. A Pharmacology Primer (Sixth Edition): Academic Press; 2022. p. 359-82. OECD Guidelines for the Testing of Chemicals: https://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788 ICH Harmonised Tripartite Guideline, S7A: Safety Pharmacology Studies for Human Pharmaceuticals: https://database.ich.org/sites/default/files/S7A_Guideline.pdf