Current Pharmacology & Toxicology Guidlines For Pharmaceutical Industry

29/11/2007 KLE University, Belgaum - 10 1

CURRENT PHARMACOLOGY & TOXICOLOGY CURRENT PHARMACOLOGY & TOXICOLOGY GUIDLINES GUIDLINES

FOR FOR PHARMACEUTICAL INDUSTRYPHARMACEUTICAL INDUSTRY

Dr. Basavaraj K. Nanjwade Dr. Basavaraj K. Nanjwade M.Pharm., Ph.DM.Pharm., Ph.D

Associate ProfessorAssociate ProfessorDepartment of PharmaceuticsDepartment of Pharmaceutics

KLE UniversityKLE UniversityBELGAUM - 10BELGAUM - 10

By


Objective of the GuidanceObjective of the Guidance

Guidance was developed to help protect clinical trial participants and patients receiving marketed products from potential adverse effects of pharmaceuticals,

Avoiding unnecessary use of animals and other resources.

Guidance provides a definition, general principles and recommendations for safety pharmacology studies.


BackgroundBackground

The term safety pharmacology studies first

appeared in ICH M3 Timing of Non-clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals and S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals as studies that should be conducted to support use of therapeutics in humans


Scope of GuidanceScope of Guidance

Guidance generally applies to new chemical entities and biotechnology-derived products for human use.

Guidance can be applied to marketed pharmaceuticals when appropriate


Safety PharmacologySafety Pharmacology

Safety pharmacology studies are defined as those studies that investigate the potential undesirable Pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above.


Pharmacology GuidancePharmacology Guidance

• Objectives of Studies• General Considerations in Selection and

Design of Safety Pharmacology Studies• Test Systems• Dose Levels or Concentration of Test

Substance• Duration of Studies• Studies on Metabolites, Isomers and

Finished Products


Pharmacology GuidancePharmacology Guidance

• Safety Pharmacology Core Battery• Follow-up and Supplemental Safety

Pharmacology Studies• Conditions Under Which Studies Are Not

Necessary• Timing of Safety Pharmacology Studies in

Relation to Clinical Development • Application of Good Laboratory Practice


Objective of StudiesObjective of Studies

1. To identify undesirable Pharmacodynamic properties of a substance that may relevance to its human safety

2. To evaluate adverse Pharmacodynamic and/or pathophysiological effects of a substance observed in toxicology and /or clinical studies

3. To investigate the mechanism of the adverse Pharmacodynamic effects observed and/or suspected.


General Considerations in Selection and General Considerations in Selection and Design of Safety Pharmacology StudiesDesign of Safety Pharmacology Studies

1.Effects related to the therapeutic class of the test substance.

(e.g. Proarrhythmia is a common feature of antiarrhythmic agents)

2.Adverse effects associated with members of the chemical or therapeutic class.

(e.g. Antipsychotics and QT prolongation)


General Considerations in Selection and General Considerations in Selection and Design of Safety Pharmacology StudiesDesign of Safety Pharmacology Studies

3. Ligand binding or enzyme assay data suggesting a potential for adverse effects

4.Results from previous safety pharmacology studies from secondary Pharmacodynamic studies from toxicology studies


Test SystemsTest Systems

1. General considerations on test systems

2. Use of In Vivo and In Vitro Studies

3. Experimental Design

a. Sample size and use of controlsb. Route of administration


Dose Levels or Concentrations of Test Dose Levels or Concentrations of Test SubstanceSubstance

1.In Vivo Studies In vivo safety pharmacology studies should be

designed to define the dose-response relationship of the adverse effect observed

The time course of the adverse effect should be investigated

e.g. onset and duration of response

2.In Vitro studies In vitro studies should be designed to establish a

concentration-effect relationship


Duration of StudiesDuration of Studies

Pharmacology studies are generally performed by single-dose administration.

Pharmacodynamic effects occur only after a certain duration of treatment OR

Results from repeat dose nonclinical studies or results from use in humans give rise to concerns about safety pharmacology effects.

The duration of the safety pharmacology studies to address effects should be rationally based.


Studies on Metabolites, Isomers and Studies on Metabolites, Isomers and Finished ProductsFinished Products

• Metabolites from humans are known to substantially contribute to the pharmacological actions of the therapeutic agent, it could be important to test such active metabolites.

• In vitro or in vivo testing of the individual isomers should also be considered when the product contains an isomeric mixture.

• The finished product formulations should be conducted only for formulations that substantially alter the pharmacokinetics and/or Pharmacodynamic of the active substance in comparison to formulations previously tested.


Safety Pharmacology Core BatterySafety Pharmacology Core Battery

1. Central nervous system

2. Cardiovascular system

3. Respiratory system


Follow-up and Supplemental Safety Follow-up and Supplemental Safety Pharmacology StudiesPharmacology Studies

1. Follow-up studies for safety pharmacology core battery

a. Central nervous systemb. Cardiovascular systemc. Respiratory system2. Supplemental safety pharmacology studiesa. Renal/Urinary systemb. Autonomic nervous systemc. Gastrointestinal systemd. Other organ systems (e.g. Skeletal Muscle, immune and

endocrine functions)


Conditions Under Which Studies Are Conditions Under Which Studies Are Not NecessaryNot Necessary

• Safety pharmacology studies may not be needed for locally applied agent.

• Safety pharmacology studies prior to the first administration in humans may not be needed for cytotoxic agents for treatment of end-stage cancer patients.


Conditions Under Which Studies Are Conditions Under Which Studies Are Not NecessaryNot Necessary

• Biotechnology-derived products that achieve highly specific receptor targeting.

• Biotechnology-derived products that represent a novel therapeutic class and/or those products that do not achieve highly specific receptor targeting.

• Additional exceptions where safety pharmacology testing is not needed.


Timing of Safety Pharmacology Studies in Timing of Safety Pharmacology Studies in

Relation to Clinical DevelopmentRelation to Clinical Development

1. Studies prior to first administration in humans

2. Studies during clinical development

3. Studies before approval


Application of Good Laboratory Application of Good Laboratory PracticePractice

• It’s important to ensure the quality and reliability of nonclinical safety studies.

• It has to be emphasized that data quality and integrity in safety pharmacology studies should be ensure even in the absence of formal adherence to the principles of GLP.

• Safety pharmacology investigations can be part of toxicology studies in such case, these studies would be conducted in compliance with GLP.

• Primary Pharmacodynamic studies do not need to be conducted in compliance with GLP.


TOXICOLOGYTOXICOLOGY“The science of poisons". It is the

study of the opposing effects of physical agents or chemicals on living organisms.


Recommended Toxicology TestingRecommended Toxicology Testing • Genetic toxicity tests

• Short-term toxicity studies with rodents(14 to 21 days)

• Subchronic toxicity studies with rodents(90 days)

• Subchronic toxicity studies with non-rodents

• One-year toxicity studies with non-rodents


Recommended Toxicology TestingRecommended Toxicology Testing• Chronic toxicity or combined chronic

toxicity/Carcinogenicity( 2 years)

• Carcinogenicity studies with rodents (2 years)

• Reproductive studies

• Developmental toxicity studies

• Metabolism and Pharmacokinetic studies

• Human studies


Genetic toxicity tests

• Test for gene mutations in bacteria

• In vitro test with cytogenetic evaluation of chromosomal damage using mammalian cells or In vitro mouse lymphoma thymidine kinase +/- gene mutation assay

• In vivo test for chromosomal damage using mammalian hematopoietic cells


Short-term toxicity studies with rodents

I. Good laboratory practiceII. Test animalsa. Care, maintenance and housingb. Selection of rodent species, strains and

sexc. Age d. Number and sexe. Infected animalsf. Animal identifications



g. Cagingh. Dieti. Assignment of control and compound treated animalsj. Mortalityk. Autolysisl. Necropsy



III. Test substancea. Identityb. Composition/Purityc. Conditions of storaged. Expiration dateIV. Experimental Designa. Duration of testingb. Route of administrationc. Dose groups 1. Selection of treatment doses 2. Controlsd. Computerized systems



V. Observations and Clinical Testsa. Observations of test animalsb. Body weight and feed intake datac. Clinical testing 1. Ophthalmic examination 2. Hematology 3. Clinical chemistry 4. Urinalyses 5. Neurotoxicity screening/testing 6. Immunotoxicity



VI. Necropsy and microscopic examinationa. Gross necropsyb. Organ weightc. Preparation of tissues for microscopic

examinationd. Microscopic evaluation.

e. Histopathology of Lymphoid Organs


Chronic toxicity or Combined chronic toxicity/carcinogenicity studies with rodents

A. Experimental animals i. Age ii. Species and strains iii. Number and sexB. Administration of the test substance i. Duration of testing ii. Dosed groups a. Assessment of the carcinogenicity of the test substance High dose Low dose Intermediate dose Optional fourth dose b. Assessment of the chronic toxicity of the test substance


Chronic toxicity or Combined chronic toxicity/carcinogenicity studies with rodents

C. Observations and Clinical Tests i. Observation of test animals ii. Clinical testing Ophthalmological examination Hematology Clinical chemistry UrinalysesD. Necropsy and histopathology examination


Reproduction studies

A. General Recommendations B. Dose Range-Finding StudyC. Main Study 1. Experimental Animals, Species and Strain Selection and Housing 2. Number, Sex, and Age 3. Assignment to Dose Groups 4. Dose Selection 5. Control Group's 6. Duration of Test



7. Substance Administration 8. Mating Procedures9. Standardizing the Number of Pups per Litter 10. Selection of Parental Animals for Next Generation 11. Optional Third Generation 12. Optional Second Mating 13. Optional Teratology Phase 14. Clinical Observation



15. Growth of Offspring 16. Optional Neurotoxicity Screening 17. Optional Immunotoxicity Screening18. Gross Necropsy and Microscopic Examination a. Necropsy of Weanlingsb. Necropsy of Parental Animals i. Fixation of Tissues and Organsii. General Histopathology iii. Histopathology of Female Reproductive Organs iv. Histopathology of Male Reproductive Organs



D. End Points of Female Reproductive

Toxicity 1. Female Fertility Index 2. Gestation Index 3. Live-born Index 4. Weaning Index 5. Sex Ratio and Percentage by Sex 6. Viability Indices



E. End Points of Male Reproductive Toxicity

1. Evaluation of Testicular Spermatid Numbers

2. Sperm Evaluation for Motility, Morphology and Numbers

F. Analysis of Data G. Reporting the Results of Reproduction

Studies


Development toxicity studies

A. General Recommendations B. Dose Range-Finding Study C. Main Study 1. Experimental Animals, Species and Strain Selection 2. Animal Husbandry 3. Number, Sex, and Age 4. Duration of Testing 5. Route of Administration 6. Mating Procedures


Development toxicity studies

7. Control and Dosed Groups 8. Maternal Toxicity and its Significance 9. Clinical Observation and Examination of Dams and Fetuses 10. Histopathology 11. End Points Measured 12. Analysis of Data D. Reporting the Results of Developmental Toxicity Studies


Metabolism and Pharmacokinetic studies

1. Considerations in the design of analysis of and use of data from metabolic and pharmacokinetic studies

a. Design and analysis of metabolic and pharmacokinetic studies

i. Test compound ii. Animals iii. Route of administration iv. Dosage regimen v. Sampling vi. In vitro studies vii. Analysis of data


Metabolism and Pharmacokinetic studies

b. Use of data from metabolism and pharmacokinetic studies Design of toxicity studies Setting dose levels Determining mechanisms of toxicity Improving the risk assessment process2. Recommended metabolism and pharmacokinetic studies3. Additional studies


Human studies

1. General considerations for clinical studies

2. Specific considerations for clinical studies a. Protocol designb. The study populationc. Statistical analyses3. Sequence of clinical studiesa. Early clinical studiesb. Further clinical studies


Human studies

4. Submitting reports of clinical studies to CFSAN (Center for Food Safety and Applied Nutrition)

5. Appendix A a. Principles of institutional review b. Principles of informed consent.


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