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CURRENT PHARMACOLOGY & TOXICOLOGY GUIDLINES FOR PHARMACEUTICAL INDUSTRY By Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Associate Professor Department of Pharmaceutics KLE University BELGAUM - 10 Objective of the Guidance

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current pharmacology toxicology guidlines for pharmaceutical industry

CURRENT PHARMACOLOGY & TOXICOLOGY GUIDLINES FOR PHARMACEUTICAL INDUSTRY

By

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

Associate Professor

Department of Pharmaceutics

KLE University

BELGAUM - 10

KLE University, Belgaum - 10

objective of the guidance
Objective 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.

KLE University, Belgaum - 10

background
Background

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 S6Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals as studies that should be conducted to support use of therapeutics in humans

KLE University, Belgaum - 10

scope of guidance
Scope 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

KLE University, Belgaum - 10

safety pharmacology
Safety 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.

KLE University, Belgaum - 10

pharmacology guidance
Pharmacology 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

KLE University, Belgaum - 10

pharmacology guidance7
Pharmacology 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

KLE University, Belgaum - 10

objective of studies
Objective of Studies
  • To identify undesirable Pharmacodynamic properties of a substance that may 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.

KLE University, Belgaum - 10

general considerations in selection and design of safety pharmacology studies
General Considerations in Selection and Design 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)

KLE University, Belgaum - 10

general considerations in selection and design of safety pharmacology studies10
General Considerations in Selection and Design 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

KLE University, Belgaum - 10

test systems
Test Systems

1. General considerations on test systems

2. Use of In Vivo and In Vitro Studies

3. Experimental Design

  • Sample size and use of controls
  • Route of administration

KLE University, Belgaum - 10

dose levels or concentrations of test substance
Dose Levels or Concentrations of Test Substance

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

KLE University, Belgaum - 10

duration of studies
Duration 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.

KLE University, Belgaum - 10

studies on metabolites isomers and finished products
Studies on Metabolites, Isomers and Finished 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.

KLE University, Belgaum - 10

safety pharmacology core battery
Safety Pharmacology Core Battery
  • Central nervous system
  • Cardiovascular system
  • Respiratory system

KLE University, Belgaum - 10

follow up and supplemental safety pharmacology studies
Follow-up and Supplemental Safety Pharmacology Studies
  • Follow-up studies for safety pharmacology core battery
  • Central nervous system
  • Cardiovascular system
  • Respiratory system

2.Supplemental safety pharmacology studies

  • Renal/Urinary system
  • Autonomic nervous system
  • Gastrointestinal system
  • Other organ systems (e.g. Skeletal Muscle, immune and endocrine functions)

KLE University, Belgaum - 10

conditions under which studies are not necessary
Conditions Under Which Studies Are Not 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.

KLE University, Belgaum - 10

conditions under which studies are not necessary18
Conditions Under Which Studies Are Not 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.

KLE University, Belgaum - 10

timing of safety pharmacology studies in relation to clinical development
Timing of Safety Pharmacology Studies in Relation to Clinical Development
  • Studies prior to first administration

in humans

2. Studies during clinical development

3. Studies before approval

KLE University, Belgaum - 10

application of good laboratory practice
Application of Good Laboratory Practice
  • 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.

KLE University, Belgaum - 10

toxicology
TOXICOLOGY

“The science of poisons". It is the study of the opposing effects of physical agents or chemicals on living organisms.

KLE University, Belgaum - 10

recommended toxicology testing
Recommended 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

KLE University, Belgaum - 10

recommended toxicology testing23
Recommended 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

KLE University, Belgaum - 10

genetic toxicity tests
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

KLE University, Belgaum - 10

short term toxicity studies with rodents
Short-term toxicity studies with rodents

I. Good laboratory practice

II. Test animals

  • Care, maintenance and housing
  • Selection of rodent species, strains and sex
  • Age
  • Number and sex
  • Infected animals
  • Animal identifications

KLE University, Belgaum - 10

short term toxicity studies with rodents26
Short-term toxicity studies with rodents

g. Caging

h. Diet

i. Assignment of control and compound

treated animals

j. Mortality

k. Autolysis

l. Necropsy

KLE University, Belgaum - 10

short term toxicity studies with rodents27
Short-term toxicity studies with rodents

III. Test substance

  • Identity
  • Composition/Purity
  • Conditions of storage
  • Expiration date

IV. Experimental Design

  • Duration of testing
  • Route of administration
  • Dose groups

1. Selection of treatment doses

2. Controls

d. Computerized systems

KLE University, Belgaum - 10

short term toxicity studies with rodents28
Short-term toxicity studies with rodents

V.Observations and Clinical Tests

  • Observations of test animals
  • Body weight and feed intake data
  • Clinical testing

1. Ophthalmic examination

2. Hematology

3. Clinical chemistry

4. Urinalyses

5. Neurotoxicity screening/testing

6. Immunotoxicity

KLE University, Belgaum - 10

short term toxicity studies with rodents29
Short-term toxicity studies with rodents

VI. Necropsy and microscopic examination

  • Gross necropsy
  • Organ weight
  • Preparation of tissues for microscopic examination
  • Microscopic evaluation.
  • Histopathology of Lymphoid Organs

KLE University, Belgaum - 10

chronic toxicity or combined chronic toxicity carcinogenicity studies with rodents
Chronic toxicity or Combined chronic toxicity/carcinogenicity studies with rodents

A. Experimental animals

i. Age

ii. Species and strains

iii. Number and sex

B. 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

KLE University, Belgaum - 10

chronic toxicity or combined chronic toxicity carcinogenicity studies with rodents31
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

Urinalyses

D. Necropsy and histopathology examination

KLE University, Belgaum - 10

reproduction studies
Reproduction studies
  • General Recommendations
  • Dose Range-Finding Study
  • 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

KLE University, Belgaum - 10

reproduction studies33
Reproduction studies

7.Substance Administration

8. Mating Procedures

9. 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

KLE University, Belgaum - 10

reproduction studies34
Reproduction studies

15. Growth of Offspring

16. Optional Neurotoxicity Screening

17. Optional Immunotoxicity Screening

18. Gross Necropsy and Microscopic Examination

  • Necropsy of Weanlings
  • Necropsy of Parental Animals
  • Fixation of Tissues and Organs
  • General Histopathology
  • Histopathology of Female Reproductive Organs
  • Histopathology of Male Reproductive Organs

KLE University, Belgaum - 10

reproduction studies35
Reproduction studies

D.End Points of Female Reproductive

Toxicity

  • Female Fertility Index
  • Gestation Index
  • Live-born Index
  • Weaning Index
  • Sex Ratio and Percentage by Sex
  • Viability Indices

KLE University, Belgaum - 10

reproduction studies36
Reproduction studies

E.End Points of Male Reproductive Toxicity

  • Evaluation of Testicular Spermatid Numbers
  • Sperm Evaluation for Motility, Morphology and Numbers

F. Analysis of Data

G. Reporting the Results of Reproduction Studies

KLE University, Belgaum - 10

development toxicity studies
Development toxicity studies
  • General Recommendations
  • Dose Range-Finding Study
  • 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

KLE University, Belgaum - 10

development toxicity studies38
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

KLE University, Belgaum - 10

metabolism and pharmacokinetic studies
Metabolism and Pharmacokinetic studies
  • Considerations in the design of analysis of and use of data from metabolic and pharmacokinetic studies
  • 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

KLE University, Belgaum - 10

metabolism and pharmacokinetic studies40
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 process

2. Recommended metabolism and

pharmacokinetic studies

3. Additional studies

KLE University, Belgaum - 10

human studies
Human studies
  • General considerations for clinical studies
  • Specific considerations for clinical studies
  • Protocol design
  • The study population
  • Statistical analyses

3. Sequence of clinical studies

  • Early clinical studies
  • Further clinical studies

KLE University, Belgaum - 10

human studies42
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.

KLE University, Belgaum - 10

slide43
THANK YOU

E-mail: bknanjwade@yahoo.co.in

KLE University, Belgaum - 10