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CURRENT PHARMACOLOGY & TOXICOLOGY GUIDLINES  FOR  PHARMACEUTICAL INDUSTRY Dr. Basavaraj K. Nanjwade  M.Pharm., Ph.D Associ...
Objective of the Guidance <ul><li>Guidance was developed to help protect clinical trial participants and patients receivin...
Background <ul><li>The term safety pharmacology studies first appeared in  ICH  M3  Timing of Non-clinical Safety Studies ...
Scope of Guidance <ul><li>Guidance generally applies to new chemical entities and biotechnology-derived products for human...
Safety Pharmacology <ul><li>Safety pharmacology studies are defined as those studies that investigate the potential undesi...
Pharmacology Guidance <ul><li>Objectives of Studies </li></ul><ul><li>General Considerations in Selection and Design of Sa...
Pharmacology Guidance <ul><li>Safety Pharmacology Core Battery </li></ul><ul><li>Follow-up and Supplemental Safety Pharmac...
Objective of Studies <ul><li>To identify undesirable Pharmacodynamic properties of a substance that may relevance to its h...
General Considerations in Selection and Design of Safety Pharmacology Studies <ul><li>1.Effects related to the therapeutic...
General Considerations in Selection and Design of Safety Pharmacology Studies <ul><li>3 .  Ligand binding or enzyme assay ...
Test Systems <ul><li>1. General considerations on test systems </li></ul><ul><li>2. Use of In Vivo and In Vitro Studies </...
Dose Levels or Concentrations of Test Substance <ul><li>1.In Vivo Studies </li></ul><ul><li>In vivo safety pharmacology st...
Duration of Studies <ul><li>Pharmacology studies are generally performed by single-dose administration. </li></ul><ul><li>...
Studies on Metabolites, Isomers and Finished Products <ul><li>Metabolites from humans are known to substantially contribut...
Safety Pharmacology Core Battery <ul><li>Central nervous system </li></ul><ul><li>Cardiovascular system </li></ul><ul><li>...
Follow-up and Supplemental Safety Pharmacology Studies <ul><li>Follow-up studies for safety pharmacology core battery </li...
Conditions Under Which Studies Are Not Necessary <ul><li>Safety pharmacology studies may not be needed for locally applied...
Conditions Under Which Studies Are Not Necessary <ul><li>Biotechnology-derived products that achieve highly specific recep...
Timing of Safety Pharmacology Studies in Relation to Clinical Development   <ul><li>Studies prior to first administration ...
Application of Good Laboratory Practice <ul><li>It’s important to ensure the quality and reliability of nonclinical safety...
TOXICOLOGY <ul><li>“ The science of poisons&quot;. It is the study of the opposing effects of physical agents or chemicals...
Recommended Toxicology Testing   <ul><li>Genetic toxicity tests  </li></ul><ul><li>Short-term toxicity studies with rode...
Recommended Toxicology Testing <ul><li>Chronic toxicity or combined chronic toxicity/Carcinogenicity  ( 2 years)  </li><...
Genetic toxicity tests <ul><li>Test for gene mutations in bacteria </li></ul><ul><li>In vitro test with cytogenetic evalua...
Short-term toxicity studies with rodents <ul><li>I. Good laboratory practice </li></ul><ul><li>II. Test animals </li></ul>...
Short-term toxicity studies with rodents <ul><li>g. Caging </li></ul><ul><li>h. Diet </li></ul><ul><li>i. Assignment of co...
Short-term toxicity studies with rodents <ul><li>III. Test substance </li></ul><ul><li>Identity </li></ul><ul><li>Composit...
Short-term toxicity studies with rodents <ul><li>V.   Observations and Clinical Tests </li></ul><ul><li>Observations of te...
Short-term toxicity studies with rodents <ul><li>VI. Necropsy and microscopic examination </li></ul><ul><li>Gross necropsy...
Chronic toxicity or Combined chronic toxicity/carcinogenicity studies with rodents <ul><li>A.  Experimental animals </li><...
Chronic toxicity or Combined chronic toxicity/carcinogenicity studies with rodents <ul><li>C. Observations and Clinical Te...
Reproduction studies <ul><li>General Recommendations  </li></ul><ul><li>Dose Range-Finding Study </li></ul><ul><li>Main St...
Reproduction studies <ul><li>7.   Substance Administration  </li></ul><ul><li>8.  Mating Procedures </li></ul><ul><li>9.  ...
Reproduction studies <ul><li>15 .  Growth of Offspring  </li></ul><ul><li>16. Optional Neurotoxicity Screening  </li></ul>...
Reproduction studies <ul><li>D.   End Points of Female Reproductive </li></ul><ul><li>Toxicity  </li></ul><ul><li>Female F...
Reproduction studies <ul><li>E .   End Points of Male Reproductive Toxicity  </li></ul><ul><li>Evaluation of Testicular Sp...
Development toxicity studies <ul><li>General Recommendations  </li></ul><ul><li>Dose Range-Finding Study  </li></ul><ul><l...
Development toxicity studies <ul><li>7.   Control and Dosed Groups  </li></ul><ul><li>8. Maternal Toxicity and its Signifi...
Metabolism and Pharmacokinetic studies <ul><li>Considerations in the design of analysis of and use of data from metabolic ...
Metabolism and Pharmacokinetic studies <ul><li>b. Use of data from metabolism and  </li></ul><ul><li>pharmacokinetic studi...
Human studies <ul><li>General considerations for clinical studies  </li></ul><ul><li>Specific considerations for clinical ...
Human studies <ul><li>4.  Submitting reports of clinical studies  to CFSAN  ( Center for Food Safety and Applied Nutrition...
<ul><li>THANK YOU </li></ul>E-mail: bknanjwade@yahoo.co.in
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Current Pharmacology & Toxicology Guidlines For Pharmaceutical Industry

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Transcript of "Current Pharmacology & Toxicology Guidlines For Pharmaceutical Industry"

  1. 1. CURRENT PHARMACOLOGY & TOXICOLOGY GUIDLINES FOR PHARMACEUTICAL INDUSTRY Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Associate Professor Department of Pharmaceutics KLE University BELGAUM - 10 By
  2. 2. Objective of the Guidance <ul><li>Guidance was developed to help protect clinical trial participants and patients receiving marketed products from potential adverse effects of pharmaceuticals, </li></ul><ul><li>Avoiding unnecessary use of animals and other resources. </li></ul><ul><li>Guidance provides a definition, general principles and recommendations for safety pharmacology studies. </li></ul>
  3. 3. Background <ul><li>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 </li></ul>
  4. 4. Scope of Guidance <ul><li>Guidance generally applies to new chemical entities and biotechnology-derived products for human use. </li></ul><ul><li>Guidance can be applied to marketed pharmaceuticals when appropriate </li></ul>
  5. 5. Safety Pharmacology <ul><li>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. </li></ul>
  6. 6. Pharmacology Guidance <ul><li>Objectives of Studies </li></ul><ul><li>General Considerations in Selection and Design of Safety Pharmacology Studies </li></ul><ul><li>Test Systems </li></ul><ul><li>Dose Levels or Concentration of Test Substance </li></ul><ul><li>Duration of Studies </li></ul><ul><li>Studies on Metabolites, Isomers and Finished Products </li></ul>
  7. 7. Pharmacology Guidance <ul><li>Safety Pharmacology Core Battery </li></ul><ul><li>Follow-up and Supplemental Safety Pharmacology Studies </li></ul><ul><li>Conditions Under Which Studies Are Not Necessary </li></ul><ul><li>Timing of Safety Pharmacology Studies in Relation to Clinical Development </li></ul><ul><li>Application of Good Laboratory Practice </li></ul>
  8. 8. Objective of Studies <ul><li>To identify undesirable Pharmacodynamic properties of a substance that may relevance to its human safety </li></ul><ul><li>To evaluate adverse Pharmacodynamic and/or pathophysiological effects of a substance observed in toxicology and /or clinical studies </li></ul><ul><li>To investigate the mechanism of the adverse Pharmacodynamic effects observed and/or suspected. </li></ul>
  9. 9. General Considerations in Selection and Design of Safety Pharmacology Studies <ul><li>1.Effects related to the therapeutic class of the test substance. </li></ul><ul><li>(e.g. Proarrhythmia is a common feature </li></ul><ul><li>of antiarrhythmic agents) </li></ul><ul><li>2.Adverse effects associated with members of the chemical or therapeutic class. </li></ul><ul><li>(e.g. Antipsychotics and QT prolongation) </li></ul>
  10. 10. General Considerations in Selection and Design of Safety Pharmacology Studies <ul><li>3 . Ligand binding or enzyme assay data suggesting a potential for adverse effects </li></ul><ul><li>4.Results from previous safety pharmacology studies from secondary Pharmacodynamic studies from toxicology studies </li></ul>
  11. 11. Test Systems <ul><li>1. General considerations on test systems </li></ul><ul><li>2. Use of In Vivo and In Vitro Studies </li></ul><ul><li>3. Experimental Design </li></ul><ul><li>Sample size and use of controls </li></ul><ul><li>Route of administration </li></ul>
  12. 12. Dose Levels or Concentrations of Test Substance <ul><li>1.In Vivo Studies </li></ul><ul><li>In vivo safety pharmacology studies should be designed to define the dose-response relationship of the adverse effect observed </li></ul><ul><li>The time course of the adverse effect should be investigated </li></ul><ul><li>e.g. onset and duration of response </li></ul><ul><li>2.In Vitro studies </li></ul><ul><li>In vitro studies should be designed to establish a concentration-effect relationship </li></ul>
  13. 13. Duration of Studies <ul><li>Pharmacology studies are generally performed by single-dose administration. </li></ul><ul><li>Pharmacodynamic effects occur only after a certain duration of treatment OR </li></ul><ul><li>Results from repeat dose nonclinical studies or results from use in humans give rise to concerns about safety pharmacology effects. </li></ul><ul><li>The duration of the safety pharmacology studies to address effects should be rationally based. </li></ul>
  14. 14. Studies on Metabolites, Isomers and Finished Products <ul><li>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. </li></ul><ul><li>In vitro or in vivo testing of the individual isomers should also be considered when the product contains an isomeric mixture. </li></ul><ul><li>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. </li></ul>
  15. 15. Safety Pharmacology Core Battery <ul><li>Central nervous system </li></ul><ul><li>Cardiovascular system </li></ul><ul><li>Respiratory system </li></ul>
  16. 16. Follow-up and Supplemental Safety Pharmacology Studies <ul><li>Follow-up studies for safety pharmacology core battery </li></ul><ul><li>Central nervous system </li></ul><ul><li>Cardiovascular system </li></ul><ul><li>Respiratory system </li></ul><ul><li>2. Supplemental safety pharmacology studies </li></ul><ul><li>Renal/Urinary system </li></ul><ul><li>Autonomic nervous system </li></ul><ul><li>Gastrointestinal system </li></ul><ul><li>Other organ systems (e.g. Skeletal Muscle, immune and endocrine functions) </li></ul>
  17. 17. Conditions Under Which Studies Are Not Necessary <ul><li>Safety pharmacology studies may not be needed for locally applied agent. </li></ul><ul><li>Safety pharmacology studies prior to the first administration in humans may not be needed for cytotoxic agents for treatment of end-stage cancer patients. </li></ul>
  18. 18. Conditions Under Which Studies Are Not Necessary <ul><li>Biotechnology-derived products that achieve highly specific receptor targeting. </li></ul><ul><li>Biotechnology-derived products that represent a novel therapeutic class and/or those products that do not achieve highly specific receptor targeting. </li></ul><ul><li>Additional exceptions where safety pharmacology testing is not needed. </li></ul>
  19. 19. Timing of Safety Pharmacology Studies in Relation to Clinical Development <ul><li>Studies prior to first administration </li></ul><ul><li>in humans </li></ul><ul><li>2. Studies during clinical development </li></ul><ul><li>3. Studies before approval </li></ul>
  20. 20. Application of Good Laboratory Practice <ul><li>It’s important to ensure the quality and reliability of nonclinical safety studies. </li></ul><ul><li>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. </li></ul><ul><li>Safety pharmacology investigations can be part of toxicology studies in such case, these studies would be conducted in compliance with GLP. </li></ul><ul><li>Primary Pharmacodynamic studies do not need to be conducted in compliance with GLP. </li></ul>
  21. 21. TOXICOLOGY <ul><li>“ The science of poisons&quot;. It is the study of the opposing effects of physical agents or chemicals on living organisms. </li></ul>
  22. 22. Recommended Toxicology Testing <ul><li>Genetic toxicity tests  </li></ul><ul><li>Short-term toxicity studies with rodents(14 to 21 days)  </li></ul><ul><li>Subchronic toxicity studies with rodents(90 days) </li></ul><ul><li>Subchronic toxicity studies with non-rodents </li></ul><ul><li>One-year toxicity studies with non-rodents </li></ul>
  23. 23. Recommended Toxicology Testing <ul><li>Chronic toxicity or combined chronic toxicity/Carcinogenicity  ( 2 years)  </li></ul><ul><li>Carcinogenicity studies with rodents (2 years) </li></ul><ul><li>Reproductive studies  </li></ul><ul><li>Developmental toxicity studies  </li></ul><ul><li>Metabolism and Pharmacokinetic studies  </li></ul><ul><li>Human studies  </li></ul>
  24. 24. Genetic toxicity tests <ul><li>Test for gene mutations in bacteria </li></ul><ul><li>In vitro test with cytogenetic evaluation of chromosomal damage using mammalian cells or In vitro mouse lymphoma thymidine kinase +/- gene mutation assay </li></ul><ul><li>In vivo test for chromosomal damage using mammalian hematopoietic cells </li></ul>
  25. 25. Short-term toxicity studies with rodents <ul><li>I. Good laboratory practice </li></ul><ul><li>II. Test animals </li></ul><ul><li>Care, maintenance and housing </li></ul><ul><li>Selection of rodent species, strains and sex </li></ul><ul><li>Age </li></ul><ul><li>Number and sex </li></ul><ul><li>Infected animals </li></ul><ul><li>Animal identifications </li></ul>
  26. 26. Short-term toxicity studies with rodents <ul><li>g. Caging </li></ul><ul><li>h. Diet </li></ul><ul><li>i. Assignment of control and compound </li></ul><ul><li>treated animals </li></ul><ul><li>j. Mortality </li></ul><ul><li>k. Autolysis </li></ul><ul><li>l. Necropsy </li></ul>
  27. 27. Short-term toxicity studies with rodents <ul><li>III. Test substance </li></ul><ul><li>Identity </li></ul><ul><li>Composition/Purity </li></ul><ul><li>Conditions of storage </li></ul><ul><li>Expiration date </li></ul><ul><li>IV. Experimental Design </li></ul><ul><li>Duration of testing </li></ul><ul><li>Route of administration </li></ul><ul><li>Dose groups </li></ul><ul><li>1. Selection of treatment doses </li></ul><ul><li>2. Controls </li></ul><ul><li>d. Computerized systems </li></ul>
  28. 28. Short-term toxicity studies with rodents <ul><li>V. Observations and Clinical Tests </li></ul><ul><li>Observations of test animals </li></ul><ul><li>Body weight and feed intake data </li></ul><ul><li>Clinical testing </li></ul><ul><li>1. Ophthalmic examination </li></ul><ul><li>2. Hematology </li></ul><ul><li>3. Clinical chemistry </li></ul><ul><li>4. Urinalyses </li></ul><ul><li>5. Neurotoxicity screening/testing </li></ul><ul><li>6. Immunotoxicity </li></ul>
  29. 29. Short-term toxicity studies with rodents <ul><li>VI. Necropsy and microscopic examination </li></ul><ul><li>Gross necropsy </li></ul><ul><li>Organ weight </li></ul><ul><li>Preparation of tissues for microscopic examination </li></ul><ul><li>Microscopic evaluation. </li></ul><ul><li>Histopathology of Lymphoid Organs </li></ul>
  30. 30. Chronic toxicity or Combined chronic toxicity/carcinogenicity studies with rodents <ul><li>A. Experimental animals </li></ul><ul><li>i. Age </li></ul><ul><li>ii. Species and strains </li></ul><ul><li>iii. Number and sex </li></ul><ul><li>B. Administration of the test substance </li></ul><ul><li>i. Duration of testing </li></ul><ul><li>ii. Dosed groups </li></ul><ul><li>a. Assessment of the carcinogenicity of the test substance </li></ul><ul><li>High dose </li></ul><ul><li>Low dose </li></ul><ul><li>Intermediate dose </li></ul><ul><li>Optional fourth dose </li></ul><ul><li>b. Assessment of the chronic toxicity of the test </li></ul><ul><li>substance </li></ul>
  31. 31. Chronic toxicity or Combined chronic toxicity/carcinogenicity studies with rodents <ul><li>C. Observations and Clinical Tests </li></ul><ul><li>i. Observation of test animals </li></ul><ul><li>ii. Clinical testing </li></ul><ul><li>Ophthalmological examination </li></ul><ul><li>Hematology </li></ul><ul><li>Clinical chemistry </li></ul><ul><li>Urinalyses </li></ul><ul><li>D. Necropsy and histopathology examination </li></ul>
  32. 32. Reproduction studies <ul><li>General Recommendations </li></ul><ul><li>Dose Range-Finding Study </li></ul><ul><li>Main Study </li></ul><ul><li>1. Experimental Animals, Species and </li></ul><ul><li>Strain Selection and Housing </li></ul><ul><li>2. Number, Sex, and Age </li></ul><ul><li>3. Assignment to Dose Groups </li></ul><ul><li>4. Dose Selection </li></ul><ul><li>5. Control Group's </li></ul><ul><li>6. Duration of Test </li></ul>
  33. 33. Reproduction studies <ul><li>7. Substance Administration </li></ul><ul><li>8. Mating Procedures </li></ul><ul><li>9. Standardizing the Number of Pups per </li></ul><ul><li>Litter </li></ul><ul><li>10. Selection of Parental Animals for Next </li></ul><ul><li>Generation </li></ul><ul><li>11. Optional Third Generation </li></ul><ul><li>12. Optional Second Mating </li></ul><ul><li>13. Optional Teratology Phase </li></ul><ul><li>14. Clinical Observation </li></ul>
  34. 34. Reproduction studies <ul><li>15 . Growth of Offspring </li></ul><ul><li>16. Optional Neurotoxicity Screening </li></ul><ul><li>17. Optional Immunotoxicity Screening </li></ul><ul><li>18. Gross Necropsy and Microscopic Examination </li></ul><ul><li>Necropsy of Weanlings </li></ul><ul><li>Necropsy of Parental Animals </li></ul><ul><li>Fixation of Tissues and Organs </li></ul><ul><li>General Histopathology </li></ul><ul><li>Histopathology of Female Reproductive Organs </li></ul><ul><li>Histopathology of Male Reproductive Organs </li></ul>
  35. 35. Reproduction studies <ul><li>D. End Points of Female Reproductive </li></ul><ul><li>Toxicity </li></ul><ul><li>Female Fertility Index </li></ul><ul><li>Gestation Index </li></ul><ul><li>Live-born Index </li></ul><ul><li>Weaning Index </li></ul><ul><li>Sex Ratio and Percentage by Sex </li></ul><ul><li>Viability Indices </li></ul>
  36. 36. Reproduction studies <ul><li>E . End Points of Male Reproductive Toxicity </li></ul><ul><li>Evaluation of Testicular Spermatid Numbers </li></ul><ul><li>Sperm Evaluation for Motility, Morphology and Numbers </li></ul><ul><li>F. Analysis of Data </li></ul><ul><li>G. Reporting the Results of Reproduction Studies </li></ul>
  37. 37. Development toxicity studies <ul><li>General Recommendations </li></ul><ul><li>Dose Range-Finding Study </li></ul><ul><li>Main Study </li></ul><ul><li>1. Experimental Animals, Species and </li></ul><ul><li>Strain Selection </li></ul><ul><li>2. Animal Husbandry </li></ul><ul><li>3. Number, Sex, and Age </li></ul><ul><li>4. Duration of Testing </li></ul><ul><li>5. Route of Administration </li></ul><ul><li>6. Mating Procedures </li></ul>
  38. 38. Development toxicity studies <ul><li>7. Control and Dosed Groups </li></ul><ul><li>8. Maternal Toxicity and its Significance </li></ul><ul><li>9. Clinical Observation and Examination </li></ul><ul><li>of Dams and Fetuses </li></ul><ul><li>10. Histopathology </li></ul><ul><li>11. End Points Measured </li></ul><ul><li>12. Analysis of Data </li></ul><ul><li>D. Reporting the Results of Developmental </li></ul><ul><li>Toxicity Studies </li></ul>
  39. 39. Metabolism and Pharmacokinetic studies <ul><li>Considerations in the design of analysis of and use of data from metabolic and pharmacokinetic studies </li></ul><ul><li>Design and analysis of metabolic and pharmacokinetic studies </li></ul><ul><li>i. Test compound </li></ul><ul><li>ii. Animals </li></ul><ul><li>iii. Route of administration </li></ul><ul><li>iv. Dosage regimen </li></ul><ul><li>v. Sampling </li></ul><ul><li>vi. In vitro studies </li></ul><ul><li>vii. Analysis of data </li></ul>
  40. 40. Metabolism and Pharmacokinetic studies <ul><li>b. Use of data from metabolism and </li></ul><ul><li>pharmacokinetic studies </li></ul><ul><li>Design of toxicity studies </li></ul><ul><li>Setting dose levels </li></ul><ul><li>Determining mechanisms of toxicity </li></ul><ul><li>Improving the risk assessment process </li></ul><ul><li>2. Recommended metabolism and </li></ul><ul><li>pharmacokinetic studies </li></ul><ul><li>3. Additional studies </li></ul>
  41. 41. Human studies <ul><li>General considerations for clinical studies </li></ul><ul><li>Specific considerations for clinical studies </li></ul><ul><li>Protocol design </li></ul><ul><li>The study population </li></ul><ul><li>Statistical analyses </li></ul><ul><li>3. Sequence of clinical studies </li></ul><ul><li>Early clinical studies </li></ul><ul><li>Further clinical studies </li></ul>
  42. 42. Human studies <ul><li>4. Submitting reports of clinical studies to CFSAN ( Center for Food Safety and Applied Nutrition) </li></ul><ul><li>5. Appendix A </li></ul><ul><li>a. Principles of institutional review </li></ul><ul><li>b. Principles of informed consent. </li></ul>
  43. 43. <ul><li>THANK YOU </li></ul>E-mail: bknanjwade@yahoo.co.in
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