Claim & Reasonable Probability (Part 2)
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This document discusses concepts related to bioequivalence studies for generic drugs, including: - Generic drugs must be pharmaceutically equivalent and bioequivalent to the reference brand name drug to be considered substitutable. - Bioequivalence studies evaluate the rate and extent of absorption of the generic drug compared to the brand name drug and ensure the generic drug performs in the same manner. - Acceptance criteria for bioequivalence studies specify that the 90% confidence intervals for AUC and Cmax of the generic must fall within 80-125% of the reference drug. - Special study designs may be needed for certain drugs based on their pharmacokinetic properties or ability to be measured in plasma.
Claim & Reasonable Probability (Part 2)
- 1. Claim & Reasonable Probability Understand Product, Control Process & Demonstrate Quality Roohi B. Obaid & Obaid Ali Civil Service Officer Drugs Regulatory Authority of Pakistan
- 2. Claim & Reasonable Probability Understand Product, Control Process & Demonstrate Quality Part B Obaid Ali
- 3. Warm up exercise Fundamental Scenarios and Bio-studies or Dissolution Studies
- 4. Drug must be available in the blood stream in the same pattern on which clinical studies have been performed Similarity & Equivalency?
- 5. If a tablet is disintegrated, in which situations, it will not reach to the blood
- 6. If a tablet is dissolved, in which situations, it will not reach to the blood
- 7. Have you ever imagined a situation where a tablet can come out from the body as it is? If so, can it produce effect
- 10. Biopharmaceutical Evaluation From Fiction to Reality
- 11. Performance should be the same way
- 12. No Worse Performance should be the same way
- 13. No Worse No Better Performance should be the same way
- 14. Please make it clear They are not clinical studies Nothing to do with Safety & Efficacy of molecule Evaluating the Similarity of Trends & Kinetics
- 15. Drug Performance Dosage Form Drug in solution Gut wall Blood Site of Activity Therapeutic Effect Dosage Form Performance Pharmacokinetic Measurement Clinical/PD Measurement
- 16. Science of Bioequivalence Developed over the last few decades Continues to evolve Specific approaches depend on a number of factors Can be simple or highly complex
- 17. Generic Drug ….. equivalent drug products that can be substituted at the pharmacy level for the reference /innovator drug, and each other, without any adjustment in dose or other additional therapeutic monitoring
- 18. Pharmaceutical Equivalence Same active ingredient Same dosage form Same route of administration Identical in strength or concentration
- 20. Generics not necessarily identical Excipients Difference Manufacturing Differences Formulation Difference Shape, color difference
- 21. Bioequivalence & Generic Drugs Pharmaceutical Equivalent & Bioequivalent Pharmaceutical Equivalence Does not mean equivalent performance
- 22. Label 1 CMC 2 Bio- studies 3 Plant GMP 4
- 23. Brand Name Drug Generic Drug 1. Chemistry 1. Chemistry 2. Manufacturing 2. Manufacturing 3. Controls 3. Controls 4. Labeling 4. Labeling 5. Testing 5. Testing 6. Animal Studies 7. Clinical Studies 6. Bioequivalence 8. Bioavailability
- 25. PK PD
- 28. What is Reference/Innovator Drug Innovator Brand Authorized Brand
- 29. 29 AUC and Cmax 90% Confidence Intervals (CI) must fit between 80%-125%
- 30. To determine rate and extent of absorption of generic, innovator From 2009
- 31. On healthy human volunteers but use patients if there is a safety concern (Etoposide, Clozapine) Male, Female both
- 32. Bio-analytical method must be validated
- 33. 33 • In vivo measurement of active moiety or moieties in biologic fluid • In vivo pharmacodynamic comparison • In vivo limited clinical comparison • In vitro comparison
- 35. 1 • Single-dose, parallel, fasted • Long Half-Life (wash-out) Amiodarone, Etidronate 2 • Single-dose, replicate design • Highly Variable Drugs 3 • Multiple-dose, two-way crossover, fasted • Less Sensitive Clozapine (Patient Trials) Chemotherapy Trials 4 • Clinical endpoint study • Topicals Nasal Suspensions
- 36. Urine may be used for measurement when drug cannot be measured in plasma e.g. Potassium Chloride Baseline in blood is too high to permit accurate measurement
- 37. Special Case: Alendronate Sodium (5 to 70 mg) Problem with plasma detection because of low concentration & re-distribution from bone
- 38. Pharmacodynamics Approach Generic topical corticosteroid, ability to produce vasoconstriction
- 39. Special Case: Tretinoin Acne Gel Problem with plasma detection, endpoint related to healing region is considered
- 40. Special Case: Highly Variable Drugs 3 period bio-studies TRR, RTR, RRT
- 41. BioWaivers IV solutions, Oral solutions, BCS class 1, old drugs with no bio-equivalency problem
- 42. Oral Solution Must not contain an excipient that may significantly affect absorption of API e.g. Prednisolone sodium phosphate oral solution Inactive must not have safety issue
- 43. Solid Oral Dosage Dissolution testing on all strengths Strength proportionality must be similar to the biostrength In-vivo BE must be established for higher strength But for safety lower strength E.g. Terazosin HCl 1, 2, 5 & 10 mg strength, 2 is acceptable
- 44. Highly Soluble, Highly Permeable, Rapidly Dissolving e.g. Ofloxacin
- 45. Dissolution e.g. Omeprazole Use of dissolution data for biowaiver of non-bio strength Two stage dissolution testing (acid medium & buffered medium)
- 47. Dissolution as a tool Batch to batch consistency Quality Assurance Formulation development Bio-waiver In vitro BE studies Alcohol induced dose dumping Post-approval manufacturing changes
- 50. Dissolution Method Development Product Specific Method Development Evaluation of method Discriminating Ability Acceptance Criteria 1 2 3
- 51. Evaluation of method 1 Solubility Profile Apparatus Selection Dissolution/Release Media Rotation speed Sink conditions Supportive data for surfactant selection
- 52. Discriminating Ability 2 Differentiates DP manufactured under target conditions vs. formulation with meaningful variations for the most relevant manufacturing variables
- 53. Acceptance Criteria 3 Bioequivalence batches 85% of drug is dissolved or where plateau of drug dissolved is reached Selection of time points should be where Q=80% of drug is dissolved
- 54. Common Deficiencies in Regulatory Submissions Dissolution method development not included in application Failure to demonstrate discriminatory power (information lacking on CMA & PP) Data not supportive of proposed acceptance criteria
- 55. Common Deficiencies in Regulatory Submissions No dissolution data for lower strength waivers, multi-media testing for MR products No method transfer report on site change after method validation Dissolution data collected on aged lots Individual dissolution data is not submitted
- 56. Dissolution Failure Formulation had not been properly validated (FDA 2008) Therapeutic failure reported in 2007 Tropol XL (Sandoz) approved in 1992 Metoprolol Succinate Tabs ER Recall due to dissolution What should we learn? What do you think? Recalled due to dissolution 2009 Ethex (KV Pharmaceuticals) 2014 Wockhardt & Ranbaxy
- 57. Sometimes Math does not favor ADHD • Mallinckrodt • Methyl Phenidate HCl tab • 18, 27, 36, 54 mg dose Failure • Fasting & fed had two different behavior in extended release
- 58. Sometimes Math does not favor Bupripion HCl tab • Study on low dose and waiver on high dose Failure • Desired kinetics was not achieved Teva • FDA asked to stop distribution in sep 2012
- 59. Sometimes Math does not favor Bupripion (Wellbutrin) IR Tab of SKB 1985 Bupripion SR Tab 1996 & XL Tab 2003 Based on evidence demonstratin g BE with low strength In 2006, Generic version Mfg by Impax/Teva were approved 85 post marketing reports from Jan-Jun 2007 Experienced undesirable effects Increased side effects, Decreased therapeutic effect Re-switched on brand B U P R I P I O N
- 60. Sometimes Math does not favor Temporal relationship under question FDA re- examined BE data Conducted study Withdrawal of Teva drug in Mar 2013 against Sep 2012 FDA advice Also generic of Actavis withdraw their version A new challenge General rule will not work always Its life, please care B U P R I P I O N