GADA Quarterly Meeting October 8, 2009

1. GADA Quarterly MeetingOctober 8, 2009 Dr. Ken Harshman, Director Division of Generic Animal Drugs

2. Comparative Dissolution for Solid Oral Dosage Forms • Principle: evidence must be provided to establish in vivo bioequivalence for all strengths of the generic drug • Types of evidence • in vivo bioequivalence study • in vitro (dissolution) test acceptable or any other approach deemed adequate by FDA • Bioequivalence waiver is granted based on successful conduct of in vitro test or other approach

3. Comparative Dissolution • Rationale for conduct of comparative dissolution on each strength • Difference in surface to volume ratio • Difference in compression of tablets • hardness can vary in different sized tablets • even with common granulation (best case) • Acceptance Criteria = f2>50 • f2 reflects the average difference in the percent dissolved • For highly soluble drugs that have >85% dissolution in 15 minutes – no f2 is required – waiver is granted

4. Comparative Dissolution • Test Design • Sampling times – one point at 15 min. and sample out to 85% dissolution • Test criteria: compare the various strengths of test drug against the strength used in bioequivalence study • For comparable dosage forms, we recommend also comparing the dissolution profile of the corresponding strengths of the test and reference drug • This comparison is of no value if dosage forms are significantly different

5. Comparative Dissolution • If all test product comparisons meet f2 criteria, biowaiver is granted • If one or two strengths fail in test drug comparisons; compare against the same strength of reference drug • Can use this information to support waiver as long as the two strengths used in BE study are comparable in vitro • Require another BE for each strength that fails in vitro comparisons • All data on all strengths of test and reference drug must be submitted at the same time • Analytical method for measuring drug concentration must be validated

6. Suitability Petitions • To submit an ANADA for a generic drug that is not identical to a reference drug - must first submit a suitability petition • Permissible changes • Changes in route of administration, • Changes in dosage form, • Changes in strength, • Changes in one of the active ingredients in a reference listed combination new animal drug, and • Changes in one of the Type A medicated articles in a reference listed feed use combination new animal drug.

7. Content of Suitability Petition • Identify the reference listed new animal drug, including its dosage form and strength • Identify the proposed change(s) to the generic drug • Provide justification for the proposed change(s) • Submit product labeling • Proposed generic drug • Current labeling for the reference drug • Identify the differences in labeling

8. Approval of Suitability Petition • Approved unless: • Investigations must be conducted to show the safety and/or effectiveness of the proposed generic new animal drug because of a proposed permissible change(s),or • Investigations must be conducted to show the safety for human consumption of any residues in food because of a proposed permissible change(s)

9. Bioequivalence Waiver Request • The request for waiver must: (1) Identify the proposed generic drug, including proprietary and established names, dosage form, and strength; (2) Identify the proposed reference drug, including proprietary and established names, dosage form, strength, sponsor name, and the application number; (3) Include copies of the approved labeling for the reference drug and facsimile labeling for the proposed generic new animal drug; (4) Provide information, to the extent such information is available, about the differences in the reference drug and proposed generic drug formulations, including pH specification if necessary;

10. Bioequivalence Waiver Request (5)Include a justification for granting the waiver; (6) Include a list of relevant patents and their expiration date; (7) Include a statement as to whether the requestor intends to submit a paragraph IV certification with respect to each such patent; and (8) Include a statement giving the date on which any exclusivity periods applicable to the reference drug end.

11. Bioequivalence Waiver Request • FDA will not accept for review a request for waiver that is submitted more than 5 years before the expiration date of: (1) the last expiring relevant patent, unless the sponsor intends to submit a paragraph IV certification claiming noninfringement or invalidity of such patent.