Bioequivalence Data Submission Requirements

Transcription

1 Bioequivalence Data Submission Requirements Hanan Kakish Medical Research Scientist, M.Sc. Pharm. Middle East and North Africa Post U.S. Food and Drug Administration Amman, Jordan 1

2 Disclaimer This presentation constitutes an informal communication that represents the best judgment of the speaker at this time but does not constitute an official advisory opinion, does not necessarily represent the formal position of U.S. FDA, and does not bind or otherwise obligate or commit the U.S. FDA to the views expressed 2

3 Topics for Discussion 1. Generic Drugs 2. Why FDA requests BE studies? 3. General BE study considerations 4. BE approaches 5. Bio-waivers and required dissolution testing 6. Regulatory authority on BE 7. Important change to requirements for submission of In Vivo BE data 8. New safety reporting requirements 9. Recommendations for better BE submissions 3

4 A Generic Drug is a copy of a Reference Listed Drugs commonly referred to as Brand-Name or Innovator Drugs FDA Practice 1. Generic Drugs: The Basics and Review Therapeutic Equivalence = Pharmaceutical Equivalence + Bioequivalence Are safe and effective alternatives to brand name prescriptions. Can help both consumers and the government reduce the cost of prescription drugs. Represent 80% of the total prescriptions dispensed in the US. Encourage research 4

5 NDA vs. ANDA Review Process Brand Name Drug Generic Drug NDA Requirements ANDA Requirements 1. Chemistry /Micro 1. Chemistry/Micro 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 5

6 2. Why BE Studies? US FDA s Definition of Bioequivalence (BE) The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents (same amount, same active, same dosage forms) or pharmaceutical alternatives (same active moiety, different chemical form or different dosage form or strength) becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Definition from 21 CFR

7 Why BE Studies? Cont. To determine rate/extent of absorption of each therapeutic moiety for: Potential generic products for which there is a reference listed drug (RLD) approved for marketing in US Potential new drug products (new salts, dosage forms) for which adequate clinical studies have already been conducted Reformulated drug products The Division of Bioequivalence Office of Generic Drugs (OGD)/CDER 7

8 Components of the in vivo BE Study Clinical Bioanalytical Statistical 3. General BE Study Considerations Each aspect of each component must be examined and determined to be acceptable for a properly conducted study. Details of each component are available in FDA s guidance documents at: formation/guidances/ucm htm 8

9 General Clinical Considerations Fed-BE Studies -The current policy 1. A single dose, two-way crossover, fed, in vivo BE study should be conducted for all orally administered immediate release (IR) drug products with the exceptions: When the RLD label clearly indicates that the drug should be taken on an empty stomach; or Study population of cancer patients with difficulty in successfully ingesting a high fat meal; or A fed study would cause safety or efficacy concerns. If label states IR product to be taken only with food, fasting and fed studies are recommended, except if there are safety concerns. 9

10 Fed BE Studies -The current policy 2. For all orally-administered modified-release (MR) drug products Rationale General Clinical Considerations (cont.) Excipients used to obtain delayed-release (DR) or extended-release (ER) behavior depend on environmental conditions of the GIT and by changing physiological conditions in GI tract, food can interact with excipients, thereby affecting drug absorption Food effects on bioequivalent test (T) and RLD products should be the same 10

11 4. BE Approaches In descending order of accuracy, sensitivity, reproducibility 1. Pharmacokinetic (PK) study in which drug concentrations are measured in plasma (IVIVC) 2. PK study in which drug concentrations are measured in urine 3. Acute pharmacological effect measured as a function of time - BE study with pharmacodynamic (PD) endpoints 4. Well-controlled clinical trial in humans (BE study with clinical endpoints) 5. Currently available in vitro test, acceptable to FDA, that ensures bioavailability as Oral insoluble binding agents binding assays Cholestyramine, Calcium Acetate 6. Any other approach deemed adequate by FDA to establish BA or BE 21 CFR

12 BE Approaches: Highly Variable Drugs New Proposal Reference-scaled average BE approach Three-period BE study Administer reference product twice and test product once Sequences: TRR, RTR, RRT BE criteria scaled to reference variability Both AUC and C max should meet BE acceptance criteria Mean AUC, C max T/R ratios must be between

13 BE Approaches: Multiphasic MR Products FDA uses pauc for some specialized dosage forms. For multiphasic MR products comprised of IR and delayedrelease (DR) and/or ER portions, where The IR portion is necessary for rapid onset of activity; The DR or ER portion is necessary to sustain activity; & Due to dosing regimen, drug does not accumulate to steadystate. 13

14 BE Approaches: Multiphasic MR Products Proposed BE metrics for multiphasic MR products Propose to use 4 metrics instead of 3 Present: C max -AUC 0-t -AUC Proposed: C max -AUC 0-T -AUC T-t -AUC AUC 0-T should compare T & RLD exposure responsible for early onset of response AUC T-t should compare T & RLD exposure responsible for sustained response All metrics should meet BE limits (80-125) T is product-specific time t is last PK sampling time Sampling time (T) for first pauc is based on time at which 90-95% of subjects are likely to achieve optimal early onset of response 14

15 BE Approaches: Multiphasic MR Products Bioequivalence Recommendations for Specific Products s/ucm htm Guidance on Zolpidem Oct % confidence intervals of the following PK parameters must meet the acceptable limits of [ ]: 1. Fasting Study: Log-transformed AUC 0-1.5, AUC 1.5-t, AUC 0- and C max, 2. Fed Study: Log-transformed AUC 0-t, AUC infinity and C max Three PK parameters are sufficient to establish BE under non-fasting conditions. Food delays the absorption of R product, and therefore, the delay due to food should eliminate the need for additional measures of early and late exposure. Draft Guidance on Methylphenidate Hydrochloride Nov 2011 Ritalin LA ER capsule is a multiphasic MR is another example 15

16 5. When Are Bio-waivers Granted? A. Self evident BE or BA: 1. Parenteral solutions: must contain the same active and inactive ingredients in the same amounts as the RLD qualitatively (Q1) and quantitatively (Q2) the same. 2. Product administered by inhalation as a gas & contains an active ingredient in the same dosage form as RLD 3. Oral solutions, solutions for application to the skin, elixir, syrup, tincture, a solution for aerosolization or nebulization, a nasal solution: an active drug ingredient in the same concentration and dosage form as RLD; and contains no inactive ingredient or other change in formulation from RLD that may significantly affect absorption of the active drug ingredient that are systemically absorbed, or that may significantly affect systemic or local availability for products intended to act locally. 21 CFR Part

17 When Are Bio-waivers Granted? B. Drug product is in the same dosage form, but in a different strength, and is proportionally similar in its active and inactive ingredients to another drug product for which the same manufacturer has obtained approval and: The BA of this other drug product has been measured; The applicant submits evidence showing that both drug products are proportionally similar in their active and inactive ingredients; & Both products meet an appropriate in vitro test approved by FDA 17

18 When Are Bio-waivers Granted? Both products meet an appropriate in vitro test approved by FDA Dissolution profiles in one medium if an appropriate regulatory dissolution method is established, and if the dissolution results indicate that the dissolution characteristics of the product are not dependent on the product strength. If an appropriate dissolution method is not established then dissolution data in 3 media (ph 1.2, 4.5, & 6.8) are recommended Use dissolution data to support requests for biowaivers 18

19 When Are Bio-waivers Granted? (MR) Not necessary to conduct in vivo studies on all strengths of MR capsules/tablets. May deem other strengths bioequivalent to corresponding reference strengths when: 1. In vivo BE is acceptable for one strength (usually highest) 2. Each capsule strength consists of same fill, differing only in size (amount of fill) or strengths are proportionally similar (in case of tablets). 2. In vitro dissolution is acceptable Only necessary to use regulatory method in case of capsules Must compare dissolution of all strengths in media of at least 3 ph values (e.g., 1.2, 4.5, 6,8) in case of tablets 19

20 When Are Bio-waivers Granted? (MR) In vitro dose dumping in alcohol Therapeutic Equivalence (TE) 20

21 Example: Venlafaxine Hydrochloride HCl ER Recommended studies: 1 study Type of study: Fed Design: Single-dose, two-treatment, two-period crossover in-vivo (Strength: 150 mg) Additional Comments: Due to safety concerns, BE studies under fasting conditions are not recommended. Waiver request of in-vivo testing: 37.5 mg, 75 mg, and 225 mg based on (i) acceptable BE studies on the 150 mg strength, (ii) acceptable in vitro dissolution testing of all strengths, and (iii) proportional similarity of the formulations across all strengths. Due to concerns of dose dumping from this drug product when taken with alcohol, please conduct additional dissolution testing using various concentrations of ethanol in the dissolution medium, as using 900 ml, 0.1 N HCl, USP apparatus 2 at 50 rpm, with or without alcohol. 21

22 When Are Bio-waivers Granted? C. Drug Efficacy Study Implementation (DESI) In vivo BE studies can be waived for solid oral dosage forms that meet these criteria Approved before 1962 in US Determined to be effective for at least one indication in a DESI notice or which is identical, related, or similar to such a drug product No BE problems Dissolution data must be acceptable (similar to R profiles) If there is a USP dissolution method available, then dissolution testing data using USP method may be adequate for the submission. When there is no USP dissolution method for the product but there is a FDA-recommended method, dissolution testing using the FDA-recommended method may be adequate. 22

23 When Are Bio-waivers Granted? D. Biopharmaceutics classification System (BCS) Class I drugs Highly soluble: An amount of drug comparable to the highest strength must be soluble in 250 ml of solution over wide ph range Highly permeable: Can be established by in vivo or in vitro methods Rapidly dissolving USP Apparatus 1 at 100 rpm (or Apparatus 2 at 50 rpm) in a volume of 900 ml or less in: (a) 0.1N HCl or Simulated Gastric Fluid USP without enzymes; (b) a ph 4.5 buffer; and (c) a ph 6.8 buffer or Simulated Intestinal Fluid USP without enzymes 23

24 When Are Bio-waivers Granted? 24

25 When Are Bio-waivers Granted? 25

26 FDA Update: Special Case FDA has approved five generic versions of Wellbutrin XL 300 mg (bupropion HCl) based on BE studies comparing the 150 mg strength of the products to RLD150 mg and the results were extrapolated to establish BE of the 300 mg product. FDA has indicated that Budeprion XL 300 mg XL tablets (manufactured by Impax and marketed by Teva) is not Therapeutically Equivalent to Wellbutrin XL 300 mg (RLD). FDA has changed the therapeutic equivalence rating for this product in Orange Book). 26

27 Why? Special Case FDA began to receive reports that patients who were switched from RLD 300 mg to its generic were experiencing reduced efficacy. FDA analyzed those reports linked to the Impax/Teva product. FDA decided to sponsor a BE study comparing Budeprion XL 300 mg to RLD 300 mg. The results show that this generic fail to release bupropion into the blood at the same rate and extent as RLD. This does not affect the Impax/Teva Budeprion 150 mg product or generic bupropion products made by other manufacturers. FDA has asked the companies manufacturing the 4 other generics to submit the data from those studies no later than March

28 Special Case FDA s actions with respect to Budeprion XL 300 mg reflect FDA s ongoing role in monitoring drugs on the market to ensure their continued safety and efficacy. The role of patients and health care professionals in sharing their experiences with generic versions of Wellbutrin XL 300 mg contributed to further studies, which led to this action. FDA remains firmly committed to its science-based responsibilities and to making sure that generic drugs are safe and effective. ationforpatientsandproviders/ucm htm 28

29 6. Regulatory Authority on BE The United States Food, Drug, and Cosmetic Act (FDCA-1938) gives FDA the authority to oversee the safety and efficacy of food, drugs, and cosmetics. Provisions for generic drugs added in 1984 FDCA ( 505(j)) states that rate and extent of drug absorption must be compared to establish BE between two products The FDA s regulations are codified in Title 21 of the Code of Federal Regulations (21 CFR) 21 CFR, Part 320 is for Bioavailability and Bioequivalence Requirements C max indicates rate of absorption AUC indicates extent of absorption 29

30 7. Important Regulatory Changes for Submission of In Vivo BE Data Final Rule published January 16, 2009 Requires applicants to submit data from ALL BE studies, including failed ones, that the applicant conducts on a drug product formulation submitted for approval CDER Guidance for Industry: Submission of Summary Bioequivalence Data for ANDAs published May 2011 Describes the types of formulations FDA considers to be the SAME drug product formulation for different dosage forms based on differences in composition 30

31 Why Submit Data from Failed Studies? FDA believes that evaluating failed BE studies will increase understanding of how changes in components, composition, and manufacturing methods may affect generic product formulation performance. For each study that fails to meet BE limits, applicant must provide valid explanation of why this was the case. OGD may send a deficiency if the explanation is missing or inadequate. 31

32 Submission of Summary Bioequivalence Data for ANDAs Guidance 1. Describes types of ANDA submissions covered by the All BE Studies Rule 2. Explains types of formulations that the Agency considers to be the same as that submitted for approval. They have minor differences in composition or method of manufacture from the formulation submitted for approval but similar enough to be relevant to the FDA s determination of BE. 3. Recommends a format for summary reports of BE studies 32

33 Same Drug Product Formulation Considered Same formulation IR products and non-release controlling excipients in MR products if: Difference in ingredient intended to affect color or flavor Different approved printing ink ingredient Difference in excipient technical grade, specification Difference in drug substance or excipient particle size Minor differences in excipient amounts, provided in guidance 33

34 NOT the same formulation IR products and non-release controlling excipients in MR products Addition or deletion of an excipient Difference in excipient weight between two formulations exceeds the percentages specified in the Guidance Same Drug Product Formulation Cumulative total of all excipient weight differences > 10% Calculating % Differences in Excipients Between Formulations Compare experimental (new) formulation versus to-be-marketed (TBM) formulation submitted for approval Expressed as the difference in excipient weight between the two formulations 100*amt. in new formulation amt. in TBM formulation amount in TBM formulation e.g., if new contains 105 mg filler and TBM contains 100 mg filler 5% 34

35 Same Drug Product Formulation Same formulation release-controlling excipients in MR products Difference in excipient technical grade, specification Difference in drug substance or excipient particle size Difference in the amount of release-controlling excipient(s) 10% NOT the same formulation release-controlling excipients in MR products Addition or deletion of an excipient Difference in the amount of release-controlling excipient(s) > 10% 35

36 Submission of BE Data: Summary Report Should submit a summary report for all pilot, non-pivotal, and failing BE studies on the same formulation as that submitted for the ANDA Model Summary Tables are posted on FDA s website evelopedandapproved/approvalapplications/abbreviatednewdrugapplicationand AGenerics/UCM pdf OGD sends a deficiency letter if summary tables do not follow the format on website Also acceptable to submit complete report 36

37 8. New Safety Reporting Requirements On September 29, 2010, FDA published a final rule amending the IND safety reporting requirements and adding safety reporting requirements for BA and BE studies. Under former 21 CFR (d), certain in vivo BA and BE studies in humans were exempted from the IND requirements under part 312 if specific conditions were satisfied. 37

38 New Safety Reporting Requirements The final rule contains new safety reporting requirements under 21 CFR (d)(3) for persons conducting BA or BE studies that are exempt from the IND requirements. These new requirements will help FDA monitor the safety of these drugs and better protect human subjects enrolled in BA or BE studies. Effective date: March 28, 2011 and FDA exercised enforcement discretion until September 28,

39 Safety Reporting 39

40 Reporting Requirements for BE/BA Sponsor or CRO must notify FDA and of any serious adverse event (SAE) regardless of whether the event is considered drug-related. Occurrence of a SAE is unusual number of subjects enrolled in these studies is small subjects are usually healthy volunteers drug exposure is typically brief Reports might reflect a problem with the drug product, formulation, subject inclusion/exclusion criteria, or other aspects of the study design Refer to the Guidance below for more information on content of reports December

41 Reporting Requirements When to Report FDA must be notified of any SAE as soon as possible but in no case later than 15 calendar days after becoming aware of its occurrence. For adverse events that are fatal or life-threatening, FDA must be notified as soon as possible but in no case later than 7 calendar days after becoming aware of its occurrence. We recommend that these notifications be made by telephone or fax. How to Submit Reports Each report must be submitted on FDA Form 3500A Identified in box G7, B5, and/or on a cover letter submitted with a 3500A as a Bioavailability/Bioequivalence Safety Report 41

42 9. Recommendations for Better BE Submissions Submission of Electronic Tables Firms complete 16 summary tables Based on Common Technical Document (CTD) Module 2 and Module 5 guidelines. Tables show: 1. study summary 5. confidence intervals 2. formulation 6. dissolution 3. bioanalytical method 7. repeat analyses 4. study demographics 8. adverse events 42

43 Recommendations for Better BE Submissions Should submit dissolution data using the recommended dissolution methods listed in Dissolution Database for comparison to different method applicant may propose. Check the periodically updated BE Recommendations Database (In form of draft or final guidance) It gives current BE study recommendations for some products and serves as answer to questions, submitted in correspondence, on specific drug products 43

44 Recommendations for Better BE Submissions FDA ask companies to submit in CTD format (or ectd) Module 2 clinical summaries Module 5 clinical study reports Electronic submission facilitates quick review BE reviewers take longer to review poorly organized submissions What happens if BE submission has problems or errors? It takes longer time for FDA to review your submission!!! You receive a deficiency letter!!! 44

45 Common Deficiencies with BE Submissions Poorly-organized ANDA submission; Electronic summary tables prepared incorrectly; Bioanalytical SOPs not submitted; Long term storage stability; time between study completion and sample analysis; Dissolution related issues; Potency and content uniformity data not included in BE section; Issues with SAS files; and PK repeats. PK repeats SOPs must be in place a priori How the need to repeat analytical analysis is identified How repeat analyses are conducted and used in BE statistics 45

46 Acknowledgements Robert L. West, M.S., R.Ph. Deputy Director, Office of Generic Drugs Barbara M Davit, Ph.D., J.D., Director, Division of Bioequivalence II, Office of Generic Drugs Timothy W. Ames, R.Ph., M.P.H., Chief, Review Support Branch, Office of Generic Drugs 46

47 Useful Links Dissolution database: Individual product BE recommendations database: uidances/ucm htm FDA guidances: uidances/default.htm Electronic Common Technical Document (ectd) Basics: onrequirements/electronicsubmissions/ucm htm 47