Evolving Science in Bioavailability and Bioequivalence Jim Wei, MD, PhD x.wei@medpace.com ACPU, Cincinnati, OH, October 18-20, 2010

Agenda Bioavailability/Bioequivalence Highly variable drugs (HVD) Study Design of Bioequivalence Average BE Replicate BE - Full replicate - Partial replicate Regulatory requirements for BE supplies, sample storage and data analysis

Bioavailability – defined “Bioavailability is the fraction (F) of an administered dose that actually reaches systemic circulation when compared to a solution (SLN), suspension (SUSP), or intravenous (IV) dosage form.” -- 21 CFR 320.25(d)(2)&(3) -- absolute: test drug vs. IV reference - BA of an IV drug is assumed to be 100%, or F = 1.00 amount reaching circulation = F x Dose relative: test drug vs. SLN or SUSP reference

Points to Consider – BA For bioavailability studies, our primary “metric” of interest is: area under the concentration-time curve (AUC) AUC is a derived parameter, it is not observed Types: AUCt = to the last detectable concentration AUC = from zero to infinity (single dose) AUC = between dosing intervals at steady-state

Approaches to Determining Bioequivalence (21 CFR 320.24) In vivo measurement of active moiety or moieties in biologic fluid In vivo pharmacodynamic comparison In vivo limited clinical comparison In vitro comparison Any other approach deemed appropriate by FDA FeV1 Albuterol Glucagon Topicals Nasal Suspensions Questran - Binding Studies Nasal Solutions-Sprayer Evaluation Propofol - Droplet Size

BE Study Designs Single-dose, two-way crossover, fasted Single-dose, two-way crossover, fed Alternatives Single-dose, parallel, fasted Long Half-Life (wash-out): Amiodarone, Etidronate Single-dose, replicate design Highly Variable Drugs Multiple-dose, two-way crossover, fasted Less Sensitive: Clozapine (Patient Trials); Chemotherapy Trials Clinical endpoint study Topicals: Nasal Suspensions

BE Statistical Analysis Bioequivalence criteria Two one-sided tests procedure Test (T) is not significantly less than reference Reference (R) is not significantly less than test Significant difference is 20% ( = 0.05 significance level) T/R = 80/100 = 80% R/T = 80% (all data expressed as T/R so this becomes 100/80 = 125%)

Highly Variable Drugs (HVD) Definition Use ANOVA Root Mean Square Error (RMSE) to estimate within-subject or intra-subject variability: Drug is classified as highly variable if RMSE ≥ 0.3 or 30% Two main types or sources of variability Highly variable PK (inherent drug characteristic) Highly variable formulation • Standard BE study approach may need more than 100 subjects

Cmax AUClast Ref-1 Ref-2 6 13 27 7 16 20 This plot is the actual data from the study High lighted are some subjects with the greatest variability between doses. The same subjects contribute to the high WSV of Cmax and AUC The next slide shows these 6 subjects only

BE Studies in Highly Variable Drugs (HVD) FDA Study to Characterize Highly Variable Drugs in BE Studies: Collected data from 1127 acceptable BE studies, submitted 524 ANDAs from 2003-2005 (3 years) Most sponsors used 2-way crossover studies Used ANOVA Root Mean Square Error to estimate within-subject variance Drug was classified as highly variable if RMSE ≥ 0.3 or 30% BE studies of HVD enrolled more study subjects than studies of drugs with low variability Average N in studies of HVD = 47 Average N in studies of drugs with lower variability = 33 Range 18 – 73 subjects 10% of studies evaluated were HVD

Reasons for Inconsistent Variability in BE Studies Differences in formulations Improperly handling of Bioanalytical assays Subjects with irregular plasma concentrations Number of study subjects Uncontrolled food status

90%CIs & BE Limits Green Low WSV (~15%) Narrow 90%CI Passes Red High WSV (~35%) Wide 90%CI Lower bound <80% Fails 125% 100% 80% GMR & the # of subjects are the same in both cases

Replicate BE Study Design Full replicate crossover design: Partial replicate crossover design: Period 1 2 3 4 Sequence T R Period 1 2 3 Sequence T R

Scaled Average BE for HVD Three-period, partial replicate design Reference product (R) is administered twice Test product (T) is administered once Sequences = RTR, TRR, RRT Sample size: Determined by sponsor (adequate power) minimum is 24 subjects BE criteria scaled to reference variability (Cmax & AUC) The point estimate (test/reference geometric mean ratio) must fall within [0.80-1.25] Both conditions must be passed by the test product to conclude BE to the reference product

Advantages of Scaled BE (Reference Scaled) Test product will benefit if: T variability < R variability The test product will not benefit if: T variability > R variability What if high variability results from formulations problems or poor study conduct? If T variability > R variability, no benefit in using scaled approach The burden is on the applicant to convince FDA that product is a HVD

21 CFR 320.36 Requirements for maintenance of records of bioequivalence testing All records of in vivo or in vitro tests shall be maintained by the manufacturer for at least 2 years after the expiration date of the batch and submitted to the Food and Drug Administration on request. Any person who contracts with another party to conduct a bioequivalence study from which the data are intended to be submitted to FDA as part of an application submitted under part 314 of this chapter shall obtain from the person conducting the study sufficient accurate financial information to allow the submission of complete and accurate financial certifications or disclosure statements required under part 54 of this chapter and shall maintain that information and all records relating to the compensation given for that study and all other financial interest information required under part 54 of this chapter for 2 years after the date of approval of the application. The person maintaining these records shall, upon request for any properly authorized officer or employee of the Food and Drug Administration, at reasonable time, permit such officer or employee to have access to and copy and verify these records.

21 CFR -320.38 Retention of bioavailability samples Each reserve sample shall be stored under conditions consistent with product labeling and in an area segregated from the area where testing is conducted and with access limited to authorized personnel. Each reserve sample shall be retained for a period of at least 5 years following the date on which the application or supplemental application is approved, or, if such application or supplemental application is not approved, at least 5 years following the date of completion of the bioavailability study in which the sample from which the reserve sample was obtained was used.

BE Sample Retention The guidance highlights how the test article and reference standard for BA and BE studies should be distributed to the testing facilities how testing facilities should randomly select samples for testing and material to maintain as reserve samples how the reserve samples should be retained.

FDA/DSI Inspection on BE Studies A frequent finding from these inspections is the absence of reserve samples at the testing facilities where the studies are conducted: In many cases, DSI finds that testing facilities return reserve samples to the study sponsors and/or drug manufacturers, In other cases, study sponsors and/or drug manufacturers, SMOs, or contract packaging facilities designate the study test article and reference standard for each subject, and preclude the testing facilities from randomly selecting representative reserve samples from the supplies. The study sponsor and/or drug manufacturer should send to the testing facility batches of the test article and reference standard packaged in such a way that the testing facility can randomly select samples for bioequivalence testing and samples to maintain as reserve samples.

FDA/DSI Inspection on BE Studies cont’d Quantity of Reserve Samples Sufficient to perform five times all of the release tests required in the application or supplemental application For solid oral dosage forms (e.g., tablets, capsules), an upper limit of 300 units each for the test article and reference standard Each site is asked to retain a reasonable amount of test article and reference standard a minimum limit (e.g., 5 dose units) for each of the test articles and reference standards In-House Studies Conducted by a Study Sponsor and/or Drug Manufacturer If a study sponsor and/or drug manufacturer conducts such a study, manufacturing reserve samples (21 CFR 211.170) and BE study reserve samples (21 CFR 320.38 and 320.63) should be separated.

Thank you! CONTACT INFORMATION JIM WEI 513-763-9770 E-MAIL:  x.wei@medpace.com