1. ANDA Bioequivalence Studies That Fail to Meet FDA’s Current Bioequivalence Criteria
Dale P. Conner, Pharm.D.
Division of Bioequivalence
Office of Generic Drugs
OPS, CDER, FDA

2. Introduction -- BE Studies
Usually two-way crossover, single-dose study
Normal volunteers
Fasting
BE criteria: 90% CI between 80 and 125%
AUC
Cmax
Fed (point-estimate between 80 and 125)

3. Examples of BE Results

4. Introduction Definition of “failed”
Sponsors often choose not to submit “failed” studies in ANDAs
Sometimes these contain important information on the to-be-marketed ANDA product

5. Background
For NDAs all human investigations made to show whether or not such drug is safe for use and whether such drug is effective must be submitted (F.D.&C. 505 (b)(1)(A))
For ANDAs (F.D.&C. 505 (j)) similar language was not included in the Act
Sponsors have interpreted this to mean that “failed” BE studies need not be submitted in ANDAs

6. Background Other important considerations
Application may not contain untrue statements of material fact (F.D.&C. 505(j) (3) (K); 21 CFR (a) (13))
Selective reporting of data may constitute untrue statements of material fact (example FR June 26,1995)
Failure to report failed studies may be considered selective reporting

7. Reasons for “Failure” of BE Studies
Under-powered study
Unusual study designs
“Outlier” response from one or more subjects
Assay issues
Wrong reference

8. Reasons for “Failure” of BE Studies
Baseline-corrected vs. not corrected
Incorrect statistical analysis
Compliance issues
Formulation that is not truly bioequivalent to the reference

9. Example 1 - Drug X Oral Liquid
Liquid dosage form mixed with beverage prior to administration
ANDA studies performed with one beverage
Additional study in another beverage completed before ANDA approval
Product was not bioequivalent under this labeled administration condition
Study was not submitted before ANDA was approved

10. Example 2 - Drug Y Solid Oral MR
Discovered by Compliance on inspection of another study
First study against a lot (A) of brand product failed -- Cmax (105, 130)
Second study against another lot (B) of brand passed (submitted in ANDA)
Third study performed testing lot A vs. lot B -- failed: Cmax (111, 131)
Problem with RLD

11. Example 3 “Outlier” Response Example
Solid oral dosage form
Standard BE study with 24 normal subjects
One subject’s T/R was ~4
Point-estimate of other subjects T/R ~1.1
Study did not pass CI criteria with all subjects
Restudy of subject with 4 other original subjects
Subject’s new T/R = ==> subject data dropped from original study

12. Questions
Should sponsors submit the results of all BE studies performed on the to-be-marketed ANDA formulation?
Full reports or complete summaries?
What should FDA do with this information?
Complete review
Brief, but careful, examination