ANDA Bioequivalence Studies That Fail to Meet FDA

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ANDA Bioequivalence Studies That Fail to Meet
FDAs Current Bioequivalence Criteria

• Dale P. Conner, Pharm.D.
• Division of Bioequivalence
• Office of Generic Drugs
• OPS, CDER, FDA

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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)

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Examples of BE Results
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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

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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

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Background

• Other important considerations
• Application may not contain untrue statements of
  material fact (F.D.C. 505(j) (3) (K) 21 CFR
  314.127 (a) (13))
• Selective reporting of data may constitute untrue
  statements of material fact (example FR 32982
  June 26,1995)
• Failure to report failed studies may be
  considered selective reporting

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Reasons for Failure of BE Studies

• Under-powered study
• Unusual study designs
• Outlier response from one or more subjects
• Assay issues
• Wrong reference

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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

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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

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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

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Example 3 Outlier Response Example

• Solid oral dosage form
• Standard BE study with 24 normal subjects
• One subjects 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
• Subjects new T/R 1.05 gt subject data
  dropped from original study

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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