On February 24, 2022, the Small Business and Industry Assistance (SBIA) group at the FDA hosted a webinar titled Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA (you can view the recording here).  The goal was to describe the eight major changes to the August 2021 revision to the guidance Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA, which was originally released in 2013, and to discuss Agency thinking on some other points.

The eight major revisions identified by the FDA are:

  1. Updates and clarifies the content on Reference Listed Drugs (RLD) and Reference Standards (RS) in the Orange Book and references new guidances
  2. Expands content on “Study Population” with regards to sex (male/female) and age (pediatric and elderly)
  3. Modifies recommendations on how to assess proportional similarity for additional dose strengths for modified-release drug products based on mechanism of release and dissolution profile similarity
  4. Adds sections on new dosage forms that also rely on systemic BE assessment (i.e., orally disintegrating tablets, sublingual, and transdermal)
  5. Adds a section on alternative routes of administration, including products administered via a nasogastric (NG) tube or a gastric (G) tube
  6. Adds a new section on handling of outliers in Appendix A
  7. Adds two new appendices (B and C) on reference-scaled average BE analyses for highly variable drugs and narrow therapeutic index drugs, respectively
  8. Removes the section related to “Orally Administered Drugs Intended for Local Action” from the 2013 draft guidance

I would like to comment on a few of these changes that I believe will have to most impact on BE testing going forward.

For as long as I can remember, choice of subjects (particularly related to age and sex) has been a concern to the Agency; however, not much was really done by the FDA to enforce the recommended requirements.  The FDA appears to be heading into a “Missouri” phase, that is SHOW ME, regarding these criteria.  The question is now, will the inclusion of all‑male panels (when the study drug is recommended for both males and females) or age groups of only 18‑55 alone be questioned, and, in some cases, no longer be found acceptable to support a BE determination?  The new guidance states, “If a drug product is intended for use in both sexes, the applicant should include similar proportions of males and females in the study or provide a justification supporting the use of a single‑sex population.”  Now, the word “justification” (which appears in other sections too) implies the expectation that there needs to be a real scientifically based rationale provided in the submission to support not having a balanced panel of males and females.  This issue also arises with age as the guidance now suggests the following:

“If the drug product is predominantly intended for use in the elderly, the applicant should include as many subjects as possible at or above age 60 or provide a justification if no subject at or above age 60 is included in the study.”


“[I]n general, a BE assessment in adults between two products can be used to support a BE assessment in pediatric patients.  If the drug product is predominantly intended for use in pediatric patients younger than 6 years, the applicant should justify that the BE study results obtained from adult subjects are relevant to the pediatric population.  FDA recommends that this justification include information supporting that the inactive ingredients in the proposed products are appropriate for use in the pediatric population.”

For those of you who have placed BE studies at CROs during the pandemic or even before, you have probably experienced issues surround recruitment of subjects in general, let alone without having more strict requirements.  In addition, IRBs may object to inclusion of elderly patients in the study population.  It is not a coincidence that many CROs are in college towns where recruitment tends to draw from a younger college-aged population.  And with COVID-19 still swirling around, recruitment has been even more difficult and study participants have been more difficult to find.  Will the Agency start cracking down on age and sex criteria?  How will you know whether your panel will be found acceptable prior to study initiation if you have recruitment problems?  Will studies take longer to initiate because willing subjects of the recommended age and proportion of males to females cannot be found?  What will be the basis for an acceptable justification for a variation in subject demographics that does not fit the Agency’s desired profile?  What is an acceptable justification for demonstrating results in adult subjects are relevant to the pediatric population?

Other issues that stood out to me included:

  • Treatment of outliers and that redosing studies (which were a common prior practice) are no longer considered evidence that a patient is an outlier. Also, the Agency now requires that all data generated for all subjects be included in the statistical analysis (which is not a big change as previously most applicants provided statistics with and without the inclusion of what they deemed to be outliers).
  • Consideration in defining dose proportionality in the BE determination of additional strengths of modified release products. This appears to give a little more formulation leeway to firms if other outlined requirements are met.

The changes can have quite a significant impact on the recruitment and/or performance of BE studies.  Thus, I advise that you listen to the webinar to avoid getting stung by making the wrong decision by moving forward with a deviation from the guidance.