The document provides an overview of regulatory aspects of pharmacokinetics related to bioequivalence. It discusses key bioequivalence terminology including pharmaceutical equivalents, pharmaceutical alternatives, and therapeutic equivalents. It also outlines FDA regulations and guidance around bioequivalence testing, including acceptable study designs and criteria for determining bioequivalence. Specific topics covered include examples of bioequivalence studies for foods effects, orally administered locally acting drugs, and narrow therapeutic index drugs. The document emphasizes that bioequivalence evaluations are done on a case by case basis depending on the specific drug.

1. Regulatory Aspects of PK:
Bioequivalence

2. 2
• The presentation today should not be
considered, in whole or in part as being
statements of policy or recommendation
by the US Food and Drug Administration.
• Throughout the talk, representative
examples of commercial products will be
mentioned. No commercial endorsement
is either implied or intended.

3. 3
Outline
• Bioequivalence Terminology
• FDA & Bioequivalence-Science, Regulation, and
Policy
• Bioequivalence Examples
– Food Effect Studies
– Orally Administered Locally Acting
– Narrow Therapeutic Index Drugs
• Product Specific Resources
• Conclusions

4. 4
BIOEQUIVALENCE TERMINOLOGY

5. 5
• To be bioequivalent and thus interchangeable you
must be a pharmaceutical equivalent.
• Products that are not pharmaceutical equivalents but
still pass the bioequivalence testing standards are not
interchangeable but are said to have “comparable
bioavailability”
• Bioequivalence has a legal and medical meaning that
encompasses therapeutic equivalence
Pharmaceutical Equivalents Pharmaceutical Alternatives
Equivalent vs. Alternative
vs Bioequivalent

6. 6
Pharmaceutical Equivalents
• Drug products are considered pharmaceutical
equivalents if they:
– Contain the same active ingredient(s)
– Are of the same dosage form
– Route of administration
– Are identical in strength or concentration
• Pharmaceutically equivalent drug products may differ
in characteristics such as:
– Shape
– Scoring configuration
– Release mechanisms
– Packaging
– Excipients (including colors, flavors, preservatives)
– Etc.

7. 7
Pharmaceutical Alternatives
• Drug products are considered pharmaceutical
alternatives if they contain the same therapeutic
moiety, but are:
– Different salts, esters, or complexes of that moiety
– Are different dosage forms or strengths
• Data are generally not available for FDA to make the determination of
tablet to capsule bioequivalence.
• Different dosage forms and strengths within a product line by a single
manufacturer are thus pharmaceutical alternatives, as are extended-
release products when compared with immediate- or standard-
release formulations of the same active ingredient.

8. 8
Therapeutic Equivalents
• Drug products are considered to be therapeutic
equivalents only if they are:
– Pharmaceutical equivalents
– If they can be expected to have the same clinical effect and
safety profile when administered to patients under the
conditions specified in the labeling.
• This is normally demonstrated via bioequivalence testing

9. 9
Bioequivalence-Not “just” for Generics
• Common Reasons for Bioequivalence Studies
– Brand vs. Generic
– Brand changes formulation
– Brand moves production
– Brand makes a new line extension
• (tablet to capsule)

10. 10
Prescribability
• Prescribability refers to the clinical setting in which a
practitioner prescribes a drug product to a patient for the
first time. In this setting, the prescriber relies on an
understanding that the average performance of the drug
product has been well characterized and relates in some
definable way to the safety and efficacy information from
clinical trials.
https://www.fda.gov/OHRMS/DOCKETS/98fr/3657gd1.pdf

11. 11
Switchability
• Switchability refers to the setting in which a practitioner
transfers a patient from one drug product to another. This
situation arises with generic substitution, as well as with
certain post approval changes by an innovator or generic
firm in the formulation and/or manufacture of a drug
product. Under these circumstances, the prescriber and
patient should be assured that the newly administered drug
product will yield comparable safety and efficacy to that of
the product for which it is being substituted.
https://www.fda.gov/OHRMS/DOCKETS/98fr/3657gd1.pdf

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Clinical Pharmacology Studies in an NDA
• Bioavailability (Absolute or Relative)
– Radiolabel
• Dose and/or Dosage Form Proportionality
• Single Dose Pharmacokinetics
• Multiple Dose Pharmacokinetics
• Metabolism Studies
– P-450 Isoenzymes
• Special Populations
– Elderly
– Renal Failure/ Hepatic Failure
– Pediatrics
• Misc.
– Formulation Studies
– Bioequivalency (Clinical vs. To-be-
marketed)
– Drug Interaction
– Protein Binding
– Mechanism of Action
– Dissolution
 Exposure Response
 Dose Response
 Dose Titration
 Surrogate Endpoint
 Pharmacometrics
 PharmacogenomicsEven though these are
not bioequivalence trials,
BE testing is often done
to show their impact on
PK

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FDA & BIOEQUIVALENCE-SCIENCE,
REGULATION, AND POLICY

14. 14
Code of Federal Regulations
Chapter 21
Part 320
Bioavailability and
Bioequivalence Requirements

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Regulatory Basis
§ 320.24 Types of evidence to measure bioavailability or establish
bioequivalence.
(a) Bioavailability may be measured or bioequivalence may be
demonstrated by several in vivo and in vitro methods. FDA may
require in vivo or in vitro testing, or both, to measure the
bioavailability of a drug product or establish the bioequivalence of
specific drug products.…
The selection of the method used to meet an in vivo or in vitro
testing requirement depends upon the purpose of the study, the
analytical methods available, and the nature of the drug product.
Applicants shall conduct bioavailability and bioequivalence testing
using the most accurate, sensitive, and reproducible approach
available among those set forth in paragraph (b) of this section. The
method used must be capable of measuring bioavailability or
establishing bioequivalence, as appropriate, for the product being
tested.

16. 16
Bioavailability Methods per CFR 320.24
• (1) (i)in vivo pk where drug concentrations are assessed at the
site of action (usually blood)
– (ii)in vitro test that is predictive of human bioavailabilty
• (2) Urinary pk measurements
• (3) An in vivo test in humans in which an appropriate acute
pharmacological effect is measured
• (4) Well-controlled clinical trials that establish the safety and
effectiveness of the drug product, for purposes of measuring
bioavailability, or appropriately designed comparative clinical
trials, for purposes of demonstrating bioequivalence. This
approach is the least accurate, sensitive, and reproducible of the
general approaches for measuring bioavailability or
demonstrating bioequivalence.

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Bioequivalence Guidance's
One Size Does Not Fit All
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

18. 18
Bioequivalence in the NDA Setting
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM389370.pdf

19. 19
“General” In Vivo PK
Bioequivalency Study
• Typically single dose, 2-sequence, cross-over study in
healthy subjects (24 subjects for an ANDA)
– A study of failed BE studies submitted for an ANDA showed that
2/3rds of all failed BE studies were underpowered.
• Based on the geometric mean test/reference ratios for
Cmax and AUC (AVERAGE BIOEQUIVALENCE)
– Tmax being a “discrete” variable and not a continuous variable is
not evaluated with CI’s as they cannot be constructed
• The log transformed 90% Confidence Intervals (CI) of the
mean ratio should be within 80 to 125%
– For NDAs, deviations from the CI interval can be considered on a
case by case basis, dependent upon the pharmacologic dose
response
– For ANDAs (Generics), deviations from the CI are not allowed
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM389370.pdf

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General Subject Selection
• Normally BA/BE studies are done in healthy adult subjects
(>18yrs) that reflect the target population as much as
possible
– Formerly the guidance called for studies in “representative US
populations”, this is no longer part of the guidance
• Males and females are to be enrolled in the study unless it
is a gender specific indication (e.g., hormonal
contraception or prostate cancer therapy for example) or
a teratogen (isotretinoin as an example)
– No specific ratio of males to females is mentioned in the
guidance, but extreme disparities will be a concern and will need
to be addressed, for example 24 subjects (22 males and 2
females) will require explanation
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM389370.pdf

21. 21
BIOEQUIVALENCE EXAMPLES

22. 22
Food Effect Studies
• The purpose of a food effect study is to demonstrate the
effect of a high fat/high caloric load meal on a dosage form
– Direct outgrowth of studies conducted in the early 1980s
of once-a-day theophylline products
• The diet used in the original study is the current FDA
recommended high fat diet
J. H. G. Jonkman (1987) Food Interactions With Once-A-Day Theophylline Preparations: A Review, Chronobiology International, 4:3, 449-458

23. 23
Meal Effects and Composition
• Meals have a number of effects on the GI system and absorption
– Delay gastric emptying
– Stimulate bile flow
– Change gastrointestinal (GI) pH
– Increase splanchnic blood flow
– Change luminal metabolism of a drug substance
– Physically or chemically interact with a dosage form or a drug substance
• The test meal should be
– A high-fat (approximately 50 percent of total caloric content of the meal)
– High-calorie (approximately 800 to 1000 calories)
• 150, 250, and 500-600 calories from protein, carbohydrate, and fat,
respectively
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070241.pdf

24. 24
Food Effect Misconceptions
• FDA High Fat Example Meal
– Two eggs fried in butter
– Two strips of bacon
– Two slices of toast with butter
– Four ounces of hash brown potatoes
– Eight ounces of whole milk
– MUST be consumed in 30min to be valid
• This is not a “typical American breakfast”
– It is designed to “stress” the dosage form
• Other diets can be used BUT you must document that the
volume, relative composition, and caloric load is similar if
not identical to the recommendations in the guidance
document.
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070241.pdf

25. 25
Orally Administered-Locally Acting
 Prior to the early 2000s, most locally acting
gastrointestinal drug products required head-to-
head bioequivalence studies with “CLINICAL
ENDPOINTS”
 As noted in the regulations this was the “least
accurate, sensitive, and reproducible of the
general approaches”

26. 26
Challenges of
Clinical Endpoint Studies
• Clinical endpoints more variable than PK but must
meet the established BE limits
• May require several hundred patients
• Study duration may be several weeks depending
upon the approved labeling
• Very expensive to conduct
• May present more safety concerns than PK studies

27. 27
Challenges of
Clinical Endpoint Studies
• Unknown inter-subject variability within reference
population
• Difficulty in achieving consistency between studies
– study design
– study population
– bioequivalence endpoints
• Some products require multiple studies

28. 28
Lubiprostone Overview
• Lubiprostone is a chloride channel activator
indicated for:
– Treatment of chronic idiopathic constipation in adults
– Treatment of opioid-induced constipation in adults
with chronic, non-cancer pain
– Treatment of irritable bowel syndrome with
constipation in women ≥ 18 years old
• Approved in January 2006

29. 29
NDA Study Package
• Clinical Package
– 1113 patients received 24mcg of lubiprostone in
Phase 2 and 3 clinical trials and were evaluated for
safety
– 1070 patients were enrolled in clinical efficacy trials
• 239 in two placebo controlled trials
• 871 in four open label trials
https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist

30. 30
Clinical Pharmacology Studies
• Pre-Approval
– 95 healthy subjects in a single dose QT Study
• 24mcg and 144mcg
– 4 healthy subjects in a mass balance Study
• 72mcg H3-lubiprostone
– 13 healthy subjects in a Food Effect Study
• 72mcg H3-lubiprostone
• Post-Approval
– 24 subjects (8 healthy and 16 with renal insufficiency)
• 24mcg
– 25 subject (8 healthy and 17 with hepatic insufficiency)
• 12mcg and 24mcg
https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist

31. 31
PK Profile of M3 Lubiprostone

32. 32
FDA Bioequivalence Guidance
for Lubiprostone
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm224220.pdf
Multi-media
Multi-Point
Dissolution
Fed BE Study
with PK
Endpoints
Fed BE Study
with PK
Endpoints
BE Study with
Clinical Endpoints

33. 33
A“Holistic” Approach to
Locally Acting GI Drugs
t
Cp
Multi-point, Multi-media Dissolution Testing In Vivo PK Using Targeted AUC’s

34. 34
What About?
• Critical Dose Drugs
• Narrow Therapeutic Range Drugs
• Bio Problem Drugs (South African Medical Controls)

35. 35
Current FDA Approach for NTI

36. 36
Advisory Committee for Pharmaceutical
Science and Clinical Pharmacology
• In the 2010 meeting, the committee recommended that the agency
should develop a list of NTIDs with clear, specialized criteria for
including drugs on the list. The list should be made public by the FDA
and clearly define the mechanism for addition to the list, the list
should be dynamic and constantly monitored and the list should focus
on BE issues. Furthermore, the committee made a list of suggestions
including ‘replication studies are important’ and ‘the requirements for
confidence intervals should perhaps be narrower (90.00–111.11 %)
and should include 100 % (or 1.0)’
– https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteefor
PharmaceuticalScienceandClinicalPharmacology/ucm201700.htm
• In the 2011 meeting, the FDA recommended for NTIDs to conduct a
four-way, two-sequence, fully replicated crossover design to assess
the within-subject variability of both the test and reference products
and to use the reference-scaled average BE approach for the statistical
comparison of the relevant PK parameters
– https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteefor
PharmaceuticalScienceandClinicalPharmacology/ucm240583.htm
Tamargo J, et. al. “Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide” Eur J Clin Pharmacol. 2015; 71(5): 549–567.

37. 37
Varying Definitions
Tamargo J, et. al. “Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide” Eur J Clin Pharmacol. 2015; 71(5): 549–567.
*
*Recommended by Advisory Committee for Pharmaceutical Science and Clinical Pharmacology but NOT adopted

38. 38
Warfarin Product Specific Guidance
Draft (2012)

39. 39
• A problem with this topic is that there is not a universally
accepted definition of what a Critical Dose Drug or Narrow
Therapeutic Index drug is.
• Lists can be prepared, but a common theme of all drugs on
the list is the routine inclusion of either pharmacodynamic
or pharmacokinetic monitoring.
– At the current time the FDA has not chosen to produce a list of such
drugs nor to establish a narrower confidence interval criteria.
• The FDA views these on a case by case basis and has
regulatory flexibility in the regulations to address this
relatively small group of drugs

40. 40
PRODUCT SPECIFIC RESOURCES

41. 41
Where Can I Get GUIDANCE?
• FDA Publishes the “Orange Book” Approved Drug
Products with Therapeutic Equivalence Evaluations

42. 42
FDA Guidance (Drugs)

44. 44
What & Where to Measure
What is needed
Study Design
Test to Use
Individual Guidance

45. 45
CONCLUSIONS

46. 46
Bioequivalence Testing
• Bioequivalence testing is designed to and is part of an overall
system of assurance that the pharmaceuticals we
manufacture and use are of the highest quality.
• The policies in place in in the United States represent almost
40yrs of institutional practice and evaluation of data.
• Prescribability and Switchability while related are different
considerations of sameness and consistency.

47. 47
Study Design
• Bioequivalence testing is done under conditions to
minimize the variability present in the study
– Healthy subjects
– Adults
– Cross-over design
– Suitable number of subjects
• Special study designs and endpoints (partial AUC)
have been adopted by guidance on an as needed
basis by the US FDA

48. 48
Conclusions
• The FDA communicates with stakeholders thru a variety of
mechanisms
– FDA Sponsored Advisory Committee Meetings
– FDA Authored Publications
– FDA Issued Guidances
– FDA Participation at National and International Meetings
– FDA Individual Company Meetings
• Communication with the FDA is important in assuring a
quality drug supply

49. 49
Regulation and Regulatory Science is
Everyone’s Business

50. 50
Acknowledgements
• The Staff of the Division of Clinical Pharmacology-3
• The Office of Clinical Pharmacology
• The Office of Translational Sciences
• The International and Chinese Society for the
Study of Xenobiotics

51. 51
Contact Information
CAPT Edward D. Bashaw, PharmD.
Director, Div. of Clinical Pharmacology-3
US FDA
10903 New Hampshire Ave
Building 51, Rm 3134
Edward.Bashaw@fda.hhs.gov