This document summarizes a presentation given by CAPT E. Dennis Bashaw on the regulatory basis and evolving standards for assessing locally acting drug products through bioequivalence testing. It discusses challenges with early approaches relying on clinical endpoints and how regulatory thinking has evolved with advances in analytical methods. Case studies on lubiprostone and linaclotide illustrate this evolution. The presentation outlines FDA's holistic approach considering multiple factors like dissolution testing and targeted PK parameters. It emphasizes the importance of regulatory science and collaboration to develop safe, effective generic drugs.

1. The Riddle of Bioavailability
Assessment of Locally Acting Drug
Products in the Gastrointestinal Tract
2016 AAPS Workshop
CAPT E. Dennis Bashaw, Pharm.D.
Division of Clinical Pharmacology-3
OCP/OTS

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Disclaimer: 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 or
software may be given to illustrate a
methodology or approach to problem
solving in drug development. No
commercial endorsement is implied or
intended.
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Outline
• Regulatory Basis of Bioequivalence Testing
• ”Paleoregulatory” & Evolving Thoughts
• Case Studies
– Lubiprostone
• Parent Undetectable-Metabolite Detectable
– Lincolatide
• Neither Parent or Metabolite Detectable
• The Future
• Conclusion

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REGULATORY BASIS OF
BIOEQUIVALENCE TESTING

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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.

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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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BE Studies With Clinical Endpoints
• 3-arm comparative trials of 505(b)(2) or generic vs.
reference listed drug (RLD) vs. placebo
• Treatment of an approved indication in a patient
population according to the labeled dosing of the RLD.
• Trial design and endpoints similar to standard (b)(1)
NDA
• Both test and RLD must be statistically superior to
placebo (p<0.05) in order to assure that the study is
sensitive enough to show a difference between
products.
• Same established BE requirements as for other types
of BE studies

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PALEOREGULATORY &
EVOLVING THOUGHTS

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Locally Acting Drug Review
“Paleoregulatory”
 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”
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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

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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

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Ongoing Concern by FDA

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FDA Continued Dialog on Standards

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The Same Questions We Ask Today
In Setting Standards and Guidance's

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Evolved Regulatory Thought

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Bioavailability Testing and
Analytical Limit of Detection
ng/mL
mcg/mL
pg/mL
fg/mL
10-6g
10-9g
10-15g
10-12g

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LUBIPROSTONE
Case Study #1 (Metabolite-No Parent)
By Fvasconcellos - Own work, Public Domain,
https://commons.wikimedia.org/w/index.php?curid=1448674

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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

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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

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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

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PK Profile of M3 Lubiprostone

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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

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LINACLOTIDE
Case Study #2-(Parent only)
By Vaccinationist - Own work, Public Domain,
https://commons.wikimedia.org/w/index.php?curid=23407171

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Linaclotide Overview
• Linaclotide is a 14-amino acid, guanylate cyclase C (GC-
C) receptor agonist structurally related to the
endogenous guanylin peptide family.
– This peptide family is involved in the regulation of intestinal
fluid homeostasis and bowel function. Activation of the GC-C
receptor increases GI secretion and transit
• It is approved for the treatment of
– Chronic Idiopathic Constipation (CIC)
– IBS-constipation in adults.
• It was approved in 2012

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NDA Study Package
• IBS-C Clinical Package
– 808 patients received active drug in two safety and
efficacy trials. 799 received placebo
• 290mcg
• Chronic Idiopathic Constipation
– 848 patients in two safety and efficacy trials received
active drug. 423 received placebo
• 145mcg or 290mcg
https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist

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Clinical Pharmacology Studies
• 30 subjects in a single oral ascending dose trial
– Subjects received a single dose of either 30, 100, 300,
1000, or 3000mcg of linaclotide
• 32 subjects in a multiple dose trial (7 days)
– 8 subjects received either 30, 100, 300, or 1000mcg of
linaclotide
• 18 subjects in a food effect trial
– 300mcg once daily for seven days fasted
– 300mcg once daily for seven days fed (high fat diet)
– 3000mcg as a single dose at the conclusion of the trial
https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist

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Clinical Pharmacology
https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist
• Following doses 10x the
approved clinical dose, only
two subjects showed 1-2
positive samples for
linaclotide.
• In vitro digestion studies
showed that, as a peptide,
linaclotide was susceptible to
degradation by intestinal
fluids.

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FDA Bioequivalence Guidance
for Linaclotide
Lincloatide has Marketing Exclusivity thru Aug. 2017 but has ORANGE BOOK
Listed patents running thru 2031.

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THE FUTURE

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

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www.fda.gov/downloads/scienceresearch/specialtopics/regulatoryscience/ucm268225.pdf
Regulatory Science
Science of developing new tools,
standards, and approaches to assess the
safety, efficacy, quality, and performance
of FDA- regulated products
Vision
FDA will advance regulatory science to
speed innovation, improve regulatory
decision- making, and get products to
people in need. 21st Century regulatory
science will be a driving force as FDA
works with diverse partners to protect
and promote the health of our nation and
the global community
Regulatory Science at the FDA

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2. Stimulate Innovation in Clinical Evaluations & Personalized
Medicine to Improve Product Development and Patient Outcomes
4. Ensure FDA Readiness to Evaluate Innovative Emerging
Technologies
6. Implement a New Prevention-Focused food Safety System
to
Protect Public Health
5. Harness Diverse Data Through Information Sciences to
Improve
Health Outcomes
7. Facilitate Development of medical Countermeasures to
Protect
Against Threats to U.S. and Global Health and Security
8. Strengthen Social and Behavorial Science to Help
Consumers
and Professionals Make Informed Decisions about Regulated
Products
1. Modernize Toxicology to Enhance Product
Safety
3. Support New Approaches to Improve Product Manufacturing
and Quality
Science Priority Areas

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FY 14 GDUFA
Regulatory Research Priorities
• FDA’s regulatory science priorities for generic drugs will be
– Post-market Evaluation of Generic Drugs
– Equivalence of Complex Products
– Equivalence of Locally Acting Products
– Therapeutic Equivalence Evaluation and Standards
– Computational and Analytical Tools
http://www.fda.gov/drugs/newsevents/ucm367997.htm
“The lack of efficient bioequivalence methods for locally acting drugs has limited the
availability of generic drugs in this category. Equivalence of Locally Acting Products
includes research into new bioequivalence (BE) methods and pathways for local
acting drugs. Product categories in priority order are inhalation, topical
dermatological, nasal, GI acting, ophthalmic and otic products. This priority includes
re-evaluation of some statistical methodologies for topical product adhesion and
irritation, and investigation of alternatives to clinical endpoint bioequivalence
studies.”

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

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Luminal Sampling
“For drugs delivered as modified release
formulations it is important to consider solubility in
different regions of the gut as significant differences
can arise which will ultimately influence drug
bioavailability. Stoma fluids provide useful
information on drug solubility and are more
reflective of in ViVo than compendia buffers that are
typically used. However, due to their variability and
the multitude of factors they are influenced by, they
are not fully representative of GI luminal fluids.”
VOL. 7, NO. 5, 1527–1532 MOLECULAR PHARMACEUTICS

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FDA Sponsored Research
on Luminal Sampling

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Conclusion
• The FDA has a clear “SCIENCE BASED” regulatory standard
• The standard has evolved and changed as technology
(bioanalytical methods) have advanced
• BE studies with clinical endpoints have their place, but where
possible a “holistic” approach leveraging all available knowledge
must be used to lessen the regulatory burden while enhancing
our ability to detect formulations that are truly different
• The FDA uses a variety of tools to communicate both policies
and to invite scientific discourse on standards
– Advisory Committee meetings
– Publications
– Meeting Attendance
– Sponsored Research

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Development of Safe and Effective
Drugs For ALL Requires a Team Effort
39
Academia
Industry
International
Collaboration
Patient
Advocacy
Regulatory
Science
Benefits
To All
Good Science is Everybody’s Business!

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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

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Acknowledgements
• The Staff of the Division of Clinical Pharmacology-3
• The Office of Clinical Pharmacology
• The Office of Translational Sciences
• American Association of Pharmaceutical Sciences