the riddle of bioavailability assessment of locally acting final (1)

The Riddle of Bioavailability Assessment of Locally Acting Drug

Products in the Gastrointestinal Tract

2016 AAPS WorkshopCAPT E. Dennis Bashaw, Pharm.D.

Division of Clinical Pharmacology-3OCP/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 RegulationsChapter 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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LUBIPROSTONECase 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


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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-mediaMulti-Point Dissolution

Fed BE Study with PK

Endpoints

Fed BE Study with PK

Endpoints

BE Study with Clinical Endpoints

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LINACLOTIDECase 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


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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


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Clinical Pharmacology


• 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 BOOKListed 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

32www.fda.gov/downloads/scienceresearch/specialtopics/regulatoryscience/ucm268225.pdf

Regulatory ScienceScience of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of FDA- regulated products

VisionFDA 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 Security8. 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

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Academia

IndustryInternational Collaboration

PatientAdvocacy

RegulatoryScience

BenefitsTo All

Good Science is Everybody’s Business!

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Contact Information

CAPT Edward D. Bashaw, PharmD.Director, Div. of Clinical Pharmacology-3US FDA10903 New Hampshire AveBuilding 51, Rm [email protected]

THE FDA IS HIRING!

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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

the riddle of bioavailability assessment of locally acting final (1)

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