Current State of the Art with Product Performance Tools: A Regulatory Perspective

Dialog and DebateAAPS Annual Meeting 2016

CAPT E. Dennis Bashaw, Pharm.D.Division of Clinical Pharmacology-3

OCP/OTS/US FDA

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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 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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BALANCING REGULATIONS WITH NEED

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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.

• (5) A currently available in vitro test acceptable to FDA (usually a dissolution rate test) that ensures human in vivo bioavailability.

• (6) Any other approach deemed adequate by FDA to measure bioavailability or establish bioequivalence.

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Role of the Regulator

• Ultimately it is the reproducibility of product performance testing between clinically studied and production lots that the regulator is concerned about.• We are not focusing exclusively on generic drugs,

as both 505(b)(1) and 505(b)(2) applications can utilize these tools for formulation changes once the are properly documented and accepted by the Agency.

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Regulator

Regulations

ScienceConservative Innovation

ClinicalPharmacology

The FDA’s “DUAL” Role

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Quo Vadis?

• Are alternative assessment methods DOA at the FDA?

• Will the FDA give innovative ideas a hearing?

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LUBIPROSTONECase Study (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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Then vs. Now

• Historically for poorly bioavailable, locally acting GI drugs all reformulations, (b)(2), and ANDAs were handled via in vivo bioequivalence studies with clinical endpoints (ie., a clinical study).

• The development of refined analytical methods with increased lower limits of quantification have allowed us to detect the time course of absorption.

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PK Profile of M3 Lubiprostone

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“Totality of Evidence”

• For locally acting GI Drugs, PK data alone does not give us sufficient assurance of equivalent therapeutic response.

• Bioavailabilty is defined as “…drug concentration at the SITE of action…”– To be effective the drug must be delivered at the SITE of action

• Time course of release in vivo• Time course of release in vitro with regards to pH profile

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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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WHY ARE THERE NOT MORE PRODUCT PERFORMANCE TOOLS/EXAMPLES?

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"The fault, dear Brutus, is not in our stars,But in ourselves, that we are underlings."

CassiusJulius Caesar (I, ii, 140-141)

TRANSLATION -The FDA cannot accept them if they are not done!

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General Test Characteristics

Well defined proceduresValidationStandardized Training

Be reproducibleRun to RunSite to Site

Be predictable Be relevant clinically

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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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Product Performance ToolsDebate and Dialog

• Product Performance Tools have many definitions and can take many shapes.

• Traditionally used for complex drug substances where traditional methods may not be adequate or desirable

• Best viewed in the “totality of evidence mode”– Can we assure “sameness”, “bioequivalence”, and “therapeutic

equivalence” and if so to what level?• Moving beyond the “Casablanca Standard”

“You know it when you see it”

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Contact Information

CAPT Edward D. Bashaw, PharmD.Director, Div. of Clinical Pharmacology-3US FDA10903 New Hampshire AveBuilding 51, Rm 3134Edward.Bashaw@fda.hhs.gov

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