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Risk Based Review and the Management of Residual Uncertainty in the Regulation of Biological Products; J Baker, CDER/FDA, IFPAC 2015

Risk Based Review and the Management of

Residual Uncertainty in the Regulation of

Biological Products

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Jeffrey C. Baker, Ph.D.

Deputy Director,

Office of Biotechnology Products, CDER

IFPAC 2015

January 26, 2015, Arlington VA

Risk Based Review and the Management of Residual Uncertainty in the Regulation of Biological Products; J Baker, CDER/FDA, IFPAC 2015 2

The Disclaimer

This presentation represents the views and perspectives of the speaker and should not be viewed or acted upon as FDA Policy or assumed to be an all inclusive list of FDA requirements.

For official policy and guidance, contributors are directed to http://www.fda.gov/

The speaker may be contacted at [email protected]

http://www.fda.gov/


“Management of Residual Uncertainty”


“The reason I like the game chess is because each move has countless

repercussions, but you're in charge of them. And it's your ability to see into the

future and the effects of the decisions you've made that makes you either a good or

not a good chess player. It's not luck.” ---Bono


Regulation of biological products in the US

Biological products are a subset of drugs and are therefore regulated under the Food, Drug, & Cosmetic Act.

Biological products are licensed for marketing in the United States under section 351 of the Public Health Service (PHS) Act using a Biologics License Application (BLA) .

The PHS Act also provides authority to immediately suspend licenses in situations where there exists a danger to public health.

http://en.wikipedia.org/wiki/File:Great_Seal_of_the_United_States_(obverse).svg


Definition: Biological Product

BPCI Act of 2009 revises the definition of “biological product” in the Public Health Service Act (PHS Act) to include “protein”:

. . . a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product … applicable to the prevention, treatment, or cure of a disease or condition of human beings …

Historically, some proteins have been approved as drugs under section 505 of the FD&C Act (e.g., human growth hormone), and other proteins have been licensed as biologics under section 351 of the PHS Act (e.g., blood factors).

An application for a “biological product” must be submitted under section 351 of the PHS Act, subject to certain exceptions during the 10-year transition period that ends March 23, 2020.


FDA has developed the following interpretation of the statutory terms “Protein” and “Chemically synthesized polypeptide.”

Protein: Any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size

Chemically synthesized polypeptide: Any alpha amino acid polymer that is made entirely by chemical synthesis; and is less than 100 amino acids in size.


Who reviews and approves BLAs?

BLAs may be submitted to either the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER)

CDER reviews applications monoclonal antibodies, therapeutic proteins extracted from plant, animals, or micro-organisms including recombinant versions of the proteins, and non-vaccine immuno-modulators.

CBER reviews allergenics, blood product, vaccines, gene therapies, xenotransplantation products, and devices used to collect and safeguard blood and blood products.


A BLA is a scientific, data driven assertion that

The drug is safe.

The drug is pure.

The drug is potent.

The process and facilities used to manufacture safe, pure, and potent drug are very likely to

do so reproducibly and predictably.


“ I am the best player in the world and I am here to prove it.”

-- Bobby Fischer

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A BLA submission is an exercise in technical advocacy!


Quality

Systems

Sound Science and Effective Engineering

Lab

Data

Pilot

Data

Site

Mfg

Data

Development

Program

Tech Transfer

Package

Validation

Master Plan

The Process Flow Document

Assurance of Predictable, High

Quality Product and Process

“Architecture of Assurance”


“You sit at the board and suddenly

your heart leaps. Your hand trembles

to pick up the piece and move it.

But what chess teaches you is that

you must sit there calmly and think

about whether it’s really a good

idea and whether there are other,

better ideas.”

--Stanley Kubrick

Choices


Discovery

Decision Phase

Development

Commercial

Development

Building Start-Up

and Launch

Continuous Learning

and Improvement

“In the opening a master should play like a book, in the mid-game he should play like a magician, in the ending he should play like a machine.” --Usually attributed to Rudolph Spielman but actually a

misquote by Spielman of Irving Chernev


In order to improve your game, you must study the endgame before everything else. For whereas the endings can be studied and mastered by themselves, the middle game and opening must be studied in relation to the end game.

-- Jose Raul Capablanca

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While the goal (safe, effective, reproducible) remains the same there are several different styles of “end game” in the development of biopharmaceuticals.

Accelerated Approval

Fast Track Review

Priority Review

Abbreviated Pathway for Biologics

Breakthrough Status

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The decision to expedite a development program is exclusively a clinical decision, based upon seriousness of the disease, unmet medical need, and availability of therapy.

Copies are available from: Office of Communications Division of Drug Information, WO51, Room 2201 Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave., Silver Spring, MD 20993 Phone: 301-796-3400; Fax: 301-847-8714 [email protected] http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm



The FDA Accelerated Review Program was initiated in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need.

Authorized under 21CFR .314(h), 21CFR 601(c), and Section 506(c) of the FD&C Act

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A drug that treats a serious condition AND generally provides meaningful advantage over available therapies AND demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or Clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, reasonably likely to predict an effect

Takes into account severity, rarity or prevalence of the condition and availability or lack of alternative treatments and sponsors must agree to conduct post-marketing confirmatory trials

Must meet the same statutory standard for safety, effectiveness, and assurance of drug quality.

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Priority Review

Drug that treats a serious condition and if approved would provide significant improvement in safety and effectiveness

FDA evaluates every original application for priority review designation.

Sponsor can request priority review FDA grants priority review within 60 days of submission

Shortens the review timeline specified by PDUFA from 10 to 6 months

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Fast Track Review

Drug that treats a serious condition

Demonstrate potential to address unmet medical need

Expedite development and review

Frequent interaction with review team

Potential Priority review

Rolling submission to the BLA review

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The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) is a recent and significant revision of the PHS Act and was passed as part of the Affordable Care Act that President Obama signed into law on March 23, 2010.

BPCI Act creates an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product.

A Special Endgame for Biologics…


“Chess problems demand from the composer the same virtues that characterize all worthwhile art: originality, invention, conciseness, harmony, complexity, and splendid insincerity."

-- Vladimir Nabokov


What is an Abbreviated Licensure Pathway for Biological Products?

A biological product that is demonstrated to be “highly similar” to an FDA-licensed biological product (the reference product) may rely for licensure on certain existing scientific knowledge about the safety, purity, and potency of the reference product.

This new licensure pathway under section 351(k) of the PHS Act permits a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data

There is no abbreviated licensure pathway for related biological products not intended to be biosimilar.


Biosimilar or biosimilarity is defined in Section 351 of the PHS Act to mean that “the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components,” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product”*.

*Section 7002(b)(2) of the Affordable Care Act, amending section 351(i) of

the PHS Act.

Definition: Biosimilarity


Clinically Meaningful Differences

Clinically meaningful differences could include differences in the expected range of safety, purity, and potency of the proposed and reference product.

By contrast, slight differences in rates of occurrence of adverse events between the two products ordinarily would not be considered clinically meaningful differences.


Clinical

Animal

Studies

Clinical

Immunogenicity

Clinical Knowledge

e.g. Post-Market Experience

Human Pharmacokinetics

and Pharmacodynamics (PK/PD)

Structural and Functional

Characterization

“Totality of the Evidence” in the evaluation of biosimilars

No “one size fits all” assessment :

FDA scientists will evaluate the applicant’s integration of various types of information to provide an overall assessment that a biological product is biosimilar to an approved reference product.


Development Framework: Comparative Analytical Characterization Continuum

Cannot be biosimilar

Similar

Needs additional information to determine if highly similar (e.g., additional analytical data, or other studies to determine if minor differences are “clinically inactive components”)

Highly similar

Permits a selective and targeted approach to determine if biosimilar

Highly similar with fingerprint-like similarity

Permits a more selective and targeted approach to determine if

biosimilar


“Nothing excites jaded Grandmasters more than a theoretical novelty.”

– Dominic Lawson, author of “The Inner Game”


Food and Drug Administration Safety and Innovation Act (FDASIA) signed into law July 9, 2012

Title I Prescription Drug User Fee Amendments of 2012

Title II Medical Device User Fee Amendments of 2012

Title III Generic Drug User Fee Amendments of 2012

Title IV Biosimilar User Fee Act of 2012

Title V Pediatric Drugs and Devices

Title VI Medical Device Regulatory Improvements

Title VII Drug Supply Chain

Title VIII Generating Antibiotic Incentives Now

Title IX Drug Approval and Patient Access

Title X Drug Shortages

Title XI Other Provisions

For more information and the full text of FDASIA visit Regulatory Information : Legislation

at www.fda.gov

2/26/2015Next Steps in Developing the Nation’s Biosimilars Program Recovery of Biological Products XV, July 29, 2012, J.C. Baker, CDER FDA


Criteria Serious Condition

Preliminary clinical evidence-clinical comparison (e.g., head-to-head, add-on, historical controls) demonstrates substantial improvement over available therapy on one or more clinically significant endpoints

The request for breakthrough designation is submitted during IND, ideally no later than end-of-Phase 2 and FDA will respond within 60 days of receipt of request

Features

FDA may grant Priority review ; Sponsor may request fast track designation

“All Hands on Deck” mentally for FDA review team and sponsor

Work to design most efficient and effective development program to confirm benefit and support approval (if warranted by the later data)

Strong organizational commitment from CDER to success of program

Early and sustained attention to expediting development of manufacturing process to support timely approval

From FDASIA Title IX: Breakthrough Therapy Designation


“Strong Organizational Commitment”

Increased involvement of senior managers Division Directors, Office Directors, Center leadership where appropriate

Experienced review staff

Cross Disciplinary Team Leader Scientific liaison within the review team

Coordinates internal and external communication in collaboration with the Regulatory Project Manager

Increased frequency of meetings and communications

Advice to facilitate an efficient development program

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Copies are available from: Office of Communications Division of Drug Information, WO51, Room 2201 Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave., Silver Spring, MD 20993 Phone: 301-796-3400; Fax: 301-847-8714 [email protected] http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm


Excerpt from the draft guidance

IX. GENERAL CONSIDERATIONS

A. Manufacturing and Product Quality Considerations

When sponsors receive an expedited drug development designation, they should be prepared to propose a commercial manufacturing program that will ensure availability of quality product at the time of approval. The proposal should consider estimated market demand and the commercial manufacturing development plan, especially with regard to manufacturing facilities, lifecycle process validation (including scale-up and comparability), methods validation, stability studies, and potency studies if applicable. The proposal should also include a timeline for development of the manufacturing capabilities with goals aligned with the clinical development program. The applicant should ensure that the manufacturing process is sufficiently developed in order to support the CMC section.

Excerpt from Draft Guidance for Industry “Expedited Programs for Serious Conditions– Drugs and Biologics, June 2013, http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

Contains non binding recommendations, Draft not for implementation; Italics are added for purposes of this presentation


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Status of product and process development programs

Plans for specifying the control strategies should consider:

CQAs for product and process intermediates

Process controls including intermediate and release testing

Container closure system

Linkages tracking process, formulation, and presentation changes throughout development

Assessment of stability data

Risk based analysis of failure modes and residual uncertainty

“…propose a commercial manufacturing program that will

ensure availability of quality product at the time of approval”


The proposed commercial manufacturing program should include anticipated commercial operations

Site sourcing and facilities issues for manufacturing, testing, and supply chain management

Scale up, bridging, or comparability exercises

Life cycle process validation plan

Role of the Production Quality Management System

Availability of product at time of launch

Plans for assurance of market supply

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“Openings teach you openings. Endgames teach you chess!” -- Stephan Gerzadowicz

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“Chess teaches foresight, by having to plan

ahead; vigilance, by having to keep watch

over the whole chess board; caution, by

having to restrain ourselves from making

hasty moves; and finally, we learn from chess the greatest maxim in life -

that even when everything seems to be going badly for us we should not

lose heart, but always hoping for a change for the better, steadfastly

continue searching for the solutions to our problems.” -- Benjamin Franklin

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