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Lawrence Yu, Ph.D. Director (acting), Office of Pharmaceutical Science FDA Center for Drug Evaluation and Research

GDUFA:

Evolving Quality Assessment

October 28, 2014

CDER Director Dr. Janet Woodcock’s Announcement on September 6, 2012

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I want to inform you about some important proposed organizational changes for

CDER... Quality is the underpinning of everything we do, and it is imperative

that we have a drug quality program as robust as those programs we presently

have for drug efficacy and drug safety.

Further, we must be strategic and have systems in place to identify and

respond to quality issues before they become problems. This is especially

critical due to the global nature of drug manufacturing and the sourcing of raw

materials outside of the United States.

Toward these goals and underscoring our commitment to drug quality, we will

be exploring the creation of a new Office of Pharmaceutical Quality (OPQ),

which would be charged with overseeing quality throughout the life cycle of a

drug…

CDER Director Dr. Janet Woodcock’s Announcement on October 16, 2014

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The new structure, to be stood up on January 5, 2015, is expected to provide

better alignment among all drug quality functions at CDER, including review,

inspection, and research…

Office of Pharmaceutical Quality (OPQ)

OPQ will combine non-enforcement-related drug quality work into one super-

office, creating “one quality voice” and improving our oversight of quality

throughout the lifecycle of a drug product. This office will provide internal

customers with a single drug quality assessment that captures the overall OPQ

recommendation on approvability, and OPQ will provide feedback on quality

deficiencies earlier in the review cycle. OPQ’s structure provides for centralized

functions for administrative activities, project management, training, quality

management systems, and policy. OPQ creates a uniform drug quality program

across all sites of manufacture, whether domestic or foreign, and across all

drug product areas – new drugs, biotechnology products, biosimilars, generic

drugs, and over-the-counter drugs…

“One Quality Voice”

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One Quality Voice for Drugs: OPQ will centralize quality drug review — creating one quality voice by integrating quality review, quality evaluation, and inspection across the product lifecycle. One Quality Voice for Patients: OPQ will assure that quality medicines are available for the American public. One Quality Voice for Industry: OPQ will establish consistent quality standards and clear expectations for industry. One Quality Voice for Health Care Professionals: OPQ will anticipate quality problems before they develop and help prevent drug shortages. One Quality Voice for Health Care Purchasers: OPQ will emphasize quality metrics.

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Mission

The Office of Pharmaceutical Quality assures that quality medicines are

available to the American public

Vision

The Office of Pharmaceutical Quality will be a global benchmark for regulation

of pharmaceutical quality

CDER OPQ

One Quality Voice

OPQ: One Quality Voice Value Statements

• Put patients first by balancing risk and availability

• Have one quality voice by integrating review and inspection across product lifecycle

• Safeguard clinical performance by establishing scientifically-sound quality standards

• Maximize focus and efficiency by applying risk-based approaches

• Strengthen the effectiveness of lifecycle quality evaluations by using team-based processes

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OPQ: One Quality Voice Value Statements (cont.)

• Enhance quality regulation by developing and utilizing staff expertise

• Encourage innovation by advancing new technology and manufacturing science

• Provide effective leadership by emphasizing cross-disciplinary interaction, shared accountability, and joint problem solving

• Build collaborative relationships by communicating openly, honestly, and directly

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OPQ: Organizing Principles of Change

• Same quality standards for all drugs; lifecycle approach

– Clinically relevant specifications

• Unified policy and standards development/analysis

• Establish clear standards for review and inspection

– Clear enforcement policies

– Surveillance using quantitative metrics

• Specialization and team review: integration of review and inspection for a quality assessment

• Accountability: Overall QMS and evaluation system

Office of Pharmaceutical Quality

Office of Program and Regulatory Operations

Acting Director: Giuseppe Randazzo

Immediate Office Acting Director: Janet Woodcock

Deputy Director: Lawrence Yu

Office of Policy for Pharmaceutical Quality

Acting Director: Ashley Boam

Office of Lifecycle Drug Products

Acting Director: Susan Rosencrance

Office of Process and Facilities

Acting Director: Christine Moore

Office of New Drug Products

Acting Director: Sarah Pope Miksinski

Office of Surveillance

Acting Director: Theresa Mullin

Office of Biotechno-logy Products

Director: Steven Kozlowski

Office of Testing and Research

Acting Director: Lucinda Buhse

Generic Quality Assessment in OPQ

Office of Program and Regulatory Operations

Acting Director: Giuseppe Randazzo

Immediate Office Acting Director: Janet Woodcock

Deputy Director: Lawrence Yu

Office of Policy for Pharmaceutical Quality

Acting Director: Ashley Boam

Office of Lifecycle Drug Products

Acting Director: Susan Rosencrance

Office of Process and Facilities

Acting Director: Christine Moore

Office of New Drug Products

Acting Director: Sarah Pope Miksinski

Office of Surveillance

Acting Director: Theresa Mullin

Office of Biotechno-logy Products

Director: Steven Kozlowski

Office of Testing and Research

Acting Director: Lucinda Buhse

Team-based Integrated Quality Assessment (IQA)

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The Office of Pharmaceutical Quality (OPQ) will use a team-based Integrated Quality Assessment (IQA) approach to maximize each team member’s expertise and provide aligned patient-focused and risk-based drug product quality recommendations, inclusive of drug substance, drug product, manufacturing, and facilities.

Therefore…

OPQ teams will be expected to work in a highly collaborative model Teams will be expected to collaborate effectively within GDUFA timelines

Collaborations/discussions should involve key stakeholders Communication/discussion of quality risk and link to the patient are critical

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• Adopting a formal risk management approach to quality assessment enable us to:

– Best focus assessment and allocate resources based on product risk, facility risk, and patient impact

– Produce more effective and consistent risk-based recommendations

– Help us strategize and work smart to ensure review timelines under PDUFA, GDUFA, and BsUFA

Science and Risk-based Approaches

Surveillance on Product Quality

• Understand how products and firms perform over lifecycle

– Assess and make quality visible and impactful—for entire inventory of drug manufacturing facilities supplying US market

• Product quality platform

• Quality metrics

– Product

– Site

– Quality System

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Advanced Manufacturing and Emerging Technology

• Advanced manufacturing

– Continuous process

• FDA CDER Emerging Technology Team

– Encourage and support the adoption of innovative technology to modernize manufacturing of pharmaceuticals and develop innovative delivery systems using an operational strategy that assures product quality over the lifecycle

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FY 2013 FY 2014 FY 2015 FY 2016 FY 2017

Original ANDA Expedite review of

paragraph IV and maintain pre-GDUFA productivity

60% in 15 months

75% in 15 months

90% in 10 months

Tier 1 first major amendment 60% in 10

months 75% in 10

months 90% in 10

months

Tier 1 minor amendments (1st – 3rd) 60% in 3 months*

75% in 3 months*

90% in 3 months*

Tier 1 minor amendments (4th – 5th) 60% in 6 months*

75% in 6 months*

90% in 6 months*

Tier 2 amendment 60% in 12

months 75% in 12

months 90% in 12

months

Prior approval supplements 60% in 6 months*

75% in 6 months*

90% in 6 months*

ANDA, amendment, and PAS in backlog on Oct 1st, 2012

Controlled correspondences 70% in four

months**

70% in two months**

90% in two months**

*10 months if inspection required

Maintain pre-GDUFA productivity

Maintain pre-GDUFA productivity

Maintain pre-GDUFA productivity

Maintain pre-GDUFA productivity

Maintain pre-GDUFA productivity

Act on 90% by end of FY 2017

Maintain pre-GDUFA levels

GDUFA Review Performance Goals

** One additional month added to goal if clinical division input required

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FDA is Receiving Many More ANDAs than GDUFA Predicted

Prepared by Glen Smith

• How does quality assessment meet the 10-month review cycle for 90% of ANDAs by Year 5 of GDUFA?

• How do we eliminate the backlog within 5 years?

• How can we enhance the efficiency and effectiveness of the quality assessment process while ensuring the patient receives quality generics?

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Team-based integrated quality assessment with focus on patient, science, and risk

Pre-GDUFA Pending Chemistry PAS Supplements…A CDER Priority

Starting backlog = 847 PAS supplements

149

48 28

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Pre-GDUFA Pending Chemistry CBE Supplements…A CDER Priority

Starting backlog = 2695 CBE supplements

1113

1295

899

650

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GDUFA Total Pending Chemistry Supplement…A CDER Priority

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GDUFA Total Chemistry ANDA Productivity…A CDER Priority

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GDUFA Total Pending Chemistry ANDAs…A CDER Priority

GDUFA Micro…A CDER Priority

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Parity: Are We There Yet?

• First cycle approval for quality assessment of generic drug is 1.4%

• First cycle approval for new drugs is 89%

• New Initiatives: 1. Enhance communication with applicants to reduce the ‘back

and forth’ formal communications and number of cycles to ANDA approval

2. Maximize review efficiency and consistency by assigning multiple ANDAs referencing a single listed drug to one team or group of reviewers

Block/Cluster Review

Real-Time Communication

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Block/Cluster Review

• Group or ‘Block’ CMC review assignments within one team of reviewers

– When multiple ANDAs reference a single Reference Listed Drug (RLD)

– When multiple ANDAs reference the same Drug Master File (DMF) for the drug substance

– Triggered by 3 or more ANDAs/DMFs

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Block/Cluster Review

• Benefits of Block/Cluster Review:

– Expertise is focused, accelerating the review process

– Eliminates the need to ‘relearn’

– Promotes communication and information sharing among reviewers for consistency and improved decision making

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Number of Cycles to ANDA Approval

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Real-Time Communication

• A system that promotes review cycles is inherently inefficient and ineffective

• The No.1 goal is timely ANDA approvals of ‘quality’ generic products for the public

• Need more communication with industry to resolve little issues in real-time

• Reduces the number of review cycles and promotes more timely ANDA approvals

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Real-Time Communication

• CMC redefining the communication of deficiencies and amendments in an effort to reduce review cycles

• Promoting real-time communication with industry to address minor deficiencies and information requests without generating review cycles

• OPS SOP 2501: Process for Issuing Deficiencies and Information Requests for Generic Drug Chemistry Review (real time communication), September 18, 2014

• Driving the process towards a more efficient 1-cycle review system that yields timely ANDA approvals of ‘quality’ generic drugs.

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Real-Time Communication

Chemistry Adequate ANDA Approval

Big Issues?

ANDA

Issue Major CR

Encourages firms to get it right the first time;

Long term impact of raising submission quality

Until the Target Review Date (TRD)

Real-Time Communication

YES

NO

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In Summary

• OPQ: One Quality Voice – Puts patients first

– Team-based integrated quality assessment with focus on patient, science, and risk

• Generic drug review has made significant progress toward GDUFA goals

• GDUFA has meant substantial program and process changes for both FDA and industry – a huge effort!