Critical Path Initiative: Challenges and Opportunities

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Critical Path Initiative Challenges and
Opportunities

• Ajaz S. Hussain, Ph.D.
• Deputy Director, Office of Pharmaceutical
  Science, CDER, FDA
• 19 October 2004 ACPS Meeting

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CDER Goals 2005
State of CDER 2004 Steven Galson Doug
Throckmorton October 6, 2004
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What is Critical Path?

• A serious attempt to examine and improve the
  techniques and methods used to evaluate the
  safety, efficacy and quality of medical products
  as they move from product selection and design to
  mass manufacture.

State of CDER 2004 Steven Galson Doug
Throckmorton October 6, 2004
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Translational Research
Critical Path Initiative
March 2004 www.fda.gov/oc/initiatives/criticalpat
h/whitepaper.pdf
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Critical Path Document (March 2004)

• The drug development process the critical
  path, is becoming a serious bottleneck to
  delivery of new medical products

State of CDER 2004 Steven Galson Doug
Throckmorton October 6, 2004
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RD Spending
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But, New Product Submissions Have Remained Flat
for NMEs submitted prior to 1992, type A and
type B applications are counted as Priority
review and type C applications are counted as
Standard review.
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Why FDA Concern?

• FDA Statutory Mission -- Not only to protect but
  also to advance public health by improving
  availability of safe and effective new medical
  products

State of CDER 2004 Steven Galson Doug
Throckmorton October 6, 2004
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FDA Has Unique Role in Addressing the Problem

• FDA scientists are involved in review during
  product development -- they see the successes,
  failures, and missed opportunities
• FDA not a competitor, can serve a crucial
  convening and coordinating role for consensus
  development between industry, academia and
  government
• FDA sets the standards that innovators must meet.
  New knowledge and applied science tools needed
  not only by innovators must also be
  incorporated into agency review

State of CDER 2004 Steven Galson Doug
Throckmorton October 6, 2004
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How to Proceed Science-Driven Shared Effort

• Drawing on available data, need to target
  specific, deliverable projects that will improve
  drug development efficiency
• Not just an FDA effort we can identify problems
  propose solutions solutions themselves
  require efforts of all stakeholders
• CMS, NIH, CDC
• Federal Register Notice requesting comments, Well
  over 100 written responses to date.

State of CDER 2004 Steven Galson Doug
Throckmorton October 6, 2004
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CDER/ FDA Next Steps on Critical Path

• HHS Medical Technologies Innovation Taskforce
  providing broad leadership
• Chaired by Dr. Crawford
• Includes CDC, CMS, NIH and FDA
• Work on addition funding.
• Meetings with external stakeholders to identify
  opportunities, enlist allies

State of CDER 2004 Steven Galson Doug
Throckmorton October 6, 2004
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Critical Path Summary

• Present state of drug development not sustainable
• FDA must lead effort to question any assumptions
  that limit or slow new product development
• Are they justified?
• Are there more efficient alternatives?
• If so, why are the alternatives not being
  utilized?

State of CDER 2004 Steven Galson Doug
Throckmorton October 6, 2004
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Three Dimensions of the Critical Path

• Assessment of Safety how to predict if a
  potential product will be harmful?
• Assessing Efficacy -- how to determine if a
  potential product will have medical benefit?
• Industrialization how to manufacture a product
  at commercial scale with consistently high
  quality?

State of CDER 2004 Steven Galson Doug
Throckmorton October 6, 2004
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Applied Science Needed to Better Evaluate and
Predict on 3 Key Dimensions on 'Critical Path' of
Development
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OPS Programs Critical Path Initiative

• The discussion today is to seek input and advise
  from ACPS on
• Aligning and prioritizing current OPS regulatory
  assessment and research programs
• Note that all research and laboratory programs
  are not intended to be focused on the Critical
  Path
• Identify gaps in the current programs
• Identify opportunities for addressing the needs
  identified by the Critical Path Initiative

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Planned Project in the OPS Immediate Office

• An immediate need is to ensure appropriate
  support
• Generic Drugs - the growing volume and complexity
  of applications
• New Drug Chemistry - their new paradigm for
  review assessment and efforts to support
  innovation and continuous improvement goals of
  the CGMP Initiative
• Biotechnology Products complete integration in
  OPS and the evolving concept of "Follow-on
  Protein Products
• Alignment of research programs in OPS

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OPS IO Critical Path Initiative Project Proposal

• To develop a common regulatory decision framework
  for addressing scientific uncertainty in the
  context of complexity of products and
  manufacturing processes in Offices of New Drug
  Chemistry, Biotechnology Products, and Generic
  Drugs

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Motivation

• Uncertainty (stochastic and epistemic) and
  complexity are two important elements of
  risk-based based regulatory decisions
• A common scientific framework, irrespective of
  the regulatory path or process for these
  products, will provide a basis for efficient and
  effective policy development and regulatory
  assessment to ensure timely availability of these
  products.

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Approach

• There are no good methods available for
  developing a standard approach for addressing
  uncertainty different approaches will be
  required in different assessment situations.
• Therefore, a decision framework for selecting an
  approach for addressing uncertainty over the life
  cycle of products is proposed.

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Project 1

• Create the "As Is" regulatory decision process
  map for ONDC, OBP, and OGD
• a representative sample of product applications
  will be selected for this mapping process

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Project 1 Steps

• Determine regulatory process efficiency and
  effectiveness (quality) using metrics similar to
  that of manufacturing process
• Identify and compare
• Critical regulatory review decision points and
  criteria
• Evaluate correlation and/or causal links between
  review process efficacy metrics and critical
  decisions criteria, and available information (in
  submissions), and
• Evaluate the role of reviewer training and
  experience

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Project 1 Steps (Contd.)

• Summarize available information on the selected
  products
• Collect and describe product and manufacturing
  process complexity, post-approval change history,
  and compliance history (including AER's)
• Describe product and process complexity and
  uncertainty with respect to
• Current scientific knowledge (mechanism of
  action, critical variables, analytical methods,
  failure modes, etc.)
• Information available in the submissions,
• Reviewer expert opinions and perceptions
• If feasible/possible, seek similar information
  from sponsor/company scientists on these same
  products

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Project 1 Deliverables

• Organize OPS Science Rounds to discuss and debate
  the "As Is" process map and the knowledge gained
• Identify "best regulatory practices" and
  opportunities for improvement
• Opportunities for improvement to include
  knowledge gaps
• Develop a research agenda for OPS laboratories
• Develop a common scientific vocabulary to
  describe uncertainty and complexity
• Develop an "ideal" scientific process map for
  addressing uncertainty and complexity
• Adapt the "ideal" scientific process map to
  different regulatory processes

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Project 2 Background

• Without a systems approach to the entire
  regulatory process from IND to NDA (BLA, ANDA)
  review and approval, to phase IV commitments and
  CGMP inspections, the broad FDA goals under the
  CGMP and the Critical Path Initiatives will not
  be optimally realized.

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Project 2 Background

• The team approach and systems perspective under
  the CGMP Initiative only addressed a part of the
  pharmaceutical system.
• Quality by design and process understanding to a
  large extent is achieved in a Research and
  Development organization.
• Pharmaceutical product development is a complex
  and a creative design process that involves many
  factors, many unknowns, many disciplines, many
  decision-makers, and has multiple iterations and
  long life-cycle

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Project 2 Background

• Significant uncertainty is created when a
  particular disciplinary design team must try to
  connect their subsystem to another disciplinary
  subsystem (e.g., Clinical-CMC-CGMP).
• Each subsystem can have its own goals and
  constraints that must be satisfied along with the
  system-level goals and constraints.
• It is possible that goals of one subsystem may
  not necessarily be satisfactory from the view of
  other subsystem and design variables in one
  subsystem may be controlled by other disciplinary
  subsystem.

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Project 2

• Using ICH Q8 as the bridge between the CGMP
  Initiative and the rest of the regulatory system
  seek to develop a knowledge management system to
  ensure appropriate connectivity and synergy
  between all regulatory disciplines (Pharm/Tox,
  Clinical, Clinical Pharmacology,
  Biopharmaceutics, Bioequivalence, CMC,
  Compliance, CGMP Inspections, Drug Safety,..)

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Project 2 Approach

• ICH Q8 CTD-Q Pharmaceutical Development, P2
  Section
• Each section within P2 can have an impact on the
  other P2 sections and similarly other sections of
  a submission and to CGMPs
• By recognizing this as a complex design system
  that involves multiple attributes, goals,
  constraints, multidisciplinary design teams
  (subsystems), different degrees of uncertainty,
  risk tolerance, etc., we wish to find
  opportunities to identify robust designs and
  design space that provides a sound basis for risk
  assessment and mitigation

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Project 2 Approach

• A significant body of knowledge exists (e.g., in
  mechanical engineering - design of aircrafts)
  that addresses this challenge for example
• Koor, I., Altus, S., Braun, R., Gage, P., and
  Sobieski, I. Multidisciplinary Optimization
  Methods for Aircraft Preliminary Desing. AIAA
  Paper 94-4325, 5th AIAA/USAF/NASA/ISSMO
  Symposium, Sept. 1994
• Balling, R.J. and Sobieski, J. An Algorithm for
  Solving System-Level Problem in Multilevel
  Optimization.Structural Optimization 9 168-177
  (1995)
• Kalsi, M., Hacker, K., Lewis, K. A Comprehensive
  Robust Design Approach for Decision Trade-Offs in
  Complex System Design. J. Mechanical Design. 123
  (2001)

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Project 2 Approach

• The applicability of multidisciplinary
  optimization methods for solving system level
  problems and decisions trade-offs will be
  explored for the NDA review process
• For example in the CDT-Q P2 section Critical
  drug substance variables that need to be
  considered in section 2.2.1 Formulation
  Development are described in section (P2.1.1.)
• P2.1.1. Drug Substance Key physicochemical and
  biological characteristics of the drug substance
  that can influence the performance of the drug
  product and its manufacturability should be
  identified and discussed.

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Project 2 Approach

• Let f(2.1) be the objective function of section
  of section P2.2.1. Formulation Development it
  describes the desired quality and performance
  attributes to be achieved by formulation
  development program (? mean of the objective
  function and ? its standard deviation)
• Let g(2.1.) be the constraints placed on
  formulation development
• The subsystem optimization problem is then
  defined as Find X(2.1.) to achieve the
  objectives of this subsystem as it relates to the
  overall system
• Minimize ?f, ?f
• Subject to a given constraint g(1.1.,..2.1.,..)

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Potential Deliverables

• In conjunction with electronic submissions this
  project can potentially provide a means to
• Link multidisciplinary information to improve
  regulatory decisions (e.g., clinical relevance of
  CMC specifications)
• Creating a means for electronic review template
  and collaboration between different disciplines
• Provide a common vocabulary for interdisciplinary
  collaboration
• Create an objective "institutional memory' and
  knowledge base
• A tool for new reviewer training
• A tool for FDA's Quality System
• Connect the CGMP Initiative to the Critical Path
  Initiative

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Project 3

• Explore the feasibility of a quantitative
  Bayesian approach for addressing uncertainty over
  the life cycle of products
• The most common tool for quantifying
  uncertainties is probability. The frequentist's
  (including classical statisticians) define
  probability as a limiting frequency, which
  applies only if one can identify a sample of
  independent, identically distributed observations
  of the phenomenon of interest.

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Project 3

• The Bayesian approach looks upon the concept of
  probability as a degree of belief and include
  statistical data, physical models and expert
  opinions and it also provides methods for
  updating probabilities when new data are
  introduced.
• The Bayesian approach may provide a more
  comprehensive approach for regulatory decisions
  process in dealing with CMC uncertainty over the
  life cycle of a product.
• It may also provide a means to accommodate expert
  opinions. The evolving CMC "peer review" process
  may be a means to incorporate expert opinions.
• Using the information collected in Project 1
  seek to develop quantitative Bayesian approaches
  for risk-based regulatory CMC decisions in OPS

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OPS Programs Critical Path Initiative

• Other OPS programs I/O, OBP, ONDC, OGD, and OTR
• The discussion today is to seek input and advise
  from ACPS on
• Aligning and prioritizing current OPS regulatory
  assessment and research programs
• Note that all research and laboratory programs
  are not intended to be focused on the Critical
  Path
• Identify gaps in the current programs
• Identify opportunities for addressing the needs
  identified by the Critical Path Initiative