Critical Path Initiative Challenges

Critical Path Initiative: Critical Path Initiative: Challenges and Challenges and OpportunitiesOpportunities

Ajaz S. Hussain, Ph.D.Ajaz S. Hussain, Ph.D.Deputy Director, Office of Pharmaceutical Deputy Director, Office of Pharmaceutical

Science, CDER, FDAScience, CDER, FDA

19 October 2004 ACPS Meeting19 October 2004 ACPS Meeting

CDER Goals: 2005CDER Goals: 2005

Our Goals for 2005

HHS Strategic

Goals

CDERInitiatives

FDAStrategic

Goals

Achieve Excellence in Management

Practices

Increase Science

Enterprise Research

Improve Quality of

Health Care Services

Enhance health care system to

respond to bioterrorism and

other public health challenges

StrongFDA

RiskManagement/

Innovation

PatientSafety

BetterInformedConsumers

ProtectingAgainst

Terrorism

QualitySystem

StrategicObjectives

CGMPsCriticalPath

StructuredProductLabeling

CounterTerrorism

Efforts

Follow-on

Biologics

State of CDER 2004; State of CDER 2004; Steven Galson & Doug Throckmorton Steven Galson & Doug Throckmorton October 6, 2004October 6, 2004

What is Critical Path?What is Critical Path?

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


March 2004: www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf

Translational Research

Critical Path Initiative

Critical Path Document Critical Path Document (March 2004)(March 2004)

The drug development process – the The drug development process – the “critical path,” is becoming a serious “critical path,” is becoming a serious bottleneck to delivery of new bottleneck to delivery of new medical productsmedical products


R&D SpendingR&D Spending

NMEs Filed by Fiscal Year

0

10

20

30

40

50

Nu

mb

er F

iled

Priority Standard

* 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.

But, New Product Submissions But, New Product Submissions Have Remained Flat Have Remained Flat

Why FDA Concern?Why FDA Concern?

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


FDA Has Unique Role in FDA Has Unique Role in Addressing the ProblemAddressing the Problem

FDA scientists are involved in review during FDA scientists are involved in review during product development -- they see the successes, product development -- they see the successes, failures, and missed opportunitiesfailures, and missed opportunities

FDA not a competitor, can serve a crucial FDA not a competitor, can serve a crucial convening and coordinating role for consensus convening and coordinating role for consensus development between industry, academia and development between industry, academia and governmentgovernment

FDA sets the standards that innovators must FDA sets the standards that innovators must meet. New knowledge and applied science tools meet. New knowledge and applied science tools needed not only by innovators – must also be needed not only by innovators – must also be incorporated into agency reviewincorporated into agency review


How to Proceed: Science-Driven How to Proceed: Science-Driven Shared EffortShared Effort

Drawing on available data, need to target Drawing on available data, need to target specific, deliverable projects that will specific, deliverable projects that will improve drug development efficiencyimprove drug development efficiency

Not just an FDA effort – we can identify Not just an FDA effort – we can identify problems & propose solutions – solutions problems & propose solutions – solutions themselves require efforts of all themselves require efforts of all stakeholdersstakeholders• CMS, NIH, CDC CMS, NIH, CDC • Federal Register Notice requesting comments, Federal Register Notice requesting comments,

Well over 100 written responses to date.Well over 100 written responses to date.


CDER/ FDA Next Steps CDER/ FDA Next Steps on Critical Pathon Critical Path

HHS Medical Technologies HHS Medical Technologies Innovation Taskforce providing Innovation Taskforce providing broad leadershipbroad leadership• Chaired by Dr. CrawfordChaired by Dr. Crawford• Includes CDC, CMS, NIH and FDAIncludes CDC, CMS, NIH and FDA

Work on addition funding….Work on addition funding…. Meetings with external stakeholders Meetings with external stakeholders

to identify opportunities, enlist alliesto identify opportunities, enlist alliesState of CDER 2004; State of CDER 2004; Steven Galson & Doug Throckmorton Steven Galson & Doug Throckmorton October 6, 2004October 6, 2004

Critical Path SummaryCritical Path Summary

Present state of drug development not Present state of drug development not sustainablesustainable

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

utilized? utilized?


Three Dimensions of the Critical Three Dimensions of the Critical PathPath

Assessment of Safety – how to predict if a Assessment of Safety – how to predict if a potential product will be harmful?potential product will be harmful?

Assessing Efficacy -- how to determine if Assessing Efficacy -- how to determine if a potential product will have medical a potential product will have medical benefit?benefit?

Industrialization – how to manufacture a Industrialization – how to manufacture a product at commercial scale with product at commercial scale with consistently high quality?consistently high quality?


Applied Science Needed to Better Evaluate Applied Science Needed to Better Evaluate and Predict on 3 Key Dimensions on 'Critical and Predict on 3 Key Dimensions on 'Critical

Path' of DevelopmentPath' of Development

OPS Programs & Critical Path OPS Programs & Critical Path Initiative Initiative

The discussion today is to seek input and The discussion today is to seek input and advise from ACPS on:advise from ACPS on:• Aligning and prioritizing current OPS regulatory Aligning and prioritizing current OPS regulatory

assessment and research programsassessment and research programs Note that all research and laboratory programs are Note that all research and laboratory programs are

not intended to be focused on the “Critical Path”not intended to be focused on the “Critical Path”

• Identify gaps in the current programsIdentify gaps in the current programs• Identify opportunities for addressing the needs Identify opportunities for addressing the needs

identified by the Critical Path Initiativeidentified by the Critical Path Initiative

Planned Project in the OPS Planned Project in the OPS Immediate OfficeImmediate Office

An immediate need is to ensure An immediate need is to ensure appropriate supportappropriate support• Generic Drugs - the growing volume and Generic Drugs - the growing volume and

complexity of applicationscomplexity of applications• New Drug Chemistry - their new paradigm for New Drug Chemistry - their new paradigm for

review assessment and efforts to support review assessment and efforts to support innovation and continuous improvement goals innovation and continuous improvement goals of the CGMP Initiativeof the CGMP Initiative

• Biotechnology Products – complete integration Biotechnology Products – complete integration in OPS and the evolving concept of "Follow-on in OPS and the evolving concept of "Follow-on Protein ProductsProtein Products

• Alignment of research programs in OPSAlignment of research programs in OPS

OPS IO: Critical Path Initiative OPS IO: Critical Path Initiative Project ProposalProject Proposal

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

MotivationMotivation

Uncertainty (stochastic and epistemic) and Uncertainty (stochastic and epistemic) and complexity are two important elements of complexity are two important elements of risk-based based regulatory decisionsrisk-based based regulatory decisions

A common scientific framework, A common scientific framework, irrespective of the regulatory path or irrespective of the regulatory path or process for these products, will provide a process for these products, will provide a basis for efficient and effective policy basis for efficient and effective policy development and regulatory assessment development and regulatory assessment to ensure timely availability of these to ensure timely availability of these products. products.

ApproachApproach

There are no good methods available There are no good methods available for developing a standard approach for developing a standard approach for addressing uncertainty; different for addressing uncertainty; different approaches will be required in approaches will be required in different assessment situations. different assessment situations.

Therefore, a Therefore, a decision framework for decision framework for selecting an approachselecting an approach for addressing for addressing uncertainty over the life cycle of uncertainty over the life cycle of products is proposed. products is proposed.

Project #1Project #1

Create the "As Is" regulatory decision Create the "As Is" regulatory decision process map for ONDC, OBP, and process map for ONDC, OBP, and OGD OGD a representative sample of product a representative sample of product

applications will be selected for this applications will be selected for this mapping processmapping process

Project #1: StepsProject #1: Steps Determine regulatory process efficiency Determine regulatory process efficiency

and effectiveness (quality) using metrics and effectiveness (quality) using metrics similar to that of manufacturing processsimilar to that of manufacturing process

Identify and compare: Identify and compare: • Critical regulatory review decision points and Critical regulatory review decision points and

criteriacriteria• Evaluate correlation and/or causal links Evaluate correlation and/or causal links

between review process efficacy metrics and between review process efficacy metrics and critical decisions criteria, and available critical decisions criteria, and available information (in submissions), and information (in submissions), and

• Evaluate the role of reviewer training and Evaluate the role of reviewer training and experienceexperience

Project #1: Steps (Contd.)Project #1: Steps (Contd.) Summarize available information on the selected Summarize available information on the selected

products products Collect and describe product and manufacturing Collect and describe product and manufacturing

process complexity, post-approval change process complexity, post-approval change history, and compliance history (including AER's)history, and compliance history (including AER's)

Describe product and process complexity and Describe product and process complexity and uncertainty with respect to uncertainty with respect to • Current scientific knowledge (mechanism of action, Current scientific knowledge (mechanism of action,

critical variables, analytical methods, failure modes, critical variables, analytical methods, failure modes, etc.)etc.)

• Information available in the submissions, Information available in the submissions, • Reviewer expert opinions and perceptionsReviewer expert opinions and perceptions• If feasible/possible, seek similar information from If feasible/possible, seek similar information from

sponsor/company scientists on these same productssponsor/company scientists on these same products

Project #1: DeliverablesProject #1: Deliverables Organize OPS Science Rounds to discuss and Organize OPS Science Rounds to discuss and

debate the "As Is" process map and the debate the "As Is" process map and the knowledge gainedknowledge gained• Identify "best regulatory practices" and opportunities for Identify "best regulatory practices" and opportunities for

improvementimprovement Opportunities for improvement to include knowledge gapsOpportunities for improvement to include knowledge gaps Develop a research agenda for OPS laboratories Develop a research agenda for OPS laboratories

• Develop a common scientific vocabulary to describe Develop a common scientific vocabulary to describe uncertainty and complexityuncertainty and complexity

• Develop an "ideal" scientific process map for addressing Develop an "ideal" scientific process map for addressing uncertainty and complexityuncertainty and complexity

• Adapt the "ideal" scientific process map to different Adapt the "ideal" scientific process map to different regulatory processesregulatory processes

Project #2: BackgroundProject #2: Background

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

Project #2: BackgroundProject #2: Background The team approach and systems perspective The team approach and systems perspective

under the CGMP Initiative only addressed a part under the CGMP Initiative only addressed a part of the pharmaceutical system. of the pharmaceutical system.

Quality by design and process understanding to a Quality by design and process understanding to a large extent is achieved in a Research and large extent is achieved in a Research and Development organization. Development organization.

Pharmaceutical product development is a Pharmaceutical product development is a complex and a creative design process that complex and a creative design process that involves many factors, many unknowns, many involves many factors, many unknowns, many disciplines, many decision-makers, and has disciplines, many decision-makers, and has multiple iterations and long life-cycle multiple iterations and long life-cycle

Project #2: BackgroundProject #2: Background Significant uncertainty is created when a Significant uncertainty is created when a

particular disciplinary design team must try to particular disciplinary design team must try to connect their subsystem to another disciplinary connect their subsystem to another disciplinary subsystem (e.g., Clinical-CMC-CGMP). subsystem (e.g., Clinical-CMC-CGMP).

Each subsystem can have its own goals and Each subsystem can have its own goals and constraints that must be satisfied along with the constraints that must be satisfied along with the system-level goals and constraints. system-level goals and constraints.

It is possible that goals of one subsystem may not It is possible that goals of one subsystem may not necessarily be satisfactory from the view of other necessarily be satisfactory from the view of other subsystem and design variables in one subsystem subsystem and design variables in one subsystem may be controlled by other disciplinary may be controlled by other disciplinary subsystem. subsystem.


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

Project #2: ApproachProject #2: Approach ICH Q8 CTD-Q Pharmaceutical ICH Q8 CTD-Q Pharmaceutical

Development, P2 SectionDevelopment, P2 Section• Each section within P2 can have an impact on Each section within P2 can have an impact on

the other P2 sections and similarly other the other P2 sections and similarly other sections of a submission and to CGMP’ssections of a submission and to CGMP’s

• By recognizing this as a By recognizing this as a complex design complex design systemsystem that involves that involves multiple attributesmultiple attributes, goals, , goals, constraints, constraints, multidisciplinarymultidisciplinary design teams design teams (subsystems), different degrees of (subsystems), different degrees of uncertaintyuncertainty, , risk tolerance, etc., we wish to find risk tolerance, etc., we wish to find opportunities to identify opportunities to identify robust designsrobust designs and and design space that provides a sound basis for design space that provides a sound basis for risk assessment and mitigationrisk assessment and mitigation

Project #2: ApproachProject #2: Approach A significant body of knowledge exists (e.g., in A significant body of knowledge exists (e.g., in

mechanical engineering - design of aircrafts) that mechanical engineering - design of aircrafts) that addresses this challenge; for example:addresses this challenge; for example:• Koor, I., Altus, S., Braun, R., Gage, P., and Sobieski, I. Koor, I., Altus, S., Braun, R., Gage, P., and Sobieski, I.

Multidisciplinary Optimization Methods for Aircraft Multidisciplinary Optimization Methods for Aircraft Preliminary Desing. AIAA Paper 94-4325, 5th Preliminary Desing. AIAA Paper 94-4325, 5th AIAA/USAF/NASA/ISSMO Symposium, Sept. 1994AIAA/USAF/NASA/ISSMO Symposium, Sept. 1994

• Balling, R.J. and Sobieski, J. An Algorithm for Solving Balling, R.J. and Sobieski, J. An Algorithm for Solving System-Level Problem in Multilevel System-Level Problem in Multilevel Optimization.;Structural Optimization 9: 168-177 (1995)Optimization.;Structural Optimization 9: 168-177 (1995)

• Kalsi, M., Hacker, K., Lewis, K. A Comprehensive Robust Kalsi, M., Hacker, K., Lewis, K. A Comprehensive Robust Design Approach for Decision Trade-Offs in Complex Design Approach for Decision Trade-Offs in Complex System Design. J. Mechanical Design. 123 (2001)System Design. J. Mechanical Design. 123 (2001)

Project #2: ApproachProject #2: Approach The applicability of multidisciplinary optimization The applicability of multidisciplinary optimization

methods for solving system level problems and methods for solving system level problems and decisions trade-offs will be explored for the NDA decisions trade-offs will be explored for the NDA review processreview process• For example in the CDT-Q P2 section: Critical drug For example in the CDT-Q P2 section: Critical drug

substance variables that need to be considered in substance variables that need to be considered in section 2.section 2.2.12.1 Formulation Development are described in Formulation Development are described in section (P2.section (P2.1.11.1.).)

• P2.1.1. Drug SubstanceP2.1.1. Drug Substance: : “Key physicochemical and “Key physicochemical and biological characteristics of the drug substance that can biological characteristics of the drug substance that can influence the performance of the drug product and its influence the performance of the drug product and its manufacturability should be identified and discussedmanufacturability should be identified and discussed..

Project #2: ApproachProject #2: Approach Let f(2.1) be the objective function of section of Let f(2.1) be the objective function of section of

section P2.2.1.section P2.2.1. Formulation Development it Formulation Development it describes the desired quality and performance describes the desired quality and performance attributes to be achieved by formulation attributes to be achieved by formulation development program (development program ( mean of the objective mean of the objective function and function and its standard deviation) its standard deviation)

Let g(2.1.) be the constraints placed on Let g(2.1.) be the constraints placed on formulation development formulation development

The subsystem optimization problem is then The subsystem optimization problem is then defined as:defined as: Find X(2.1.) to achieve the objectives Find X(2.1.) to achieve the objectives of this subsystem as it relates to the overall of this subsystem as it relates to the overall system system • Minimize [Minimize [f, f, f] f] • Subject to a given constraint g(1.1.,..2.1.,..)Subject to a given constraint g(1.1.,..2.1.,..)

X(2.1) = Design Variables for the P2 section (2.1)Y(1.1)(2.1) = Linking variable that are evaluated in section (1.1)

and required in section (2.1) as the inputf(2.1) = Objective function addressed by section (2.1)g(2.1) = Constraints in section (2.1)f= Mean of objective function ff= Standard deviation of objective function fX= Deviation range of design solution (a design space

boundary)

2.1.1 Drug Substance2.2.1 Formulation

Development

X(1.1) f(1.1) g(1.1)Y(1.1)(2.1)

X(2.1) f(2.1) g(2.1)

Y(1.1.)(*.*)

Y(*.*.)(1.1.)

Y(2.1)(1.1)

Y(*.*)(2.1)Y(2.1.)(*.*)

API Manufacturing Processor Quality control unit

Potential DeliverablesPotential Deliverables In conjunction with electronic submissions this In conjunction with electronic submissions this

project can potentially provide a means toproject can potentially provide a means to• Link multidisciplinary information to improve regulatory Link multidisciplinary information to improve regulatory

decisions (e.g., clinical relevance of CMC specifications)decisions (e.g., clinical relevance of CMC specifications)• Creating a means for electronic review template and Creating a means for electronic review template and

collaboration between different disciplines collaboration between different disciplines • Provide a common vocabulary for interdisciplinary Provide a common vocabulary for interdisciplinary

collaborationcollaboration• Create an objective "institutional memory' and Create an objective "institutional memory' and

knowledge baseknowledge base• A tool for new reviewer trainingA tool for new reviewer training• A tool for FDA's Quality SystemA tool for FDA's Quality System• Connect the CGMP Initiative to the Critical Path InitiativeConnect the CGMP Initiative to the Critical Path Initiative


Explore the feasibility of a quantitative Explore the feasibility of a quantitative Bayesian approach for addressing Bayesian approach for addressing uncertainty over the life cycle of productsuncertainty over the life cycle of products• The most common tool for quantifying The most common tool for quantifying

uncertainties is probability. The frequentist's uncertainties is probability. The frequentist's (including classical statisticians) define (including classical statisticians) define probability as a limiting frequency, which probability as a limiting frequency, which applies only if one can identify a sample of applies only if one can identify a sample of independent, identically distributed independent, identically distributed observations of the phenomenon of interest. observations of the phenomenon of interest.

Project #3Project #3 The Bayesian approach looks upon the concept of The Bayesian approach looks upon the concept of

probability as a degree of belief and include probability as a degree of belief and include statistical data, physical models and expert statistical data, physical models and expert opinions and it also provides methods for updating opinions and it also provides methods for updating probabilities when new data are introduced. probabilities when new data are introduced.

The Bayesian approach may provide a more The Bayesian approach may provide a more comprehensive approach for regulatory decisions comprehensive approach for regulatory decisions process in dealing with CMC uncertainty over the process in dealing with CMC uncertainty over the life cycle of a product. life cycle of a product. • It may also provide a means to accommodate expert It may also provide a means to accommodate expert

opinions. The evolving CMC "peer review" process may opinions. The evolving CMC "peer review" process may be a means to incorporate expert opinions. be a means to incorporate expert opinions.

Using the information collected in Project #1 seek Using the information collected in Project #1 seek to develop quantitative Bayesian approaches for to develop quantitative Bayesian approaches for risk-based regulatory CMC decisions in OPSrisk-based regulatory CMC decisions in OPS

OPS Programs & Critical Path OPS Programs & Critical Path Initiative Initiative

Other OPS programs – I/O, OBP, ONDC, Other OPS programs – I/O, OBP, ONDC, OGD, and OTROGD, and OTR

The discussion today is to seek input and The discussion today is to seek input and advise from ACPS on:advise from ACPS on:• Aligning and prioritizing current OPS regulatory Aligning and prioritizing current OPS regulatory

assessment and research programsassessment and research programs Note that all research and laboratory programs are Note that all research and laboratory programs are

not intended to be focused on the “Critical Path”not intended to be focused on the “Critical Path”

• Identify gaps in the current programsIdentify gaps in the current programs• Identify opportunities for addressing the needs Identify opportunities for addressing the needs

identified by the Critical Path Initiativeidentified by the Critical Path Initiative

Economy & Finance

Critical Path Initiative Challenges