FDA Update

1
FDA Update

• Janet Woodcock M.D.
• Deputy Commissioner/Chief Medical Officer, FDA

2
Agenda

• Globalization and the FDA Recent Developments
• Public recognition of hazards
• FDA and Congressional response
• New Legislation The FDA Amendments Act and
  budget outlook
• Drug safety New authorities for the Agency
• Multiple new obligations
• Re-authorization of drug and device user fee
  programs
• Update on FDAs Critical Path Initiative

3
Globalization and the FDA

• Industries regulated by FDA have changed from
  primarily domestic to largely global over the
  past 20 years
• Food imported from all over the globe
• Source materials often originate in developing
  countries
• Clinical trials conducted worldwide
• Drug API manufacture in China and India
• FDA authorities, organization, and resources have
  not kept pace with this evolution

4
Recent Issues Involving Imports

• Melamine contaminated pet food (China)
• Ethylene glycol in toothpaste
• Heparin recall
• Heparin sourced from pig intestine
• Last few months reports of anaphylactoid
  reactions after bolus administration
• Hypothesis low level contaminant
• API manufactured in facility in China

5
Recent Actions

• Dec 11, 2007, HHS Secretary signed binding
  agreements with Chinese officials on foods, drugs
  and devices
• Chinese authorities will require registration of
  facilities in phased approachFDA plans to
  establish a presence in china and potentially
  other countries

6
The FDA Amendments Act (FDAAA) of 2007

• Title I Prescription Drug User Fee Amendments
• Title II Medical Device User Fee Amendments
• Title III Pediatric Medical Device Safety and
  Improvement Act
• Title IV Pediatric Research Equity Act
• Title V Best Pharmaceuticals for Children Act
• Title VI Reagan-Udall Foundation
• Title VII Conflicts of Interest
• Title VIII Clinical Trial Database
• Title IX Enhanced Authorities Regarding
  Postmarket Safety of Drugs
• Title X Food Safety
• Title XI Other Provisions

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TITLE I PRESCRIPTION DRUG USER FEE AMENDMENTS
OF 2007

• Provides an additional 400 million in annual
  revenues, plus 225 million over 5 years for drug
  safety
• Allows use of fees to fund drug safety activities
  without any date restrictions
• The additional funds are also intended to support
  premarket review activities such as providing
  regulatory advice on development programs CDER
  has over 1000 such meetings per year.

8
TITLE II MEDICAL DEVICE USER FEE AMENDMENTS OF
2007

• Reauthorizes device user fees for FY 2008-2012
• Requires electronic registration and listing
• Requires establishment of unique device
  identifier
• Summary reporting of malfunctions for some
  devices
• Extends third party 510K reviews and modifies
  program

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TITLE VI REAGAN-UDALL FOUNDATION

• Independent 501(c)(3) corporation
• Mission advance the mission of FDA to modernize
  product development, accelerate innovation, and
  enhance product safety, including post-market.
• How grants, contracts, consortia, fellowships
• FDA is non-voting ex officio board member
• Private funding (some FDA support for operations,
  500K - 1.25M / year)
• By October 27, 2007, FDA Must
• Appoint Board
• Obtain nominations from National Academy and
  specified public groups (through FR notice)
• Select initial Board (with NIH, CDC, AHRQ)
• Incorporate Foundation
• Prepare articles of incorporation
• Identify resident agent
• Support initial operations
• Locate interim space
• Identify interim executive director
• Develop initial administrative work plan

10
TITLE VIII CLINICAL TRIAL DATABASES

• Expands clinical trial registry and adds results
  database
• Primarily responsibility of NIH to implement
  however significant FDA directives and actions
• Civil money penalties for failures to register,
  etc.
• Expansion of registry
• Goes beyond serious and life-threatening trials
• All beyond Phase I for controlled clinical
  trial of a drug and device trials comparing and
  intervention with a device
• Basic Results Database 9/29/2008 (1 year of
  enactment)
• Include new elements of results information
• Expanded Results Database 9/28/2010
• Certain elements required rulemaking
• Public meeting by 3/28/2009 for input on
  regulation

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Section 905 Pharmacovigilance/ Active
Surveillance

• Applies to drugs and biologics
• FDA must, through collaborations
• develop methods to obtain access to disparate
  data sources and
• develop validated methods for the establishment
  of a risk identification and analysis system to
  link and analyze safety data from multiple
  sources
• Goals system to include 25 million patients by
  7/1/2010 and 100 million by 7/1/2012
• After the system is developed, FDA must establish
  and maintain procedures
• FDA must establish collaborations with public and
  private entities to provide for advanced analysis
  of drug safety data to improve the quality of
  postmarket risk/benefit analysis, provide access
  to outside expertise, and enhance ability of FDA
  to make timely assessments of drug safety data
• FDA is to convene a meeting of experts on data
  privacy and security to make recommendations on
  development of tools and methods for the ethical
  and scientific uses for and communication of
  postmarketing data, including effective research
  methods for the study of drug safety questions

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Pharmacovigilance/Active Surveillance

• FDA must establish collaborations with public and
  private entities to provide for advanced analysis
  of drug safety data to improve the quality of
  postmarket risk/benefit analysis, provide access
  to outside expertise, and enhance ability of FDA
  to make timely assessments of drug safety data
• At least biannually, FDA must consult DSARM AC on
  priority drug safety questions and mechanisms for
  answering the questions such as through active
  surveillance or studies or trials

13
TITLE IX OTHER PROVISIONS TO ENSURE DRUG SAFETY
AND SURVEILLANCE

• Landmark new provisions giving FDA additional
  authorities in the postmarket phase
• Go into effect 180 days after enactment
• Three major authorities
• Require epidemiologic or clinical trials
• Order label changes
• Require sponsors to develop and comply with risk
  evaluation and mitigation strategies (REMS)

14
TITLE XI OTHER PROVISIONS

• Sec. 1102 Tropical Diseases
• Sponsor that gets approval for a drug to treat or
  prevent a listed tropical disease (including TB
  and malaria) may get a priority review voucher
  that entitles them to a priority review for any
  other application
• Voucher can be transferred (i.e., sold) to
  someone else
• Must be for NME submitted and approved after
  enactment voucher not issued until 1 year from
  enactment, and sponsor must notify FDA of intent
  to use voucher not later than 1 year before use
• FDA to establish and collect extra user fees
  based on average cost of priority reviews in
  previous fiscal year

15
FDA Budget Profile

• Overall budget FY 08
• Total budget about 1.3 B
• 1.7 B in appropriated and 549 M in user fees
• FY 09 Presidents Budget
• 50 M increase in appropriated and 80 M increase
  in user fees

16
FDA Critical Path Initiative Conceptual Framework

• Drug discovery and development in the 2000s did
  not appear to be producing at the expected level
• Multiple explanations had been offered by various
  experts
• Critical Path offered a new explanation
• lack of investment in development sciences

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Science Underlying The Critical Path of Drug
Development
Science to evaluate safety efficacy of new
products, and enable manufacture, is different
from basic discovery science
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Approach to Date

• Critical Path emphasizes collaborative ways of
  accomplishing objectives
• Funds are scarce, so pool resources, especially
  those that have been underused
• Use industry data generated during compound
  development in a collaborative and
  pro-competitive manner
• Use NIH-funded trials and research to help
  qualify promising biomarkers

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Specific Areas of Progress

• Biomarker Development
• Clinical Trial Modernization
• Bioinformatics
• Manufacturing

20
Biomarker Development

• Framework for adoption and regulatory use
• International progress
• Pharmacogenomics
• Safety biomarkers
• Cancer
• Targeted therapy
• Imaging

21
Biomarker Qualification

• Broad acceptance of notion of qualification or
  fitness for use
• FDA concept paper on topic under development
  will clarify terminology
• CDER review divisions surveyed on their use of
  and terminology for biomarkers (highly variable)
• Regular meetings between CDRH and CDER on use of
  diagnostics with drugs
• Formal biomarker qualification process set up at
  CDER
• Agency-wide biomarker qualification process being
  developed

22
International Progress on Biomarkers

• Biomarker discovery and development a major theme
  of EUs Innovative Medicine Initiative (IMI)
  proposed funding 1B Euros over 2007-13 from EU,
  with matching contributions from industry
• EMEA and Japanese regulators participating in FDA
  biomarker qualification process
• Step 2 guidance at ICH on pharmacogenomics
  terminology (E15)

23
Safety Biomarkers

• Side effects dont happen to everyone so what
  causes a specific individual to have one?
• Need to improve drug safety through better
  mechanistic understanding of AEs
• Certain biomarkers may be low hanging fruit in
  improving drug safety

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Safety Biomarkers

• Genomic markers offer new promise for identifying
  subpopulations at risk e.g.
• Abacavir and genomic marker for skin reactions
• HLA markers for carbemazepine skin reactions
• Genomic markers to identify populations that
  metabolize warfarin at different rates
• Genomic markers for ultra-rapid metabolizers of
  codeine resulting in morphine toxicity
• New biomarkers for nephrotoxicity are under
  investigation

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Imaging Biomarkers

• Great promise slow progress
• Need to enhance agency review function
• Alzheimers Neuroimaging Initiative one effort to
  study natural history along with imaging
  biomarkers
• Need way to support general human research use of
  molecular probes
• Without repeating preclinical workup
• With due respect to IP

26
Clinical Trial Modernization

• FDA regulation of trials
• Design and methodology issues
• Modeling and Simulation

27
Quantitative Disease Models

• Good early progress at FDA
• In my opinion, this is part of the future of drug
  development
• Basis for systematizing biomarker information
  linked to clinical course simulations of
  interventions
• Need infusion of resources at FDA

28
Drug Manufacturing Product Quality for the 21st
Century

• This initiative begun in 2004 and now part of CPI
• Why is this important? Manufacturing costs
  approximate RD investment lack of flexibility
  in production limits agility
• In implementation phase
• New drugs pharmaceutical development assessment
• Generic drugs Question-based review
• International cooperation EU and US working
  together on change control process
  (EUvariations) (USmanufacturing supplements)

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Drug Manufacturing, cont.

• Focus on the science Quality by Design
• Pharmacology of the drug very important
• Understanding critical process and product
  parameters can lead to larger design space
  freedom to operate
• Additional focus on new technologies such as PAT

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What is Vision for Future Drug Development?

• Preclinical toxicology and clinical development
  move from empirical evaluations to quantitative,
  model-based, learn-confirm cycles
• Links between preclinical and clinical
  development data
• Necessary degree of confirmation premarket
  dependent on indication (as is the case
  currently)
• Predictive capacity of development system greatly
  enhanced
• Amount of information generated by system greatly
  increased

31
Vision for Postmarket Safety Surveillance?

• We (collectively, collaboratively) must build
  postmarket evaluation system
• Electronic health records
• Emerging EHR will provide robust data on
  real-world outcomes of product use
• Amalgamation of national databases
• Will need to continue to exploit vast quantities
  of claims data
• PPPs are being developed to expedite access to
  diverse databases containing electronic patient
  information
• Methods for adverse event surveillance and signal
  generation are being explored
• Provisions in section 905 of FDA Amendments Act

32
Greater Role of Biomedical Engineering in Medical
Product Development

• Shift to quantitative model-based approaches to
  disease and intervention
• Incorporation of extensive amounts of biological
  information (biomarkers, natural history,
  response to intervention) into models, with trial
  simulations
• Linking quality by design on manufacturing side
  through clinical experiences