FDAs Critical Path Initiative

1
FDAs Critical Path Initiative

• History, Objectives, Approach

• MN ACRP Chapter
• Minneapolis District Office Presentation
• Amy Johnson, Public Affairs Specialist
• November 17, 2005

2
Acknowledgement

• This presentation is adapted from one given
  previously by Lisa Rovin, Project Manager,
  Critical Path Initiative at FDA's Center for Drug
  Evaluation and Research (CDER)

3
Presentation Overview

• General Info
• Informed Consent
• Enforcement Action examples
• The Challenge
• The Diagnosis
• The Prescription
• Activities-To-Date
• Next Steps

4
General Information for Researchers

• Informed Consent
• Informed consent must be obtained before doing
  anything with a subject that would not otherwise
  happen to him/her
• Filling out screening questionnaires, blood draw,
  any tests
• An FDA investigator will expect to see a signed
  consent form before anything study-related is
  done.
• 2. Consent forms for FDA-related studies should
  contain a statement that the purpose includes
  determining safety and efficacy

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Elements of Informed Consent

• Consent documents for studies of investigational
  articles should include a statement that a
  purpose of the study includes an evaluation of
  the safety of the test article.
• Statements that test articles are safe or
  statements that the safety has been established
  in other studies, are not appropriate when the
  purpose of the study includes determination of
  safety.
• In studies that also evaluate the effectiveness
  of the test article, consent documents should
  include that purpose, but should not contain
  claims of effectiveness.
• http//www.fda.gov/oc/gcp/guidance.html
• http//www.fda.gov/oc/ohrt/irbs/toc4.htmlscreenin
  g

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FDA Guidance on Screening

• Appropriate pre-entry activity
• An investigator may discuss availability of
  studies and the possibility of entry into a study
  with a prospective subject without first
  obtaining consent
• BUT, informed consent must be obtained prior to
  initiation of any clinical procedures that are
  performed solely for the purpose of determining
  eligibility for research
• Includes withdrawal from medication (wash-out).
• When wash-out is done in anticipation of or in
  preparation for the research, it is part of the
  research.

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FDA Guidance on Screening

• Physician-investigators should take extra care to
  clarify with their patient-subjects why certain
  tests are being conducted.
• Allowed without consent - procedures which would
  be done whether or not study entry was
  contemplated. The results can then be used for
  determining study eligibility without first
  obtaining consent.
• Not allowed without consent - any clinical
  screening procedures performed solely for the
  purpose of determining eligibility for research

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Elements of Informed Consent

• http//www.fda.gov/oc/ohrt/irbs/informedconsent.ht
  mlchildren
• 21 CFR 50.25 Elements of informed consent
• A statement that the study involves research
• An explanation of the purposes of the research
• The expected duration of the subject's
  participation
• A description of the procedures to be followed
• Identification of any procedures which are
  experimental

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Elements of Informed Consent

• The study involves research statement is
  important to clarify the subject-investigator
  relationship
• Any procedures relating solely to research (e.g.,
  randomization, placebo control, additional tests
  ) should be explained to the subjects
• The procedures subjects will encounter should be
  outlined in the consent document, or an
  explanation of the procedures, such as a
  treatment chart, may be attached to and
  referenced in the consent document

10
FDA Enforcement Examples

• Warning Letters to 5 clinical investigators
  included at least one of the following
  violations
• (1) Failure to protect the rights, safety, and
  welfare of subjects under the investigators care
  
• (2) Failure to ensure that the investigation was
  conducted according to the investigational plan
• (3) Failure to obtain informed consent
• (4) Failure to maintain adequate records of the
  disposition of the investigational drug
• (5) Failure to assure Institutional Review Board
  (IRB) review by not promptly reporting changes in
  the research activity
• (6) Failure to prepare and maintain adequate and
  accurate case histories
• (7) Failure to furnish accurate reports to the
  sponsor

11
FDA Enforcement Examples

• IRB Violations
• (1) Failure to prepare, maintain, and follow
  written procedures for conducting the review of
  research, including periodic review
• (2) Failure to determine that risks to subjects
  are minimized
• (3) Failure to conduct continuing review of
  research at intervals appropriate to the degree
  of risk
• (4) Failure to require that information given to
  subjects as part of informed consent is in
  accordance with the provisions of 21 CFR 50.25
• (5) Failure to ensure that research is reviewed
  free from conflict of interest
• (6) Failure to review proposed research at
  convened meetings at which a majority of the
  members of the IRB are present
• (7) Failure to prepare and maintain adequate
  documentation of IRB activities.

12
FDA Enforcement Examples

• Example of violations that merited
  disqualification of a clinical investigator
• Repeated and deliberate violations of the
  clinical investigation and human subject
  protection regulations included
• (1) administering the cell supernatants when no
  IND was in effect
• (2) enrollment of an ineligible subject
• (3) failure to obtain informed consent
• (4) administration of prohibited concurrent
  investigational treatments
• (5) failure to account for the all subjects in
  the studies
• (6) failure to obtain IRB approval of protocol
  amendments
• (7) failure to maintain case histories
• (8) failure to document the administration of
  investigational drugs to subjects
• (9) failure to document concurrent medications
• (10) failure to retain records.

13
Critical Path Initiative
14
Critical Path Initiative

• March 16, 2004, FDA report - "Innovation/Stagnatio
  n Challenge and Opportunity on the Critical Path
  to New Medical Products"
• Addressed the recent slowdown in innovative
  medical therapies submitted to the FDA for
  approval
• Report describes the urgent need to modernize the
  medical product development process -- the
  Critical Path -- to make product development more
  predictable and less costly

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Critical Path Initiative

• We face a tremendous potential for new medicines
  to prevent and cure diseases, but fewer new
  products are actually reaching the FDA
• Promising technology in development in the
  clinical labs needs to get to patients more
  quickly and less costly
• FDA wants to work with academics and industry to
  identify ways the medical product development
  process can be improved to keep pace with basic
  science innovation

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FDAs Critical Path Initiative Mission

• A serious attempt to bring attention and focus
  to the need for targeted scientific efforts to
  modernize the techniques and methods used to
  evaluate the safety, efficacy and quality of
  medical products as they move from candidate
  selection and design to mass manufacture.

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Despite Increasing Investments in Biomedical
Discovery ..
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We are Not Seeing the Expected Payoff in New
Medical Products
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Device Picture Unclear
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Disturbing Trends

• Despite notable advances in innovative fields of
  biomedical research as genomics, proteomics and
  nanotechnology
• Downward trend in recent years in the number of
  innovative medical product applications to FDA
  and its counterpart agencies world-wide
• Most of these new scientific fields are not yet
  having a fundamental impact on patient care
• FDA's report focuses on one important cause -
  that new science is not being adequately
  harnessed to guide the technology development
  process in the same way that it is accelerating
  the discovery process

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The Challenge

• 8 of compounds entering Phase 1 will make it to
  market, down from 14 fifteen years ago.
• Costs of development are increasing.
• Phase 3 failure rate reported to be 50, up from
  20 10 years ago.

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The Challenge

• Not enough advanced applied scientific work has
  been done to create new tools to provide early,
  less costly, and more dependable answers about
  the tested products' potential for demonstrating
  safety and effectiveness.
• A mere 10 improvement in predicting products'
  failures in clinical trials could save 100
  million in development costs per drug
• Public health consequence - drug sponsors
  focusing on me-too drugs of proven performance,
  and shying away from the risks of developing
  medications for rare diseases, counter-terrorism,
  and the Third World

23
The Diagnosis

• Investment and progress in basic biomedical
  science has far surpassed investment and progress
  in the medical product development sciences.
• The scientific development process the critical
  path to patients is becoming a serious
  bottleneck to delivery of new products.
• We are using the evaluation tools and
  infrastructure of the last century to develop
  this centurys advances.

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The Prescription

• Bring scientific advances to the medical product
  development process (e.g., simulation models,
  validated biomarkers, new trial designs, novel
  rapid pathogen identification).
• Stimulate development of robust applied research
  programs in critical path scientific areas, to
  develop techniques that remove specific obstacles
  in product development.
• Modernize regulatory standards to reflect the
  best science, intensify FDA involvement.

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FDAs Critical Path Initiative Activities

• Bring focus to need to upgrade infrastructure.
• Trigger public and private critical path
  research. Needs effort from all stakeholders.
• Collaborations and partnerships. Expertise and
  information needed is spread across disciplines
  and organizations.
• Guidances. FDA leadership in collaborative
  development of appropriate scientific standards
  can reduce uncertainty in product development
  planning.

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Initial Steps Identify Priority Hurdles

• Outreach and In-reach -- solicit input from wide
  array of stakeholders and experts.
• Identify/prioritize the most severe development
  problems and areas that provide the greatest
  opportunity.
• Define specific opportunities for overcoming
  these hurdles Construct a national Critical
  Path Opportunities List -- examples of concrete,
  deliverable steps that could be accomplished.
• FDA received over 100 solutions from input to an
  open public docket

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Outreach

• Overwhelming Concurrence With Critical Path
  Diagnosis Recognition of science infrastructure
  problem.
• Overwhelming Concurrence With CP Rx Initiative
  focus on research, science-based standards, and
  collaboration.

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Biggest Concerns

• Clinical Trials
• Innovative trial design, new statistical tools
  and analytic methods
• Modeling and simulation
• Disease-specific trial protocols
• Biomarkers and Endpoints
• Conceptual framework/process for qualifying
• Establish known biomarkers for specific
  conditions
• Standards on imaging as biomarker

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Examples of Collaboration

• FDAs National Center for Toxicological Research
  (NCTR) and BG Medicine, a Massachusetts biotech
  research company, have agreed to collaborate on a
  project designed to overcome one of the obstacles
  to efficient development of safe drugs
• Better ways to predict liver toxicity in human
  drug trials
• Goal to discover signs of human liver toxicity
  in a standard test used in the initial stages of
  drug development
• Early detection satisfies CP goal of making
  process more predictable and successful, and less
  costly

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Examples of Projects Underway

• Developing new animal models for speeding the
  assessment of safety and effectiveness of next
  generation medicines against anthrax, smallpox
  and other bioterrorist threats.
• Developing a four company-sponsored 40,000
  patient study of the comparative accuracy of
  digital and conventional mammography - a study no
  one company could develop or mount, but which is
  of vital importance to millions of women.

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Examples of Projects Underway

• Working with the U.S. Centers for Disease Control
  and prevention, industry and America's blood
  banks, FDA rapidly developed and made available
  the target viral assays required for the
  manufacture of blood screening tests for West
  Nile Virus.
• Using the unique incentives of the Orphan Drug
  Act and FDA's knowledge of the drug development
  process to collaborate with industry, government
  and patient groups to produce more than 250
  approvals of Orphan Drugs over the last 21 years.
  These products, in the aggregate, treat more than
  12 million patients in the US.

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Other Priority Hurdles Examples

• In Vitro Diagnostics
• Data Pooling / Mining, and Simulation
  Models
• Industrialization of Biologics
• International Harmonization
• Medical Countermeasures Against Bioterrorism,
  Antibiotics

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Next Steps

• Publish 2005 National Critical Path Opportunities
  List -- examples of concrete work that could
  produce better tools for product development.
• Collaborations with NIH, other Govt Agencies
• Public-Private Collaborations
• FDA Leadership

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The Continuing Challenge

• Problem identification and priority setting must
  be on-going.
• Resources Demand for FDA action exceeds FDA
  capacity, far more proposed than FDA can
  undertake.
• Public understanding

35
Resources

• Archived video broadcast of 2004 Critical Path
  Initiative
• http//www.connectlive.com/events/fdacriticalpath/

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Resources

• Docket for Critical Path Initiative
• http//www.fda.gov/ohrms/dockets/dockets/04n0181/0
  4n0181.htm

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For More Information

• www.fda.gov/oc/initiatives/criticalpath/

Contact me! Amy Johnson 612-758-7131 amy.johnson_at_f
da.gov