Scientific Data for Evidence-Based Drug Regulation

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Scientific Data for Evidence-Based Drug Regulation

• Janet Woodcock, M.D.
• Director, Center for Drug Evaluation and Research
• Food and Drug Administration
• September 24, 2009

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Agenda

• Background
• Scientific data in regulations, policy standards,
  and guidance
• Scientific data in decision-making
• Generating new scientific data
• Improving transparency

3
Background

• Pharmaceuticals are among the most tightly
  regulated products in the U.S.
• Manufacturing, human investigations, market
  access, label claims, advertising and promotion
  all regulated by the FDA
• Regulation based on scientific standards to the
  extent possible
• Drug regulation has always been controversial

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Background (cont.)

• Many pharmaceutical standards are harmonized
  internationally
• It is very difficult for FDA regulations,
  guidance, and policy to keep pace with scientific
  innovation
• There is also much remaining uncertainty in the
  biological and social sciences

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Scientific Data in Regulations

• Rulemaking process
• Currently can take 8 years at FDA
• Avoid using specific numbers in regulation (i.e.,
  limits) if possible (specify in guidance)
• Science informs approach
• Example
• Pregnancy Labeling Rule (proposed)
• Data Animal toxicology
• Pharmacologic data
• Human exposure
• Communications Science Data
• How to relay sensible information to clinicians
  and pregnant women on risks and benefits of using
  a drug?

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Scientific Data in Policy Decisions

• How to approach the CFC withdrawal, mandated by
  the Montreal Protocol, for asthma inhalers?
• How do deal with stearate in drug products in the
  face of BSE?
• If there is a shortage of a medically necessary
  drug, how to decide if unapproved drugs are OK?

7
Scientific Data in Standards

• Many FDA standards are technical
• FDA will often defer to SDOs that establish
  technical standards
• Many scientific standards for drugs established
  internationally through the International
  Conference on Harmonization of Technical
  Requirements for Pharmaceuticals (ICH)
• Toxicology testing
• Manufacturing standards
• Clinical procedures such as Good Clinical
  Practices
• NOT approval standards
• FDA will go through Good Guidance Practice
  Procedures to establish these ICH standards in
  the U.S.

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Scientific Data in Guidance

• Good Guidance Practices
• Started by FDA
• Involves dissemination of draft, public comment,
  potentially workshops and public meetings, final
  guidance
• Large number of science-based guidances
• Not binding on outside parties or FDA represent
  FDAs best scientific judgment

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Regulation, Policy, Standard and Guidance
Development

• Transparent, data-driven processes
• Generally involve extensive input from the
  affected communities, including the scientific
  experts
• Frequently involves public workshops and
  scientific meetings
• Used as basis for decisions on specific product
  applications

10
Scientific Data in Decision-Making

• Individual applications are reviewed against
  scientific standards
• Massive amounts of scientific data often
  evaluated-generated and submitted by industry
• Investigational drug applications 10,000
• New drug applications 140
• Abbreviated new drug applications 800
• Manufacturing data 5,000 submissions

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Scientific Data in Decision Making

• 140 New Drug Applications (NDAs)
• Estimate that each NDA contains an average of
  10GB of data
• FDA scientists review these data against the
  established regulations, policies, standards and
  guidance (guidance not binding)
• Reviewers document whether the data meet the FDA
  standards in each area

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Example Animal Toxicology

• For an average, chronically dosed oral medication
  that is a new molecular entity, there may be 12
  formal toxicology studies performed (all
  specified internationally), each of which may be
  preceded by an informal dose ranging study
• Most of these will be submitted during the IND
  phase of development

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Example Generic Drugs

• 800 new applications per year
• Contain scientific data (per standards) on
  manufacturing, stability, impurities, and, if
  parenteral, microbiology
• For pills, will have both fed and fasting
  bioequivalence studies that have to pass limits
  established in regulations, using studies
  specified in guidances

14
Scientific Data in Decision-Making

• Standards for Drug Labels (package insert)
• Each label statement must be backed up by
  scientific data
• Data reviewed by FDA staff to ensure label
  accuracy
• Standards for Drug Advertising
• Claims must be supported by data
• Enforcement against transgressions going beyond
  the data

15
New Scientific Data

• There are huge knowledge gaps throughout drug
  regulation
• Poor translation of basic science into actionable
  regulatory science
• Lack of understanding/data on real world outcomes
  of using drugs
• Lack of application of known communication
  science to drug labeling, promotion and
  advertising

16
Translation of Basic Science

• FDA Critical Path Initiative seeks to bridge gaps
  between basic science and drug developmental
  science
• Use of public-private partnerships to fill gaps
• Multiple successful partnerships ongoing
• Put all results into public domain

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Example Predictive Biomarkers in Toxicology

• Multiple drug companies had biomarkers for drug
  induced kidney toxicity
• Consortium sponsored by C-Path Institute brought
  16 companies together to share knowledge
• Resulted in acceptance of new renal biomarkers by
  FDA and EMEA
• Now starting human testing

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New Scientific Knowledge about Drug Use Outcomes

• FDA carrying out the Sentinel Initiative
• Use eHRs and other electronic health data (e.g.,
  claims) to form a distributed network to do
  analyses about drug use outcomes
• Pilot starting this year
• Will be a powerful source of new data intend to
  use public-private partnerships

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Improving Transparency

• Broad availability for scrutiny, analysis, and
  replication of results is a hallmark of good
  science
• Transparency of drug regulatory process has
  improved, but still needs to be improved
• Transparency of decision-making process
• Transparency of basis (scientific data) for
  decisions

20
Particular Challenges

• Animal toxicology and human data considered
  commercial confidential and not releasable
• These data could be invaluable in advancing the
  science of toxicology and of human clinical
  trials (and drug development)
• Arguably, all human data should be made publicly
  available in some form

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Particular Challenges

• Not all FDA drug reviews are made available in a
  timely manner
• FDA lacks the staff to perform the needed
  redaction of trade secret/commercial confidential
  data
• FDA releases adverse event reporting data on a
  quarterly basis (receives about 250,000 important
  reports annually)

22
Transparency

• More needs to be done on data availability and
  transparency
• FDA has data that might be invaluable in
  advancing human health if it were available to
  researchers
• Resource and legal barriers exist

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Summary

• Drug regulation in the United States is a
  extensively scientific data-driven process, from
  the development of standards to the review of
  applications against the standards
• Many of these scientific standards are
  internationally accepted
• More needs to be done on data access and
  transparency