Peter R' Paradiso, PhD

1
The Regulatory Environment and Its Impact on
Supply

• Peter R. Paradiso, PhD
• Vice President, New Business/Scientific Affairs
• Wyeth Vaccines

January 24, 2005
2
Topics for Discussion

• The changing environment globally
• Product licensure vs. post-licensure issues
• Regional specific policies
• The impact on supply

3
Vaccine Supply

• Background
• Vaccines are complex biological products
• inactivated subunit vaccines (DTaP, Hib, Hep b,
  Prevnar, IPV)
• live attenuated vaccines (MMR, V)
• All require production from live organisms
  (virus, bacteria, mammalian cells)
• All must induce an immune response and do not
  themselves have anti-pathogen activity
• Are generally given to healthy populations
• As such, vaccines are unlike most drugs

4
FACTORS INFLUENCING VACCINE SUPPLY

• Supply of any given product is ultimately
  influenced by the overall vaccine environment
• The desire of companies to be in the vaccine
  business overall
• The ability of vaccine companies to maintain
  product portfolios
• The vaccine environment is dynamic and not always
  positive
• The value of vaccination is often not fully
  appreciated
• Societal adversity to risk along with advances in
  technology has resulted in more stringent
  guidelines driving up costs of development,
  manufacturing, maintenance and time to licensure
• Liability continues to be an issue
• Manufacturing is complex
• Production cycles are measure in years

5
Vaccine Supply

• Vaccine Regulation in the U.S.
• Tested, reviewed and licensed by FDA (CBER)
• Post licensure review by the Office of Vaccines
  Research and Review (OVRR) and the Office of
  Compliance (DMPQ)
• Over past 3 years shift to more drug-like
  standards of manufacturing
• more stringent guidelines for systems and
  processes
• less reliance on biological evaluations

6
The Changing Regulatory Environment

• Overall guidelines have become more stringent
• Clinical trials pre-licensure
• Post-market requirements
• cGMP
• Changes to be reported
• Supply impacted by manufacturing interruptions
  required to maintain cGMP standards
• It is often difficult to continue manufacturing
  at the same time as making procedural and
  physical changes

7
Product Licensure vs. Post Licensure Issues

• Prevnar (7-valent pneumococcoal conjugate
  vaccine) was licensed in 2000
• Within 2 years significant facilities upgrades
  were required
• gt300M in capital improvements have been spent
  since licensure
• Around 2000 people are involved in manufacturing
  and an additional 500 are involved in compliance
• COGs have doubled since 2000

8
Compliance

• Greatest change over past 5 years
• Focus on process more than product
• U.S. and EU not always in agreement about
  fundamental cGMP standards
• Focus on different areas
• Manufacturers must use the most stringent common
  denominator

9
U.S. vs. EU Regulatory Process

• In general, facility changes are less
  reportable in the EU
• EU considers these changes part of GMP and deals
  with them during inspections
• US generally requires supplement filing and
  approval
• Specifications can be different
• Air handling requirements around filling are
  different EU is more stringent near the line

10
U.S. vs. EU Harmonization

• New product licensure process
• Common technical document all inclusive
• Approach to review quite different
• Post-licensure
• Process or equipment changes need to be approved
  by all licenseesf which takes a long time
• or
• Two processes and segregated product is required
  which adds complexity to the supply chain
• Lack of harmonization or mutual recognition of
  standards negatively impacts supply

11
Indirect Impact of the Compliance Environment

• Internal company standards have become very
  stringent
• Risk avoidance
• Anticipating expanding requirements
• Product rejection rate increases and supply can
  be impacted

12
Clinical Trials Pre- and Post-licensure

• Clinical trials have expanded in scope and size
• Trials done with 75/group now require 300/group
• Stringent non-inferiority standards drive numbers
• Concommitant use trials have increased in number
  and complexity
• Consistency lot studies are required in the U.S.
• Clinical investigators frustrated by the
  paperwork required to do trials
• Post-licensure commitments are expanding
• Regional specificity

13
The Precautionary Principle

• Government should take regulatory measures to
  prevent or restrict actions even if they are
• Mere conjectural threats to human health
• Potential significance is questionable in terms
  of scientific evidence
• Sometimes represented as
• Erring on the side of safety
• or
• Better safe than sorry

• Miller and Conko. Precautionary Principle.
  Priorities for Health volume 13, number 3.

14
The Precautionary Principle

• Following the Precautionary Principle can lead
  to
• The establishment of unscientific policies that
  inhibit innovation and scientific research
• Extravagant corporate and governmental
  expenditures
• Undue restrictions on consumer options

• Miller and Conko. Precautionary Principle.
  Priorities for Health volume 13, number 3.

15
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16
Impact of Precautionary Approach to Vaccines

• Extended time and cost of development
• Increasing requirements cGMP, cGCP, toxicology,
  and clinical safety, efficacy, concomitant use,
  consistency, bridging
• Reduced probability of success
• Restriction in usage labeling
• Significant decrease in number of development
  programs that can be pursued
• A difficult business to enter, or to stay in
• Decreased number of companies
• Many vaccines recently withdrawn from the market
• End result fewer new vaccines, fewer suppliers,
  and a potential negative impact on public health

17
Conclusions

• Continue focus on the assurance of product safety
• Safety record of vaccine manufacturing has been
  excellent
• As standards for product licensure and
  maintenance evolve, there needs to be a continued
  focus on scientific justification
• Manufacture and release of biological products
  should be standardized wherever possible to avoid
  being a disincentive to new company entry and old
  product maintenance
• There must be a balance between safety concerns
  and the public health
• Specifications and requirements should be to
  enhance product quality, not because its possible