# Presentation: 546997

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

**Vice President, New Business/Scientific Affairs**
**Wyeth Vaccines**

**The Regulatory Environment and It’s Impact on Supply**

**January 24, 2005**

## Topics for Discussion

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

**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**

**Vaccine Supply**

## 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**

## 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

**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

**Vaccine Supply**

## 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

## Product Licensure vs. Post Licensure Issues

**Prevnar (7-valent pneumococcoal conjugate vaccine) was licensed in 2000**
- Within 2 years significant facilities upgrades were required
- >$300M 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

## 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

## 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

## 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**

## 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**

## 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

## 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.*

## 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.*

## Slide 15

## 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**

## 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 it’s possible