CBER Presentation

(PDF of Presentation, 1.1 MB)

Accelerating the development & availability of vaccines for a pandemic or other emerging threats: present and future

Jesse L. Goodman, MD, MPH
Director, Center for Biologics Evaluation and Research (CBER), FDA
FDA Science Forum, Washington, DC, 4/20/06

---

 

Meeting the Pandemic Flu Vaccine Challenge: Ongoing FDA Actions

• Increasing manufacturing diversity & capacity
• Developing needed pathways to speed vaccine availability (e.g. guidances, accelerated approval)
• Facilitating vaccine manufacturing/evaluation/availability
• current and evolving technologies
• needed/improved assays, reagents, virus strains for development, manufacturing and release
• antigen sparing: adjuvants and delivery
• "holy grail" vaccines: cross-protective antigens
• considering priming and prevention strategies
• Global assistance, cooperation, harmonization
• Assuring safety and public confidence

Overview: Rapid Development and Deployment for Emerging Threats

• Big picture – how much risk vs. how much benefit?
• Where are we?
• Special tools to speed process
• So how quickly can we respond now?
• Two scenarios providing examples
• Promising evolving technologies and approaches
• A "roll out" concept for phased development and use?
• There are other important needs (e.g. immunization process itself and non-medical interventions)

Big picture – risk vs. benefit

• All medicine, public health and regulation is (or should be) risk/benefit based
• Challenge with developing and testing new vaccines for EIDs frequently is uncertainty of benefit (e.g. what is actual risk of disease) – evolves continuously and then changes dramatically when/if outbreak “arrives”
• FDA assesses risk/benefit for each product/use in context of the situation on the ground at that time
• Treatment: for otherwise untreatable, serious illness, reasonable to tolerate significant risk
• Prevention: for well individuals, balance shifts, especially if pre-exposure (or pre-outbreak)
• Lack of efficacy can be a safety issue
• Something is not always better than nothing
• Ineffective therapy can inhibit development of effective therapies

Risk-benefit cont.

• All products themselves also have uncertain risks
• Unexpected events occur, even following appropriate development, clinical studies and review (e.g. GBS with Swine flu, IS with RotaShield)
• Even uncommon AEs can have large impacts in setting of broad immunization of healthy population (1/100,000 = 3500 deaths) – of course far less than the impact of a potential pandemic
• Uncertainty about risk can be reduced by:
• Appropriate initial studies and continuing data acquisition and analysis during use
• Use of technologic approaches with historic experience
• Quality and experience in manufacturing and product testing
• Objective and effective risk communication critical

Progress- yes- but flies in ointment

• Major determinants of innovation,production speed and capacity are:
• Economics of industry
• Vaccine industry and capacity stabilized-improving
• First blockbuster vaccines, investments in CT and influenza are helping but maintenance will be critical
• Limitations: EID market inherently uncertain - government dependent if actions to be taken ahead of time, when needed
• Limits of technology and manufacturing
• Science has provided many new tools
• Rapid detection and cloning of new antigens (e.g. PCR for SARS, RG for flu), new adjuvants, production methods, delivery systems, platform technologies
• Limitations: knowledge gaps and inexperience - many approaches not predictable for given application. Lack of redundancy and resilience in manufacturing base.

How quickly can we respond now?

• Not as fast as we like or may need to!
• Components of response:
• Isolation of agent
• Preparation of seed strain/antigen
• Pilot manufacturing (bulk, purification, formulation)
• Proof of concept
• Clinical immunogenicity/efficacy and safety data as needed
• Scaled manufacturing, bulk, purification
• Fill and finish, product testing
• Delivery and administration
• Production, testing and quality does take time

Tools to Speed Product Evaluation and Availability

• Early and frequent consultation
• Fast track
• Priority review
• Accelerated approval - surrogate
• Approval under “Animal Rule”
• Availability for emergency use under IND or Emergency Use Authorization (EUA)

“Animal Rule”

• Products to reduce or prevent serious conditions caused by exposure to lethal or permanently disabling toxic chemical, biological, radiological, or nuclear substances
• Human efficacy studies not feasible or ethical
• Use of animal data scientifically appropriate

Animal Rule (cont.)

• Still need human clinical data
• PK/immunogenicity
• Safety
• Approval subject to post-marketing studies
• Potential limitations
• No valid or comparable animal model of disease
• How to predictably bridge animal data to humans
• Confidence an issue, even with valid models

Studies may also become helpful in some cases for development of vaccines and therapeutics for animals( and vice versa)

Emergency Use Authorization (EUA):

• Sec. of HHS can declare emergency after Sec. of Defense, Homeland Security, or HHS determines an emergency (or potential for one) exists, affecting national security
• Sec. of HHS (FDA) can authorize use of product:
• For serious or life-threatening condition
• No adequate, approved, available alternative
• Known & potential benefits outweigh known & potential risks

EUA: Conditions of Authorization

• Inform health care workers or recipients, if feasible
• Product authorized specifically for emergency use
• Significant known & potential risks and benefits
• Alternatives
• Option to accept or refuse
• Authority for additional conditions, e.g., who may distribute or administer, data collection & analysis

Groundwork is Needed for Broad Emergency Use Under IND or EUA

• Product may be used very widely in multiple populations
• Therefore, should have reasonable evidence of safety and support for efficacy or likely surrogate
• Primary time challenge in development is typically proof of principle and making product consistently - rather than clinical studies or review
• If product can be made, core data can be generated rapidly – example GSK Fluarix: 900 patients/~1 month/
• This should be done before emergency (or pre-pandemic/epidemic) wherever possible
• Managed, prioritized, funded processes needed to identify and develop candidates, assure data will be available to support use in an emergency

How Quickly: continued

• Time and data needs in each stage depend on disease and vaccine specific factors
• Experience with similar/related pathogens re: biology and protective response correlates
• Experience/capacity with needed technology, related vaccine(s)
• Clinical data needs: immunogenicity/effectiveness and safety
• Disease/host specific challenges, unknowns/concerns
• Two illustrative possible scenarios
• Fast: High experience, likely correlate, similar vaccines made, substantial capacity, no special concerns
• Moderate - uncertainties e.g. biology and/or correlate not understood and/or special concerns
• And then there are "black holes" e.g. retrovirus, prion disease

"Fast": New Influenza Strain

• Positives:
• High familiarity, annual experience
• Many licensed processes/facilities
• Ability to rapidly obtain antigen and develop seed strain
• Good safety record, limited need for clinical data for existing processes/vaccines
• Likely immune surrogate and bridge to effective licensed vaccines
• Negatives:
  • Rapid antigenic changes and egg based technologies difficult to scale up
  • Limited industrial capacity
  • Manufacturing risks
  • Testing for contamination important

Moderate - ?: SARS CoV

• Positives:
• Animals and people make protective neutralizing antibodies
• Small animal and primate models developed
• Negatives:
  • No familiarity, experience, licensed products
  • Possible safety concern- Ab dependent enhancement
  • Killed vaccines not maximally effective
  • Major proteins have complex glycosylation
  • Need for immunogenicity and safety data – lack of correlate
  • Animal disease models imperfect

Vaccine technologies to accelerate production or improve immunogenicity

• Reverse vaccinology (sequence based) - prior to culture
• Immunogen identification technology– xreactive epitopes
• Reassortants, reverse genetics*
• Cell culture* - scalability, potential use of contract facility
• Live atten* - rapid, broad antigenicity, Ab+CTL but safety
• Viral/bacterial vectored: "
• DNA (poor human responses) & "prime/boost": Ab + CTL
• Recombinant protein(s)*: mono-multi-antigen
• insect/animal cells for glycosylation
• plant, edible: dosing, environmental issues
• Synthetic or natural peptide*: "
• Virosome/pseudovirus/liposome – Ab + CTL

SARs: Virus Like Particles

Platform Technologies

• Use of standard platform as cassette/carrier for immunogen
• Examples: gene cassette, viral vector, virosome
• Potential benefits:
  • with adequate experience, likely to gain predictability in safety, immunogenicity
  • Speed of development/production
• Problem: not there yet- but worthwhile to systematically explore/invest

Adjuvants

• Enhance immune response- quantity +/- quality
• Highly variable in actions and effectiveness
• Increased potency often correlates with reactogenicity
• Mineral salts (e.g. alum) – most widely used Ab
• Emulsions/oils may be stronger adjuvants and stimulate more cross-reactive Abs and Th-1 CTL
  • MF59 licensed flu vax in Europe
• Microbial "derivatives" (e.g. lipid A, CpG, toxins) – most stimulate innate immunity through different TLRs
• Microparticles and virus like particles – traffic antigen to APC's, can also serve as platform vectors/adjuvants
• Cytokines

Delivery Routes/Systems

• May enhance local humoral and cellular immunity, invoke APC and elicit CTL responses
• May allow more rapid practical delivery, delivery outside of health care settings, or self-immunization
• May conserve antigen
• Transcutaneous
• Mucosal
• Oral

Urgent Use? - Relevant Lessons of Swine Flu

• Communication re: benefit/risks critical
• Includes uncertainty of pandemic/epidemic - as vaccine benefit depends on it
• Likely better in non-crisis or routine situation - priming
• Ability and process to reevaluate changing situations
• Public's safety concerns and expectations are important and significant (and even more so today) and can affect, and even derail, vaccination plans
• Importance of safety monitoring in use
• Confidence in vaccines, governments and public health systems will be on the line

Relevant Lessons of CT Efforts

• Vaccine production complex, time consuming, not always predictable- vaccines are not widgets.
• Short-cuts seldom are.
• Less expensive seldom is.
• FDA and other global regulatory counterparts can play important and facilitating roles
• Help facilitate production, maximize the efficiency of investments
• Rapidly and objectively evaluate scientific findings re: safety, manufacturing and efficacy in face of urgency

A New Conceptual Framework: "Roll Out"?

• In true or evolving emergencies, even accelerated vaccine development and evaluation approaches likely to fall short
• Can we integrate and speed the process through a "roll out" approach coordinating manufacturing and broadening clinical studies with initial use?
• In any case, effective deployment, roll out, and data acquisition of safety and efficacy studies will be needed for new products early during emergency availability

Conclusions

• Much accomplished and ongoing to improve vaccine technologies and nimble evaluation & regulatory pathways
• Many promising innovations are not yet "solutions"
• Even best case scenarios require months
• Thus, while success possible, we must also focus on:
• Enhanced surveillance and predictive sciences
• Ahead of time vaccine development against possible threats
• Better and predictive understanding of rapid platform vaccine technologies, adjuvants and manufacturing approaches
• Technologies to overcome antigenic variation, enhance stability
• Broad anti-infectives and nonspecific immune enhancement
• Development and evaluation of early non-medical interventions (e.g. personal protection/masks, social measures etc.)
• Much can be evaluated ahead of time - during annual flu seasons, for example

Thanks!

CBER: INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH

Your input welcome - jgoodman@cber.fda.gov or 301-827-0372

CBER Information

Useful Government Sites