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FDA’s Role in Overseeing Vaccine

Development, Approval and

Post-Marketing Surveillance
Peter Marks, M.D., Ph.D.
National Press Foundation
July 30, 2019
Topics to Cover
• FDA’s role in the vaccine ecosystem
• Licensure pathways
• Post-marketing surveillance
• Manufacturing initiatives

www.fda.gov 2
How a Regulatory Agency
Comes into Existence
13 children in St. Louis, MO die of tetanus after
1901 receiving contaminated diphtheria antitoxin and
9 children in Camden, NJ die after receiving
contaminated smallpox vaccine

Biologics Control Act passed requiring the

licensing of manufacturers of vaccines, serums,
1902 and antitoxins, as well as authorizing the
inspection of manufacturing facilities
www.fda.gov 3
Human Medical Product Centers
• Center for Drug Evaluation and Research
• Center for Devices and Radiologic Health
• Center for Biologics Evaluation and Research

www.fda.gov 4
CBER’s Regulatory Portfolio
Blood Related Products
Derivatives Devices FMT

Blood, Blood

Gene Tissues Preventive
Therapies &
Cell Therapies plantation Allergenic
Products Products

www.fda.gov 5
Regulatory Framework for Biologics
• Constitution
• Laws/Statutes
• Public Health Service Act
• Section 351
• Section 361
• Federal Food Drug and Cosmetic Act
• Regulations/Rules
• Guidance
www.fda.gov 6
Vaccine Confidence
• Preventative vaccines have unique benefit-risk
considerations when compared to other
medical products
– Low tolerance for adverse effects
• Need to deal with the challenge of coincidence:
conditions that emerge coincident with, but
independent of vaccine administration
www.fda.gov 7
FDA and Vaccines
• Ensure adequate availability of vaccines that are
safe, pure, potent, and effective
– Conduct relevant applied scientific research
– Provide advice on vaccine development
– Evaluate submissions for licensure
– Develop and distribute reagents for vaccine production
– Lot release testing
– Post-marketing surveillance
www.fda.gov 8
Example of Vaccine Research
There has been a resurgence in
whooping cough caused by B.
CBER scientists developed a non-human primate
model for this disease that could facilitate further
vaccine development
– Warfel JM et al. Infect Immun. 2012; 80: 1530–1536.

www.fda.gov 9
Baboon Model Suggests
Mechanism of Vaccine Failure
• Acellular pertussis vaccine (current) compared to whole cell pertussis
vaccine (older generation prior to 1980’s)
• Both vaccines induced robust antibody responses, but T cell responses
were significantly different
A 10 9
10 8
Acellular vaccine protected aP

CFU (per ml)

6 wP
against disease related to 10 5 Conv.

10 4
pertussis, but failed to prevent 10 3

infection and transmission 10 2

10 1

Day post-challenge
www.fda.gov 10
Expedited Development Programs
• Fast Track
• Priority Review
• Accelerated Approval
• Breakthrough Therapy

These programs may be applicable to drugs or

biologics intended to treat serious conditions
www.fda.gov 11
Animal Rule
• For some products, including certain vaccines,
demonstrate efficacy in humans is not possible
• The Animal Rule allows the demonstration of
safety and pharmacokinetics in humans and
efficacy in qualified animal models
– Efficacy is evaluated in a field trial when possible
www.fda.gov 12
INitial Targeted Engagement for Regulatory
Advice on CBER producTs
• To further encourage early interaction with
sponsors and replace the pre-pre-IND meeting
process across the Center regarding preclinical,
manufacturing and, clinical development plans
www.fda.gov 13
Post-Market Studies
• Use of real world evidence at FDA for evaluation of product
safety has been ongoing for a number of years using large
healthcare databases
– Sentinel, Medicare, Healthcore, others
• Rigorous methodology developed including protocol
development and execution to facilitate signal identification and
• Investigation of the ability of real world evidence to evaluate
effectiveness is in progress
www.fda.gov 14
Comparison of High-Dose and
Standard-Dose Influenza Vaccine
• Used Medicare Database to evaluate efficacy of high-dose (929,730
recipients) versus standard-dose vaccine (1,615,545 recipients)
• High-dose vaccine was 22% (95% CI 15-29) more effective than the
standard-dose vaccine for prevention of probable influenza infections
and 22% (95% CI 16-27%) more effective for prevention of influenza
hospital admissions
• In agreement with a randomized clinical trial conducted in 31,989
individuals which showed relative efficacy of 24.2% (95% CI 9.7-36.5)
Izurieta H et al. Lancet 2015; 15:293-300.
www.fda.gov 15
Manufacturing of Biologics
Smallpox Vaccine Zoster Vaccine Recombinant, Adjuvanted
(Dryvax) (Shingrix)

The product is the process 16
Vision for Manufacturing
• There will be national capacity to produce
ample quantities of high quality vaccines in a
timely and cost effective manner to address
existing and emerging infectious diseases

www.fda.gov 17
Vaccine Manufacturing Challenges
• Vaccine manufacture is a time consuming
process with constraints on agility and capacity
that limit response to emerging pathogens
including seasonal and pandemic influenza
– Working to improve yield from cell-based and
recombinant production processes
– Considering potential of advanced manufacturing
www.fda.gov 18
CATT Meetings
CBER Advanced Technology Team
• Provides an interactive mechanism to prospective
developers of novel therapies to discuss the
implementation of the needed technologies in the
development of CBER-regulated biologics products
• Allows access to early interactions on more general
topics before filing of a regulatory submission
www.fda.gov 19