Transcript SAFETY and efficacy DHHS/NIH/NIAID/DAIDS September 8, 2004

ADDRESSING THE
INFORMATIONAL REQUIREMENTS
OF REGULATORY AGENCIES IN
INTERNATIONAL VACCINE
DEVELOPMENT
STUART Z. SHAPIRO MD,PhD
Vaccine & Prevention Research Program
DAIDS/NIAID/NIH
[email protected]
DHHS/NIH/NIAID/DAIDS
September 8, 2004
The US FDA routinely approves export
of unlicensed drugs/biologics to
countries with similar or allied
regulatory authorities:
 Australia, Canada, Israel, Japan, New
Zealand, Switzerland, South Africa, and
any member of the European Union or the
European Economic Area
DHHS/NIH/NIAID/DAIDS
September 8, 2004
Preclinical Research
Design and Synthesis of Test
Molecules
Immunogenicity Evaluation of
Test Molecules
GMP Process Development
GMP Pilot Lot Manufacture
Selection of Vaccine
Molecules
Plan IND-Enabling Studies
(immunogenicity, toxicology,
other)
Contact Regulatory Agency
Decision to Start
GMP Production
IND Preparation
Perform IND-Enabling
Studies
Pre-IND Meeting
Produce GMP Material
File IND, Other Approvals
Start Phase I Clinical Trial
DHHS/NIH/NIAID/DAIDS
September 8, 2004
What are the Regulatory Agencies’ Major
Concerns?
SAFETY and efficacy
DHHS/NIH/NIAID/DAIDS
September 8, 2004
What are the critical stages in vaccine clinical
testing from the regulatory perspective?
DHHS/NIH/NIAID/DAIDS
September 8, 2004
PHASE One  PHASE Two  PHASE Three 
BLA  PHASE Four
Safety;
Safety;
Safety;
Data to support
Safety;
Immunogenicity; Immunogenicity; Immunogenicity;
approval;
Efficacy;
Dose ranging
Efficacy
Inspection
Inspection;
Lot Release



Pre-IND meeting
End of Phase Two meeting
Pre-BLA meeting
(to discuss):
(to discuss):
(to discuss):
Product; Animal safety &
Phase One/Two data;
Clinical data summary
Immunogenicity;
Efficacy trial protocol(s);
(safety & efficacy);
Manufacturing;
Rationale;
Update on product, etc.;
Lot release criteria;
Update on product, etc.;
Outline of BLA
Phase I protocol
Assay data
STAGES OF CLINICAL TESTING, REVIEW AND REGULATION
DHHS/NIH/NIAID/DAIDS
September 8, 2004
The Three Basic Laws of the FDA (and ALL
Regulatory Agencies) are:
SAFETY! SAFETY! SAFETY!
DHHS/NIH/NIAID/DAIDS
September 8, 2004
Safety Studies
(for more detailed information see: Shapiro, S.Z.,
Vaccine 20: 1261-1280, 2002.)
1. routine toxicology (human inoculations+1/human dose
not dose per Kg/+adjuvant/4-6 rabbits per group/
follow clinically then with thorough necropsy)
2. specialized toxicology for different types of vaccines
a. DNA vaccines (biodistribution/integration)
b. virus- and bacterial- or eukaryotic cell-vectored vaccines
(non-pathogenic replication comp vs. replication incompetent)
c. “whole-killed” virus vaccines (demonstrate killing)
d. pseudovirion vaccines (demonstrate no live virus)
e. Live attenuated virus vaccines (demonstrate attenuation)
DHHS/NIH/NIAID/DAIDS
September 8, 2004
What Else Regulatory Agencies want to
know about your vaccine:
1.
2.
3.
4.
5.
description of the product
previous human data relevant to the vaccine, if available
description of the manufacturing process
description of the manufacturing facility
proposed Phase One clinical protocol and the clinical
development plan
6. preclinical immunogenicity data with the proposed vaccine
that justifies a clinical study
DHHS/NIH/NIAID/DAIDS
September 8, 2004
DESCRIPTION OF THE
MANUFACTURING PROCESS
(flowchart, description of the manufacturing process
steps, description of the source and quality of starting
materials, description of in-process testing, and
tentative lot-release specifications, i.e. description,
identity, purity, sterility, general safety, potency)
a.
b.
c.
d.
e.
f.
cell substrate testing (Ca and Adventitious agents)
steps in the manufacturing process (GMP)
in-process testing
lot-release tests
potency testing
assay validation
DHHS/NIH/NIAID/DAIDS
September 8, 2004
What is GMP?
“Good Manufacturing Practices”
Stanley Steamer vs. Model T Ford
The Taylor System
DHHS/NIH/NIAID/DAIDS
September 8, 2004
“We must organize in Russia the study and
teaching of the Taylor system and
systematically try it out and adapt it to our
own ends.”
- V. I. Lenin
“The Immediate Tasks of the Soviet Government”
Pravda, no. 83, April 28, 1918
DHHS/NIH/NIAID/DAIDS
September 8, 2004
GMP=Manufacturing Consistency
Why is manufacturing consistency so
important for biologicals?
Because inability to completely define end
product by testing, GMP ensures:
• Reproducibility of safety
• Reproducibility of activity (efficacy)
DHHS/NIH/NIAID/DAIDS
September 8, 2004
FDA (and related) DOCUMENTS (and how to get them)
1.
2.
3.
4.
5.
6.
7.
8.
CBER Investigational New Drug Application (IND) website:
http://www.fda.gov/cber/ind/ind.htm
Code of Federal Regulations:
http://www.access.gpo.gov/nara/cfr
http://www.access.gpo.gov/nara/cfr/cfr-table-search.html
CBER Draft Guidances:
http://www.fda.gov/cber/guidelines.htm
CBER Points to Consider documents:
http://www.fda.gov/cber/points.htm
How to obtain CBER documents by CBER’s “Fax-on-demand” or mail:
http://www.fda.gov/cber/pubinfo/FAXinfo.htm
International Conference on Harmonisation Guidelines:
http://www.ifpma.org/ich5.html
CDER’s orientation web site for drug development:
http://www.fda.gov/cder/regulatory/applications/default.htm
FDA Guidance on Export of Drugs
http://www.fda.gov/opacom/fedregister/frexport.html#quick%20locator
DHHS/NIH/NIAID/DAIDS
September 8, 2004
SUGGESTED READING
Chandler, D.K.F., McVittie, L.D., and Novak, J.M., “IND Application
Submissions for Vaccines: Perspectives of IND Reviewers” Chapter 6 in
VACCINES: FROM CONCEPT TO CLINIC, Paoletti, L.C. & McInnes, P.M.
(1999). CRC Press, Boca Raton, FL.
Paoletti, L.C., “Considerations in the Production of Vaccines for
Use in Phase I Clinical Trials and Preparation of the Manufacturer’s
Protocol” Chapter 4 in VACCINES: FROM CONCEPT TO CLINIC…
Shapiro, S.Z. “The HIV/AIDS Vaccine Researcher’s Orientation to
the Process of Preparing a US FDA Application for an Investigational New
Drug (IND): What it is all about and how you start by preparing for your
pre-IND meeting” Vaccine 20: 1261-1280, 2002.
DHHS/NIH/NIAID/DAIDS
September 8, 2004