May 28, 2003

VETERINARY SERVICES MEMORANDUM NO. 800.205

Subject: General Licensing Considerations: Biotechnology-derived Veterinary 

Biologics Categories I, II, and III

To: Biologics Licensees, Permittees, and Applicants

Directors, Center for Veterinary Biologics

This guideline provides information and recommendations about the submission of 

documents in pursuit of licensure for biotechnology-derived veterinary biological 

products. 

I. BACKGROUND

The Center for Veterinary Biologics (CVB) is announcing the availability of three 

documents entitled “Summary Information Format” (SIF) for Category I, II, and III 

Veterinary Biologics, respectively. These documents outline important scientific 

questions and information that should be addressed during the preparation of a U.S. 

Veterinary Biological Product License Application to the United States Department of 

Agriculture (USDA) for new biotechnology-derived biologics. The documents are 

accompanied by three example SIF submissions, one for each category.

The Categories for biotechnology-derived biologics are defined as follows. Category I 

consists of 3 divisions, I-A, I-B-1, and I-B-2. I-A includes bacterins, killed viruses, and 

subunit vaccines. I-B-1 consists of monoclonal antibodies (Mab) for therapeutic or 

prophylactic use, and I-B-2 includes Mab and expressed proteins for use in diagnostic test 

kits. Category II is comprised of live gene-deleted vaccines. Category III contains live 

vectored vaccines.

These guidance documents represent the agency’s current thinking on this topic. They do 

not create or confer any rights for or on any person and do not operate to bind the USDA 

or the public.

II. SPECIFICATIONS

The SIF documents are designed to allow both the participating firm as well as CVB to 

assess the risk associated with the manufacture and release of biological organisms. 

Specifically, information must be provided to allow communication between the 

participating firm and CVB to assess the risk associated with genetically modified 

organisms released into the environment. Licensing of biotechnology-derived veterinary 

biologics products begins with the submission of data from the applicant in a standard 

format designated as a SIF. The purpose of the SIF is twofold: to provide specific data 
Veterinary Services Memorandum No. 800.205 2

about the design, construction, and testing of the biological agent construct and to 

provide a basis for the Risk Analysis (RA).

The SIFs are separated into three basic parts: I. The Introduction (Part A and B); II. 

The Description of the Regulated Biological Agent (RBA) Construction (Parts A-C); and 

III. Biological Properties or Virulence for the Regulated Biological Agent Used for 

Master Seed (Parts A-G). The introduction (Part I) should clearly state the name of the 

participating firm plus any collaborative departments, institutions or investigators 

involved with the construction or testing of the organism. The introduction should 

include a brief statement on the objective for the use of the proposed product, including 

proposed modes of administration, target species, and geographical area intended for use 

and where genetic engineering events took place. The introduction should also include a 

brief statement on the proposed development of the construct and safety testing.

The Description of the RBA Construction (Part II) should provide detailed information 

about the documented genetic characteristics and history of the organisms used to 

construct the final RBA. The genotype of the expression cassettes, selectable marker 

cassettes, replication cassettes, and integration cassettes must be characterized as to their 

origin and use within the final RBA. The biological properties of each genetic cassette 

(such as virulence, host animal tropism, tissue tropism, horizontal gene transfer potential, 

and recombination potential) must be detailed. The risk-associated properties of the 

genetic cassettes or RBA (such as environmental distribution, geographic distribution, 

recommended NIH/CDC biosafety levels, and survivability in the environment) must be 

addressed. Part II will culminate in a description of how the Master Seed (MS) or RBA 

will be characterized based on the data and information provided.

Documents containing Parts I and II of the SIF should be submitted to the CVB as soon 

as the proposed genetically modified organism has been constructed and before the 

animal testing needed for licensure has begun. An early submission will allow the CVB 

to provide the participating firm feedback, which will be valuable in risk management 

during the development of the product. It is accepted that the SIF will not be complete at 

this time due to the need to conduct further studies according to Part III in support of 

licensure. It is likely that firms will need to evaluate several constructs in host animals 

prior to selecting the final RBA for submission as a Master Seed. For these preliminary 

evaluations, it is appropriate that the firm’s Institutional Biosafety Committee (IBC) 

review, approve, and monitor the animal studies. However, submission of the initial 

documents to CVB does not preclude the firm’s IBC oversight of the project throughout

the development and manufacturing process.

A team composed of CVB staff with molecular biology expertise reviews Parts I and II of 

the SIF and, if appropriate, obtains approval from the CVB Institutional Biosafety 

Committee to work with the recombinant organism in the laboratory at CVB. The Master 

Seed is then submitted to the CVB for confirmatory testing of the identity and purity. 

Following Master Seed approval, the host animal test protocols are reviewed and 

approved, which will include recommendations as to the appropriate containment for the 
Veterinary Services Memorandum No. 800.205 3

host animal safety and efficacy studies. Host animal studies that are undertaken prior to 

CVB approval of the MS are at the firm’s risk.

Part III of the SIF is designed to provide safety data related to virulence of the proposed

product. These data are often not available until the firm has Master Seed and host 

animal protocols approved by CVB and continues development of the desired product. 

Because the data generated during the development phase will require introduction of the 

organism into animals, it is important that the design of the experimental clinical 

protocols be structured using the best information contributed by both the participating 

firm and CVB. Peer-reviewed scientific literature about the construct or similar 

constructs may provide adequate documentation for some considerations. Others will 

require testing of the specific construct. The level of documentation available impacts 

the Risk Analysis (RA) and provides a basis for certainty. Thus, a detailed SIF will 

support the documentation required prior to authorization for release of the construct in 

the environment. Prior to publication of a Federal Register Notice of availability of a RA 

and an Environmental Assessment (EA) for public comment, the SIF must be as complete 

as possible.

The RA begins with the Biological Risk Assessment (BA), which is reviewed by an 

expert panel; the panel may include academic or non-CVB federal scientists and is 

approved by the Section Leader of Biotechnology, Immunology, and Diagnostics. The 

RA and a confidential business information-deleted SIF are then made available for 

public comment with notification in the Federal Register. Comments are reviewed by 

CVB licensing staff. If a Finding of No Significant Impact (FONSI) is made and all 

NEPA requirements are met in the protocol, the field trial may be approved. Mitigation 

procedures are included in the approval, and the firm must notify CVB immediately if 

adverse events occur.

Once data from Part III is completed and a preliminary RA submitted, a request for 

permission to ship the product for field trials may be submitted. A decision to grant 

permission to conduct the field trial will depend on the submission of efficacy data, an 

approved SIF, a study protocol, results of testing of the proposed serials, experimental 

labels, permission from state authorities, an RA, and responses to comments received 

from the Federal Register Notice. The CVB may require additional safety tests prior to 

authorization of field trials, including evaluation of tissue or host animal tropism 

alterations, safety studies in non-target animal populations, overdose studies, shed and 

spread studies, environmental survival studies, recombination studies, or other studies as 

appropriate for the design of the construct and the manner in which it will be used. Field 

trial results are carefully evaluated for compliance with the protocol and for adverse 

events. The RA, which consists of the BA, risk characterization, risk mitigation, and risk 

communication (via the Federal Register Notice) is then finalized. Licensure may 

proceed if all requirements are met and no significant adverse events have been 

identified.
Veterinary Services Memorandum No. 800.205 4

II. GLOSSARY

1.1 Category I Biological Product 

A product that is biotechnology-derived and inactivated. Examples of Category I 

include gene-deleted bovine rhinotracheitis and pseudorabies killed virus 

vaccines, feline leukemia virus subunit vaccine, therapeutic canine lymphoma 

monoclonal antibody, and plasmid-expressed EIA virus p26 and gp45 proteins, 

for use in diagnostic kits.

1.2 Category II Biological Product

A product that is biotechnology-derived, gene-deleted, and live. Examples of 

Category II include the numerous pseudorabies virus modified live vaccines with 

deletions in gX (gG), gI (gE), gIII (gC), TK, inverted repeat and Us regions.

1.3 Category III Biological Product

A product that is a biotechnology-derived, live vector for a foreign gene insert. 

Examples of Category III include the avian influenza H5 and Newcastle HN and 

F genes in the fowl pox vector, and the canine distemper F and HA and the rabies 

GP in the canarypox vector.

1.4 Backbone Biological Agent (BBA)

The agent from which the genetic material from a single biological agent 

contributes the primary genetic and biological characteristics of the Regulated 

Biolgical Agent, including replication and regulatory sequences. 

1.5 Donor Biological Agent (DBA)

The virus, bacterium, fungus, plant tissue, or other organism that will donate 

DNA or gene sequence inserted into the Backbone Biological Agent. The DBA 

contributes sequences encoding specific antigenic characteristics to produce gene 

product foreign to that of the Backbone Biological Agent.

1.6 Donor DNA or gene

The nucleic acid of the Donor Biological Agent, which may be derived from a 

previously isolated nucleic acid, or engineered DNA segment; however, each 

nucleic acid of a construct that was derived from a Donor Biological Agent 

should be identified. Well-characterized genes or sequences need only be 

referenced. 
Veterinary Services Memorandum No. 800.205 5

1.7 Downstream sequence

The DNA sequence that exists at the termination sequence, or 3’ end, of a gene or 

DNA sequence. 

1.8 Flanking region or flanking sequence

The sequence of DNA of the Regulated Biological Agent contiguous to the 5’ or 

3’ end of the inserted DNA cassette or modified genetic sequence. 

1.9 Gene or DNA cassette

Any nucleic acid sequence that can be isolated for genetic engineering purposes. 

It can be derived from RNA or DNA and can include sequence for regulatory

genes, structural genes, or DNA sequence encoding expressed gene product(s). 

1.10 Marker Gene

The nucleic acid of the Backbone Biological Agent that can be used to distinguish 

an attenuated and non-attenuated form of Backbone Biological Agent. The 

thymidine kinase gene is a marker gene since it provides a means for a tk- virus to 

grow in the presence of bromodeoxyuridine. Alternately, foreign marker genes 

that are useful for distinguising the RBA may be inserted.

1.11 Regulated Biological Agent (RBA)

The final construct used to produce a proposed or licensed biologic of a specified 

lot of RBA that is established as master seed (for microorganisms) or Stable 

Transformed Plant Stock (for plants). The RBA was previously referred to as the 

recipient organism with a DNA insert.

1.12 Regulatory Sequence

The nucleic acid sequences that can be identified by regulatory gene products, 

including: promoters, poly A addition sites, termination regions, enhancers, 

origins of replication, insertion sequences, transposition sequences, restriction 

enzyme sites and methylation sites.

1.13 Reporter Gene

A nucleic acid inserted into the Backbone Biological Agent that expresses a 

specific gene product. The expressed product serves as a signal or reporter 

molecule to signify a successful recombination event into the Backbone 

Biological Agent.
Veterinary Services Memorandum No. 800.205 6

1.14 Upstream sequence

The DNA sequence that exists at the start site of, or 5’end of, a gene or DNA 

sequence.

III. COMMENTS

These documents are being distributed for implementation at this time. Interested 

persons may submit comments or questions regarding these guidance documents to 

Louise M. Henderson, Ph.D., at the Center for Veterinary Biologics. 

IV. ELECTRONIC ACCESS

Persons with access to the Internet may obtain the documents at the following location:

http://www.aphis.usda.gov/vs/cvb

 /s/ W. Ron DeHaven

W. Ron DeHaven

Deputy Administrator

Veterinary Services