Title: Shipping Experimental Product
Release Date: 23 Aug 2022 Author: Document Number: CVB-WI-0172.03
CONTROLLED//PROPIN/IBASIC

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Title: Shipping Experimental Product
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The proper State animal health authority usually is the State Veterinarian. Occasionally the
State’s animal health authority is not a veterinarian, but is a designated commissioner.

Some state authorities do not issue authorization letters, responding instead that they have no
statutory authority to either approve or disapprove these studies. The CVB’s position on
these “neutral” responses is that the state was given the opportunity to take a position. In the
absence of a state disapproval, reviewers may authorize shipment if the documentation
presented to the CVB is otherwise acceptable.

2. Tentative list of proposed recipients (study participants) and the quantity of product to be
shipped to each recipient. If this list changes, an update must be submitted. The number of
doses should be reasonable for the study objective. Studies proposing thousands of animals
for poorly defined objectives (or objectives not directly related to meeting licensing
requirements) are generally not acceptable. Authorization to ship under 9 CFR 103.3 should
not be used as a mechanism to gain early market exposure for products.

3. A description of the product (or Outline of Production, if available), including the serial
number(s). It should include recommendations for use (often found on a label sketch) and
results of preliminary research (if available).

4. Test results for each serial to be shipped. Each serial must have tested satisfactorily for
purity, safety, and any other tests required by the CVB. Currently VS Memo 800.67 states in
Section IV.D.2:

Safety Tests. Products administered to animals must have satisfactory
safety test results. Conduct testing as specified in pertinent parts of the
9 CFR, where applicable, or as required by the CVB. This testing is not
required for test kits.

Safety tests are not routinely required by CVB for pivotal or proof-of-concept studies where
animals are owned by the vaccine manufacturer or their research partner(s). Safety tests may
be appropriate for studies where animals are client owned, or for studies with large numbers
of animals at risk of potential safety issues such as field safety studies. In such instances, the
Firms should request Reviewer input. Animal safety tests should be clearly justifiable by
CVB and in line with the 3 R principles.

Decisions regarding the need for animal safety studies will be independent of those required
for risk evaluation such as shed/spread and environmental release. Live recombinant
products will need to be evaluated for potential environmental release according to the
National Environmental Policy Act and USDA implementing policy.

5. Label sketches, which show the true name of the product and bear a statement “Notice!
For Experimental Use Only-Not For Sale” or equivalent. (Ensure that alternate syntax truly is
equivalent.) The U.S. Veterinary License No. must not appear on experimental labels. An
example of an experimental sketch template is included in Appendix 4.

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Follow-up on experimental studies

At the conclusion of studies using product shipped under 9 CFR 103.3, firms must submit results
to the CVB. At a minimum, results must be summarized, but if the studies are pivotal to
licensure, complete reports should be submitted. Results are expected within the prescribed
timeframe (usually one year) determined by the CVB.

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5. Acknowledgement of receipt of written permission from proper state regulatory officials
where field trial is to be conducted.

6. Acknowledgement of protocol. Provide comments on the protocol, as applicable, if they
have not been addressed under separate cover.

7. Citation of applicable regulation (9 CFR 103.3)
8. Statement that firm must comply with additional State regulations, if applicable.

9. Time limit for authorization (1 year is typical). Also include a reminder that extensions, if
needed, must be formally requested.

10. Reminder that results of the study must be reported to the CVB

11. Enclose a “date-stamped” copy of the experimental label. Experimental labels are Hi
stamped with a

ate and returned to the firm for their files.

Filing 9 CFR 103.3 authorizations for uncoded products

Often, permission is requested to ship products for preliminary discovery (proof-of-concept)
studies. These products have not yet progressed to the point where the firm is proposing them for
licensure; thus, they do not have a product code assigned to them. Uncoded correspondence such
as this would ordinarily be filed as Code NA0000, but such items are subject to archival each
year. If Reviewers do not want authorizations to ship experimental product to be archived
annually because some of these products will eventually be proposed for licensure, they must
either remove the 103.3 designation from the portal entry OR place the item into a licensing plan.
Also, the original request should remain in the active files to ensure that the summary report is
submitted.

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6. A study protocol, including methods and procedures.

7. If the product is intended for parenteral use in food animals, the firm must submit data
demonstrating that use of the product will not result in adulterated meat/poultry/fish. The
firm should also provide a statement from the research investigator(s) that they will provide,
upon our request, information concerning all food animals involved prior to movement of
these animals from the study premises.

Reviewing 103.3 Requests

The reviewer must ensure that all of the requirements for shipment, listed above, are met.
Additionally, he/she must determine if the provisions of the National Environmental Policy Act
(NEPA) of 1969 (42 U.S.C. 4371) are triggered. Provisions of NEPA are triggered whenever
there is a proposed Federal action with a potential impact upon the environment. APHIS
approval to release an experimental veterinary biological product into the environment can be
such a Federal action.

Theoretically, any experimental veterinary biologic may trigger NEPA. In current practice,
however, the CVB performs environmental assessments (EA) only on Category II (live
microorganisms that contain gene deletions and/or heterologous marker genes) and Category III
(live expression vectors that contain heterologous genes) recombinant products. Additional
categories (e.g., GMO plants producing veterinary biological products) will likely be added in
the future. In such cases, a firm must submit the appropriate Summary Information Format (see
SIF chapter in Reviewer’s Manual) and environmental assessments (EAs). See Veterinary
Services Memoranda 800.50 and 800.205 for additional guidance on SIFs and EAs. Shipment of
experimental product is authorized only after a conclusion of No Significant Impact is found on
environmental risk assessment.

If the 103.3 request is made by submission of APHIS Form 2071, Application for Authorization
to Ship Experimental Veterinary Biological Product, the reviewer only needs to sign the bottom
of the form, if all supporting materials are included and are satisfactory.

Upon approval of the request, a response letter is prepared, if the incoming submission came by a
letter, and not using APHIS Form 2071. See the example letter in Appendix I of this chapter.
Response letters should include the following:

1. Standard opening text (date of submission, true name of product, product code)

2. Serial(s) to be shipped

3. Name(s) of authorized recipients and quantity of product to be shipped.

4. Type of study being performed.

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Title: Shipping Experimental Product
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9 CFR 103.2 prohibits animals from leaving study premises for at least 14 days after
administration of the experimental product or live organisms (vaccination or challenge). The 14-
day holding period may be increased or decreased by APHIS following review of relevant data.
Criteria described in 9 CFR 103.3 may be required for animals vaccinated for high
visibility/politically sensitive diseases (for example birds vaccinated for avian influenza, or cattle
vaccinated with a synthetic Foot and Mouth Disease product).

Food animals may be sent to slaughter provided they meet the conditions described in the 9 CFR
103.2 and are accompanied by a Slaughter Permit issued by the Food Safety Inspection Service.
A slaughter permit is not required if the study is conducted after a slaughter withdrawal period
for the product has been approved by the CVB and the animals are held for that period prior to
slaughter.

Regarding dairy cattle vaccinated with experimental product, vaccines are exempt from
Pasteurized Milk Ordinance (PMO) labeling requirements. Local state officials must still be
notified, however, if milk from dairy cattle vaccinated with experimental vaccine is to be sold for
human consumption. The CVB should advise the firm to notify appropriate state officials.

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Title: Shipping Experimental Product
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Health Inspection Shipping Experimental Product

Veterinary Services

Center for Veterinary
Biologics

1920 Dayton Avenue
PO Box 844
Ames, IA 50010

(15) 337-6100

Document Number: CVB-WI-0172 Revision: 03
Previous Number: PEL Reviewer Manual Ch. 6.1

Vault: CVB-Released

Section/Area: CVB-WI-PEL-REV

Effective Date: 23 Aug 2022

Notes:

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Title: Shipping Experimental Product
Release Date: 23 Aug 2022 Author: — Document Number: CVB-WI-0172.03
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Experimental Product
: — Document Number: CVB-WI-0172.03

CONTROLLED//PROPIN//BASIC

Release Date: 23 Aug 2022

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Title: Shipping Experimental Product
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All authorizations for coded products are filed under the Product Code for that product.

Requests to ship licensed products for off-label use or for oses outside of established product
license restrictions

Firms will frequently submit requests to ship licensed product for off-label use or for purposes
outside of the product license restrictions.

Examples:
e To ship a licensed vaccine currently labeled for dogs to be used in a ferret efficacy
study intended to expand label claims
e To ship a licensed vaccine, restricted to use in state and federal regulatory programs,
to a foreign country for use in their government-authorized study

Reviewers should write an authorization letter in regard to all requests for field studies conducted
by offlabel use. The documents that the firm must submit to support the request, however, can
vary.

Technically, if a firm is shipping a licensed serial that IC has released AND if the containers are
labeled with a CVB-approved label (their usual market label), the firm does not need
authorization under 9 CFR 103.3 to ship it. Nonetheless, the firm will be directing the study
cooperators to use the product off-label. While we cannot regulate voluntary off-label use by
end-users, we do not allow firms to endorse off-label use of their products themselves. For this
reason, a protocol and a letter from the state vet, indicating that they will allow the off-label
study, should be submitted. Other documents associated with a 103.3 request are probably not
necessary in such a situation.

The CVB response letter should authorize the off-label study, but does not need to say that it is
authorized "under 103.3". If the containers are to be labeled with an experimental label instead of
the approved market label, then an experimental label needs to be submitted in addition to the
protocol and state vet letter. Additional documentation may be required, at the reviewer's
discretion, for other case scenarios.

When shipping a licensed, released serial for an off-label use authorized by a government
authority like Wildlife Services (WS), a notification letter to CVB should be submitted but
documents including authorization by the State Regulatory Authority, or a protocol are usually
not necessary. NEPA requires risk assessments, Federal Registrar notices, FONSIs, ete for
products to be introduced into the wilderness or wildlife populations and WS ensures compliance
with these requirements.

Extreme deviations from usual product use may cross the line into 103.3 (Example: using a
product in a manner that is outside the use restrictions placed on the product license). For those,
all of the requirements for 103.3 submissions apply.

Shipping and Disposition of animals that have received experimental products

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Shipment of materials between two Establishments that are under the

same ownershi

Shipment of DEREA products overseas prior to CVB acknowledgement

of foreign marketing authorization.

Shipment of challenge organisms.

Miscellaneous

Authorization under 103.2 is required for movement of vaccinated
animals prior to 14 days postvaccination (or after 14 days postvaccination
if there is a concern regarding shedding or slaughter withdrawal).

A copy of the recipient’s IBC approval must be submitted for shipments
of recombinant materials prior to the issuance of a FONSI. Refer to CVB
Notice No. 07-06.

Blanket 103.3 approvals for specific products, specific recipients, and a
specified time period can be granted upon the reviewer’s discretion. The

firm’s request must meet all requirements of 103.3. iy

Additional guidance is found in Veterinary Services Memorandum 800.67. This regulation does
not apply to experimental product shipped between licensed premises of a single establishment
for use on licensed premises, nor does it apply to product shipped for in vitro evaluation (e.g.,
laboratory analysis). In general, 103.3 authorization is required to ship unreleased serials
manufactured in production to sites that are not listed on the establishment license, for use in
animals. General Department of Transportation shipping regulations (e.g., hazardous goods,
select agents), however, apply to all shipments, regardless of destination or intended use.

Any exceptions to these generalizations should be approved by PEL, documented with a letter to
the firm, and kept on file.

A request for authorization to ship an unlicensed biological product for experimental study
must be accompanied by the following:

1. Letter of authorization, from the proper State or foreign animal health authority, to conduct

experimental studies in that State/country. Multi-site studies require permission from each
participating State/country.

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Appendix IV: Experimental Label Sketch Template

1 Kit or content description

True Name Store
FOR EXPERIMENTAL USE ONLY at 2-
NOT FOR SALE 8°C
Serial
Company name
Company location #
XXXXX
x
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Require 103.3

Master Seeds/Cells and anything derived from Master Seeds/Cells that
will be used in animals. This includes any purpose from field trials to the
generation of sera.

Shipment of experimental product between independently owned
Establishments if the material will be used in animals.

Shipment of prelicense FFM if the material will be used in animals.
Shipment of prelicense diagnostic test kits.

Shipment of unreleased licensed product between independently owned
Establishments if the product will be used in animals.

Shipment of licensed product for off-label use if there are license
restrictions.

Shipment of any of the above materials to ARS or other government
agencies, except for materials shipped to the CVB for confirmatory
testing.

Require permission from CVB, but do not require 103.3

Shipment of materials between independently owned Establishments if the
material will not be used in animals.

Shipment of prelicense FFM if the material will not be used in animals.
Shipment of unreleased licensed product between independently owned
Establishments if the product will not be used in animals.

Shipment of licensed product for off-label use if there are no license
restrictions; the firm must provide permission from the State Veterinarian
for the off-label use.

Do not require permission from CVB or 103.3

Master Seeds/Cells and anything derived from Master Seeds/Cells that
will not be used in animals. Notification of shipment is recommended,
particularly for select agents and high profile antigens.

Materials to be used for hybridoma development in laboratory rodents.

Notification of shipment is recommended, particularly for select agents
and high profile antigens.

Shipment of materials between different sites of the same Establishment.

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Title: Shipping Experimental Product
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Production and Shipment of Experimental Veterinary Biological Products and Related
Issues

Source Document: CVB-MAN-5100, CVB Operations Manual, Chapter 7

Introduction

Production and distribution of experimental veterinary biological products are regulated by title
9, Code of Federal Regulations (9 CFR), section 103, as is the disposition of animals that have
been administered experimental products.

The CVB considers experimental product to include Master Seeds and Master Cells, and any
product or intermediate derived from them, excluding licensed product. Unlicensed diagnostic

test kits are considered experimental product.

Production of Experimental Product in Licensed Facilities

Production of experimental product on licensed premises is regulated in 9 CFR 103.1.

When experimental product is produced in a licensed facility, it is best if it can be done in a
research facility that is separate and apart from production facilities. In many small firms,
however, there is no clear separation between research and production. It is permissible to
prepare experimental products that contain only previously approved seeds and cells in
production facilities. If a firm wishes to use unapproved seeds or cells in production facilities (or
research facilities that are not separate and apart), however, the firm must request permission
from the CVB-PEL; guidance regarding such requests is found in Veterinary
Memorandum 800.64.

Shipment of Experimental Product Intended for Use in Animals

Persons wishing to ship an unlicensed biological product for experimental use in animals must
request permission from the CVB, per 9 CFR 103.3. This includes shipment of unlicensed
product for use in host animals (field efficacy or safety trials), as well as some instances of use of
unlicensed product in laboratory animals. The following table lists the most common shipment
scenarios that require 103.3 authorization or permission from the CVB:

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