Regulatory Issues with New and Unlicensed Veterinary Biological Products

To ensure that veterinary biologics are pure, safe, potent, and efficacious, the process of bringing a product to full licensure can be lengthy. However, other, more limited types of licenses are available to facilitate effective responses in emergency situations. In addition, the use of innovative products in veterinary biologics has the potential to improve efficiency and safety in managing animal disease, but such products bring new regulatory challenges.

The United States Congress passed the Virus-Serum-Toxin Act (21 US Code 151-159) in 1913, providing for federal regulation of veterinary biological products in the US. The United States Department of Agriculture (USDA), Animal and Plant Health Inspection Service's (APHIS's) Center for Veterinary Biologics (CVB) is the regulatory authority that issues licenses and permits for these products. Regulatory oversight includes prelicense evaluation, quality manufacturing requirements, inspection, testing, serial (batch) release, and vaccinovigilance. Administrative regulations and standards are found in Title 9, Code of Federal Regulations (9 CFR) Parts 101-118, with additional program guidance to be found in CVB Notices, Veterinary Services Memoranda, General Licensing Considerations, and other documents.

LICENSES FOR SPECIAL CIRCUMSTANCES

Under the standard licensing process, there is complete characterization and identification of seed material and ingredients, laboratory and host animal safety and efficacy studies, stability studies, and postlicensing monitoring of field performance. During the emergence of a new animal disease or during a foreign animal disease incursion, it may not be possible to provide the complete spectrum of evaluation that candidates for full licensure typically undergo. Under emergency conditions, there are six mechanisms for bringing a product into use more rapidly, including experimental product approvals, autogenous biologics licenses, conditional product licenses, permits for the importation of products used elsewhere in the world, preapproved vaccine banks, and exemptions for products used by or under the supervision of USDA.

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Experimental Product Approvals. A request to produce, distribute, and conduct experimental evaluation of unlicensed biological products in a limited number of animals may be granted under very specific circumstances (9 CFR Part 103.3). As outlined in 9 CFR, the following information should accompany the request:

• a permit or letter of permission from the proper state or foreign animal health authorities of each state or foreign country involved
• a tentative list of the names of the proposed recipients and quantity of experimental product to be shipped to each individual
• a description of the product, recommendations for use, and results of preliminary research
• labels or label sketches showing the name or identification of the product and bearing the statement, "Notice! For Experimental Use Only—Not For Sale" or equivalent (the US Veterinary License legend shall not appear on such labels)
• a general plan covering the methods and procedures for evaluating the product and for maintaining records of the quantities prepared, shipped, and used
• data demonstrating that use of the experimental biological product in meat animals is not likely to result in the presence of any unwholesome condition in the edible parts of animals subsequently presented for slaughter
• a statement from the research investigator or sponsor agreeing to furnish, upon the APHIS Administrator's request, additional information concerning each group of meat animals prior to moving these animals from the test site, including the owner's name and address; the number, species, class, and location of animals involved; the date shipment is anticipated; and the name and address of consignee, buyer, commission firm, or abattoir
• evidence of the product's impact on the environment.

The approval of the oral bait rabies vaccine, used since 1995 in Texas to control the virus in coyotes, is an example of an experimental product approval.

Autogenous Product Licenses. Autogenous biologics are inactivated, nontoxic cultures of microorganisms which have been isolated from sick or dead animals from a particular herd and believed to be the cause of the disease affecting the animals (9 CFR Part 113.113). Such products can be used only by or under the direction of a veterinarian within the context of a veterinarian-client-patient relationship.

Under certain circumstances, a particular autogenous biologic may be used in herds adjacent to the herd of origin when such herds are considered to be at risk, but microorganisms from one herd typically are not used in another herd. Microorganisms may not be used for the production of autogenous biologics more than 15 months after the date of isolation or more than 12 months after the harvest date of the product's first serial, whichever comes first. Master seed testing by the manufacturer is not required nor is there USDA confirmatory testing of the seeds, but the firm must test final container samples for purity and must conduct safety tests in mice or guinea pigs. Master cell lines used for autogenous viral products are tested by the firm and undergo USDA confirmatory testing. Product labels must state that potency and efficacy have not been established. Licenses for autogenous products do not authorize production, distribution, or shipment of autogenous vaccine or bacterin for foot-and-mouth disease, rinderpest, any H5 or H7 subtype of avian influenza, any subtype of avian influenza in chickens, swine vesicular disease, Newcastle disease, African swine fever, classical swine fever, Brucella abortus, vesicular stomatitis, rabbit hemorrhagic disease, or any other disease that USDA determines may pose a risk to animal or public health. The infectious salmon anemia virus vaccine is an example of a product licensed as an autogenous vaccine for an emerging animal disease.²

Conditional Product Licenses. Conditional licenses (9 CFR Part 102.6) are authorized under very special circumstances — such as an emergency — using an expedited procedure to assure purity, safety, and a reasonable expectation of efficacy. Preparation of such products must comply with all applicable regulations and standards and may be restricted (per 9 CFR) as follows:

• The preparation may be limited to a predetermined time period which is established at the time of issuance and specified on the license.
• The license restricts distribution in keeping with the basic criteria for issuance of the conditional license. For example, some licenses may restrict distribution to certain states, laboratories, or authorized recipients.
• Product labels may be required to contain information on the conditional status of the license.
• Product licenses may be reissued when substantiated with data and information obtained since the initial license was issued which support progress towards a conventional license.

The vaccines for protection against H3N2 swine influenza and West Nile viruses are examples of products licensed conditionally to meet emerging animal diseases in the US.^3-5

Importation of Products. Permits for biological products imported into the US may be authorized for a variety of purposes (9 CFR Part 104). A separate permit is required for each shipment of biological product to be imported. Permits may be issued to persons who reside within the US or operate a business establishment within the US. Permits are not issued for biological products from countries known to have exotic diseases, including but not limited to foot-and-mouth disease, rinderpest, highly pathogenic avian influenza (fowl plague), swine vesicular disease, Newcastle disease, and African swine fever, if such products are deemed a potential danger to the livestock or poultry of this country. Three types of permits for importing biological products are available.

Permit for Research and Evaluation. This permit is similar to the experimental product authorizations described above, except that a risk assessment is conducted on the importation of the biological product. Research and evaluation permits do not require inspection of the equipment and facilities of the producer.

Permit for Distribution and Sale. This permit is similar to conventional product licenses described above, except that a risk assessment is conducted. A permit is not issued until an inspector has determined that the condition of the equipment and facilities of the producer and the applicant meet defined standards.

Permit for Transit Shipment. This permit applies only to products moving through a US port and not entering the US. An example of a product considered for importation under an import permit is the rabbit calicivirus vaccine.^6-8

Vaccine Bank. No specific regulations exist for the creation and maintenance of a vaccine or seed bank. Where the potential need for rapidly available vaccine exists, a bank can be used to store relevant strains as inactivated antigen concentrates and live master seeds. Bank components typically meet standards for conventional licensure and are pretested and approved. It is necessary to reevaluate the strains within the bank periodically for antigenic relevance as well as degradation of product during storage. A good example is the North American Foot-and-Mouth Disease Vaccine Bank.

USDA Exemption. Under very special circumstances, biological products may be exempted from one or more of the requirements of 9 CFR Parts 101-118, as authorized by 9 CFR Part 106.1. Exemption is warranted if products will be used by USDA or under the supervision or control of USDA in the prevention, control, or eradication of animal diseases in connection with an official USDA program, an emergency animal disease situation, or USDA's experimental use of the product. The Brucella abortus reagents used in the national Brucella eradication program are examples of products distributed under this authority.

INNOVATIVE NEW PRODUCTS

There are numerous innovative products on the regulatory horizon for veterinary biologics. These include nucleic acid vaccines, multivalent vectored constructs, cancer immunotherapies and diagnostics, egg yolk-based biologics, oral or feed-based vaccines, gene therapy, new delivery systems, transgenics (animals, plants, insects), and rapid diagnostics. Our goal as regulators is to keep pace with technology, publish guidance documents when needed, and adapt and change the licensing standards appropriately.

Licensing of biotechnology-derived veterinary biologics products begins with the submission of data from the applicant in a standard format designated as a "Summary Information Format" or SIF. These documents outline important scientific questions and information that should be addressed during the preparation of a US Veterinary Biological Product License Application for a new biotechnology-derived biologic. SIFs are designed to allow both the participating firm as well as CVB to assess the risk associated with manufacturing and releasing of biological organisms — genetically modified organisms in particular — into the environment. 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 USDA or the public.⁹

There are separate SIFs for three categories of biotechnology-derived biologics. Category I consists of 3 divisions: bacterins, killed viruses, and subunit vaccines (1-A); monoclonal antibodies (MAbs) for therapeutic or prophylactic use (I-B-1); and MAbs and expressed proteins for use in diagnostic test kits (I-B-2). Category II is comprised of live gene-deleted vaccines and category III contains live vectored vaccines. The SIFs are separated into three basic parts: the introduction, a description of the regulated biological agent (RBA) construction, and the assessment of the biological properties or virulence of the RBA used for master seed.

The introduction (Part I) should clearly state the name of the participating firm and any collaborative departments, institutions, or investigators involved with the construction or testing of the organism. It should include a brief statement of purpose for the proposed product, including proposed modes of administration, target species, geographical area intended for use, and where genetic engineering events took place. The introduction should also include a brief discussion of the proposed development of the construct and safety testing.

The description of the RBA construction (Part II) should detail 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 National Institutes of Health and Centers for Disease Control and Prevention biosafety levels, and survivability in the environment) also must be addressed. Part II culminates in a description of how the master seed or RBA will be characterized.

Parts I and II of the SIF should be submitted to 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 CVB to provide feedback to the participating firm, which will be valuable in risk management during the development of the product. It is understood that the SIF will be incomplete at this time due to the need for further studies in support of licensure. It is likely that firms will need to evaluate several constructs in host animals before selecting the final RBA for submission as a master seed. For these preliminary evaluations, it is appropriate that the firm's institutional biosafety committee review, approve, and monitor the animal studies. Submission of the initial documents to CVB does not preclude the firm's oversight of the project through 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 identity and purity. Following master seed approval, the host animal test protocols — which will include recommendations as to the appropriate containment for the host animal safety and efficacy studies — are reviewed and approved.

Part III of the SIF provides safety data on the virulence of the proposed product. These data often are not available until the firm has master seed and host animal protocols approved by CVB and is continuing development of the product. Because the generation of data during the development phase requires introduction of the organism into animals, it is important that the experimental clinical protocols use the best information available to 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 and provides a basis for certainty of the construct's safety. The SIF must be as complete as possible prior to publication of a Federal Notice of availability of a risk analysis and an environmental assessment for public comment.

The risk analysis begins with a 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 at CVB. Next, the risk analysis and a confidential business information-deleted SIF are announced in the Federal Register and made available for public comment. The resulting comments are reviewed by CVB licensing staff, and, if a Finding of No Significant Impact (FONSI) is made and the protocol meets all National Environmental Protection Act requirements, 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 are completed and a preliminary risk analysis is submitted, the sponsor may request permission to ship the product for field trials. Granting permission to conduct the field trial depends on efficacy data, an approved SIF, a study protocol, results of testing of the proposed serials, experimental labels, permission from state authorities, a risk analysis, and responses to comments received from the Federal Register notice. CVB may require additional safety tests before authorizing 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 construct and its proposed use. Field trial results are carefully evaluated for compliance with the protocol and for adverse events. The risk analysis, which consists of the biological risk assessment, 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.

Conclusion

CVB works to maintain the purity, safety, potency, and efficacy of veterinary biologics, but sometimes — especially in emergencies — the regulatory review process must operate with extra flexibility. It must provide decisions quickly when needed but not so quickly that an unworthy product is licensed. Toward that end, the CVB promotes proactive vaccine development and use strategies, such as the creation of vaccine and master seed banks, pre-approval of potentially useful products, development of an index of vaccines available around the world, and provisions for innovative research. When the unexpected arises, such as the discovery in December 2003 of a cow positive for BSE, CVB can respond quickly to the need for increased and quicker testing.

BSE DIAGNOSTIC TEST KITS

Various test methods and commercial test kits have been developed to aid in the diagnosis of bovine spongiform encephalopathy. The test methodologies include immunohistochemistry, ELISA, and Western blot. European Union and Japanese regulatory officials have already approved some of these kits for BSE surveillance. It is expected that the recent BSE cases in North America will result in increased BSE testing in the US. Consequently, CVB announced in January and again in March that it will accept and review veterinary biologics product license and permit applications for BSE diagnostic test kits, including "rapid tests." Any resulting permits or licenses will have the following restrictions:

• Sale and use in the US will be restricted to laboratories approved by state and federal (USDA) animal health officials, in accordance with 9 CFR 102.5(d).
• Potency testing, distribution, and use of BSE test kits will fall under the supervision or control of APHIS's Veterinary Services. The APHIS Administrator may apply additional conditions.
• In addition, in accordance with 9 CFR 104.1, each shipment of biological product distributed and sold under a permit must be accompanied by an original certificate endorsed by a full-time salaried veterinarian representing the agency responsible for animal health of the government of the country of origin (or other assurances acceptable to the Animal and Plant Health Inspection Service at USDA), attesting that: 1) No ingredients of animal origin used to produce the product were obtained from ruminants that have been in any country at risk for BSE, as cited in 9 CFR 94.18, or countries considered to be equivalent status by the National Center for Import Export. 2) During the manufacturing process, the manufacturing facility did not receive, store, or process any ingredients of ruminant origin from countries cited in 9 CFR 94.18. 3) The product complies with all other provisions of 9 CFR 113.53.

Information and guidance pertaining to application for licensure is available on the CVB website: www.aphis.usda.gov/vs/cvb/regsandguidance.htm.

References

1. Hill RE, Foley PL, Carr MY, Elsken LA, Gatewood DM, Ludemann LR, et al. Regulatory considerations for emergency use of non-USDA licensed vaccines in the United States.

Dev Biol.

2003; 114:53-58.

2. USDA/APHIS. Infectious salmon anemia. January 2002 Technical Note. Available at URL: www.aphis.usda.gov/oa/pubs/tnisa.html.

3. Webby RJ, Swenson SL, Krauss SL, Gerrish PJ, Goyal SM, Webster RG. Evolution of swine H3N2 influenza viruses in the United States. J. Virol. 2000; 74:8243-8251.

4. de Jong JC, Van Nieuwstadt AP, Kimman TG, Loeffen WL, Bestebroer TM, Bijlsma K, et al. Antigenic drift in swine influenza H3 haemagglutinins with implications for vaccination policy. Vaccine 1999; 17:1321-1328.

5. Garmendia AE, Van Kruiningen HJ, French RA. The West Nile virus: its recent emergence in North America. Microbes and Infect. 2001; 3:223-229.

6. USDA Center for Emerging Issues. Rabbit calicivirus disease impact worksheet. 2000. USDA Center for Emerging Issues. Available at URL: www.aphis.usda.gov/vs/ceah/cei/rabbitcal.htm.

7. USDA/APHIS/VS. Rabbit calicivirus disease factsheet. Wash., DC: 2000.

8. Mehra, C. Rabbit community on alert after second outbreak of deadly virus. VetCentric 2001. Available at URL: www.vetcentric.com/magazine/magazineArticle.cfm?ARTICLEID=1517.

9. The SIFs and three sample submissions are available on the CVB website at URL: www.aphis.usda.gov/vs/cvb/lpd/sifs.htm.