1.

USDA and Biotechnology

The US Code (USC) and the Code of Federal Regulations (CFR) consist of sections known as
titles. There are 52 titles in the USC and 50 in the CFR. A title number in the CFR corresponds
to the title number in the USC where the law discussed in the CFR is located. In other words a
topic will have the title number in the USC and the CFR. All the federal laws and regulations
that govern the land can be found in those documents (laws in the USC, regulations in the CFR).
Most of us (except for those in the legal profession) do not directly relate to these laws even
though we are regularly impacted by them directly or indirectly. The regulations as we know
them today have evolved over time and have been influenced by the fact that increasing degrees
of inter-agency interaction is called for as our society gets more complex and understanding of
our environment improves. For example as biotechnology evolved as a tool for designing new
drugs for the clinics, the extent of its potential impact on our environment or the agricultural
industry were not immediately fully appreciated. As this became more evident, it is not
surprising that over time, areas of regulation could be seen to overlap between different federal
agencies. Thus for example, the FDA is responsible for ensuring that drugs that come into the
country for public use meet certain predefined criteria. However, meeting those criteria does not
guarantee entry of the drug into the country. For that, you have to go through an entirely separate
process to meet the importation requirements as defined by a different agency (USDA). In this
context, one can better appreciate the observation in the Coordinated Framework that a multi-
pronged regulatory approach would be necessary to fully regulate the biotechnology industry.

When agriculture and food laws were first enacted, nobody could envision the scientific
advancements of the last 100 years. The events of the day and the foresight diligence and
persistence of a number of individuals were responsible for shaping the development of the
regulations that we rely on today to control biotechnology. Some of the individuals include
Upton Sinclair who wrote "The Jungle" and Harvey Wiley assembled his band of men, the
“poison squad", to test chemicals in food.

While the US FDA is ordinarily associated with the regulation of biotech products, we will
begin by exploring the role of The US Department of Agriculture (USDA) in shaping and
implementing regulations governing biotechnology.

You can find lots of information about biotechnology regulations at the USDA website.

1. Take a look around the USDA website to familiarize yourself with the types of
biotech products the USDA regulates and the different offices within USDA
responsible for writing, enacting, and enforcing the regulations.
2. Think about any instances in which USDA regulatory authority may influence
biotechnology products that go beyond the scope of the products that USDA
regulates (in other words, can you locate or think about examples where USDA
influences, or has to interact with other agencies in order to get biotech products to
the consumer?).
3. Does the USDA only regulate products intended for commercial use? Does USDA
regulatory authority extend to biotech products intended for research or personal
use?
 4. What are veterinary biologics? Are all veterinary products regulated by USDA?

2. The Virus-Serum-Toxin Act and the Plant Protection Act of 2000 are two laws that mandate
and authorize the USDA to regulate biotechnology products.

2a. The Virus-Serum-Toxin act gave the USDA authority to regulate veterinary biologics.
Currently, Center of Veterinary Biologics, in APHIS, is the regulatory arm of USDA for
veterinary biologics. Veterinary drugs, on the other hand, are regulated by the FDA (Center for

Veterinary Medicine).

"Biological products" include: vaccines, bacterins, allergens, antibodies, antitoxins, toxoids,

immunostimulants, certain cytokines, antigenic or immunizing components of live organisms,
and diagnostic components, that are of natural or synthetic origin, or that are derived from
synthesizing or altering various substances or components such as microorganisms, genes or
genetic sequences, carbohydrates, proteins, antigens, allergens, or antibodies.

The intent*of the Plant Protection Act (PPA) of 2000 was to streamline the actions and
authorities of USDA to create a smaller, more efficient and effective agency, the national
invasive species council http://www.invasivespecies.gov/ . The council consolidated existing
acts (for example, the Plant Quarantine Act, the Federal Plant Pest Act, and Federal Noxious
Weed Act). The laws called for substantial increases in penalties for intentional smuggling of
prohibited agricultural items into the US. Because of global travel and trade in today's world,
there is a great deal more potential for movement of plants and pests (often unintentionally) than
when USDA laws were originally written. The PPA is codified* under 7 CFR 340.

You should be familiar with the implications and intentions of the Virus-Serum-Toxin Act and
the Plant Protection Act, as they pertain to USDA regulation of biotechnology.
  Some of the terminology used to describe regulations and laws deserve particular
attention. For example, Intent is a very important legal concept- in short, when Congress
passes a law, there are usually specific things congress intends for the law to do, or things
for the law to cover. This intent isn't always evident in the legal language of the law, but
when the Courts are asked to rule on what a law means, the most important factor in what
a law means goes back to what Congress intended when they passed the law. This intent
can be deduced from committee reports and transcripts of the deliberations of Congress
leading up to passing a law. Codified refers to how the law is simplified for everyday use
in the Code of Federal Regulations. This is distinct from how a law might be written --
rather, the language is more familiar and is meant to provide guidance on how the law is
to be implemented.

3. Product Establishment licensing

To be sold in the U.S., veterinary biologics must be:

 produced at a USDA-approved establishment, meaning manufacturing facilities must

hold a Veterinary Biologics Establishment License
 safe, pure, potent, and efficacious - when this is demonstrated, the product gets a
Veterinary Biologics Product License

What is the review process like?

The review of Veterinary Biological License applications is a confidential process until the
product is licensed (remember this when we talk about FDA, which is more open in their
decision making). The sponsor generally writes or calls the director of CVB in Ames, Iowa when
they are ready to file a submission. A review team is assigned by the director. The review team is
made up of members from LPD (Licensing and Policy Development) unit and the IC (Inspection
and Compliance) unit. The review team may also include relevant experts outside the USDA.
The scientific review of the product is done by LPD, while the review of the establishment is by
IC.

There are about 120-150 new product licenses granted each year. CVB publishes the list of new
product licenses on their website. 'New' products are not necessarily new molecular entities.
'New' products may include products to treat an old disease in a new species, or a new use for a
previously approved product. Reviewers are typically advanced degree scientists or
veterinarians.
The field testing of a new veterinary biologic is a rather straightforward process. Unlike human
drugs which are evaluated for safety and pharmacologic properties in animals before they're
introduced in humans, veterinary products can be studied in (you guessed it) the target species.
As you would expect, this significantly streamlines the review.

The USDA's CVB publishes Regulations and guidances to clarify the licensing process.

Visit and explore CVB site to get an overview of the CVB licensing process and acquaint
yourself with the location and content of guidance materials.

The memoranda published by CVB explains the requirements for a biologic license application
for both products and establishments. These memoranda are useful, but include more information
than what is needed for the scope of this class. However, you should become familiar with this
finding, reading, and interpreting guidance documents. You should be able to address the
following for at least one memorandum:

Provide a brief summary (5 sentences or so). Your summary should include the title, topic
or subject addressed, and principal guidance provided. (Note: No submission required).

4. US regulatory agencies and their role in Biotechnology

Regulation of GE Plants: One of the most controversial areas of the biotech regulation is the
regulation of crops derived from biotechnology. Biotech crops are used extensively in agriculture
for both food and non-food purposes. Transgenes primarily confer pest or herbicide resistance,
however other purposes include biopharmaceutical production.

Over 5,000 field trials have been safely conducted since 1987. Over 40 new agricultural products
have completed all the federal regulatory requirements (from all relevant agencies) and may be
sold commercially. They range from longer-lasting tomatoes to pest-resistant corn. A daily
listing of the status of biotech products can be found at the APHIS website.

One of the highly controversial areas in the public eye is that of GMO food labeling. While one
could argue that nearly all crops are genetically modified, for the purpose of this discussion, only
biotech derived crops are addressed. The USDA has regulatory authority over meat and poultry
and egg products only. FDA has regulatory authority over all other foods. There are currently no
transgenic meat, poultry, or egg products in the food supply (see Food supply safety and Food
Security ), but the USDA and APHIS are preparing for this and studying the issues of ensuring
safety of transgenic animal products. (You can get an idea of the future of APHIS by browsing
their Strategic Plan for 2010-2015). Biotech food labeling for all other foods will be covered in
the FDA-foods section.

In previous lectures, we saw that the regulatory agencies are often reactive in nature, especially
when it comes to the development of regulations for new technology. The Starlink corn fiasco
caught the attention of the public, industry, and regulators by presenting some unique issues of
biotechnology regulation. The increased development of transgenic crops has been the impetus
for the agencies to further clarify and coordinate their regulatory efforts within the coordinated
framework policy. The agencies have published draft guidance regarding the regulation of
Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans
and Animals. These are also regulated in field testing by Draft Guidance for APHIS Permits for
Field Testing or Movement of Organisms with Pharmaceutical or Industrial Intent. You can read
how agricultural and other product biotechnology risk analysis occurs in the federal government
here. (You can begin to explore by doing a search for “Risk Analysis” at the site).

Post comments or questions

5. Permitting and licensing

Permitting and Notification are at the heart of the USDA regulatory scheme for biotechnology
products.

We usually think in terms of getting regulatory 'approval' to do something. For example, new
drugs and biologics are approved for marketing by the FDA. The USDA is a little different.
USDA does not 'approve' a new genetically engineered plant for release. Instead, it 'deregulates'
new plants. The assumption here is that a new plant is considered to be a threat to agriculture
until it proves itself to be otherwise.

A sponsor must demonstrate their new (transgenic) plant is not a threat to agriculture or the
environment before it is deregulated and released.

The Biotechnology Permit Branch at APHIS is responsible for deregulating genetically

engineered plants. There are three stages to gaining deregulated status:

1. Early on in development, the plant is in the Greenhouse stage. The plant at this point is still
considered experimental and it is completely contained in the testing facility. The plant has no
contact with the outside environment. The USDA does not have any regulatory authority at this
stage - NIH guidelines for research apply. (This is an example of a disconnect between
regulations for research and regulation for commercial purposes. One could debate the pros and
cons of a multi-pronged regulatory system.)

2. Once a variety is developed, it is ready for Field Testing. This is where the USDA has
regulatory authority. There is controlled contact of the plant with the environment. Field testing
may take 2-4 years. A sponsor must have a permit from APHIS to field test a transgenic plant.
The purpose of field testing is to assess: Durability of growth; Disease resistance; Residues of
concern for either the EPA or the FDA; Performance of the new plant; Isolation distances
(how far does the crop spread?).

In some cases, a sponsor may apply for a Notification. This is a 'streamlined' permit. Only
certain transgene/plant combinations qualify, all others must go through the permit process. The
first criterion is that the plant must belong to one of the following species: corn (Zea mays);
cotton (Gossypium hirsutum); potato (Solanum tuberosum); soybean (Glycine max); tobacco
(Nicotiana tabacum); tomato (Lycopersicon esculentum).

To qualify, the transgenic crop cannot present any risk to the environment and the gene function
in the new plant must be well known. To qualify for Notification the gene:

 Cannot have an animal or human pathogen as part of the genetic material

 Is not for pharmaceutical intent (that is, the plant isn’t producing a
biopharmaceutical)
 Cannot have the potential to create a virus
 Will not result in a plant disease
 Must stably integrate into the hosts genome
 Only applies to certain species: corn, cotton, potato, soy, tobacco, and tomato

If these criteria are not met, the transgenic crop does not qualify for Notification and it must go
through Permitting.

Permits/Notification can be denied if: (1) the science is questionable/unsubstantiated; (2) there is
insufficient information regarding safety to the environment, etc., even if there is no problem
with the science.

As part of field testing, sponsors must ensure that varieties being field tested are contained
during testing and sponsors are subject to reporting and inspection requirements, both before and
after field testing.

3. Once these criteria are met, the Sponsor may apply for a Petition for Deregulated Status.
The crop is releasable into the environment (but still is subject to reporting to APHIS).

Can you distinguish between licensing, permitting and notification as they apply to
biotechnology products and the USDA? Post comments or questions you may have in the
discussion under the topic.

For an example of the application of agricultural biotechnology, take a look at the attached
article:

http://www.biotechniques.com/multimedia/archive/00036/BTN_A_04373TN01_O_36993a.pdf

Agricultural Biotechnology: A growing field. (2004).Biotechniques 37(3):332-333.

For an idea of the public attitudes towards agricultural biotechnology ten years ago, take a look
at the following (both references are also available in the week’s content area.

http://ageconsearch.umn.edu/bitstream/23810/1/wp040009.pdf

Feel free to post any questions or comments that you may have.
6. US Regulatory agencies and their role in Biotechnology: One of the most difficult
problems with biotechnology is determining who regulates what. You will find that there is
quite a bit of overlap between the different regulatory agencies. In this course, we focus on the
EPA, FDA, and USDA. In this series, we covered the role of APHIS, a branch of the
USDA. However, what if we were to think about a product such as Bt corn?

For a quick review of Bt corn, see this website

(http://en.wikipedia.org/wiki/Bt_corn#Bt_corn). Bt stands for Bacillus thuringiensis, a rod-
shaped bacterium that expresses a toxin that kills insects. Bt corn was transgenically designed to
express this protein, therefore providing a built-in resistance to insects such as the European
Corn Borer.

So who should regulate this plant (Bt corn)? We know that APHIS is concerned about
potential pest plants. But Bt is technically a pesticide, so does APHIS regulate this plant or
not?

Post a comment on this issue.

. We will next explore two other regulatory agencies.