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**Public Research and the Regulatory Review of**

**Small-Market (Specialty) Biotechnology-Derived Crops Workshop**

#### 

**Proceedings**

**November 8--9, 2004**

**USDA, APHIS (Animal and Plant Health Inspection Service), Riverdale,
Maryland**

**Organizers**

National Center for Food and Agricultural Policy

Langston University

Cooperative State Research, Education, and Extension Service, USDA

Agricultural Research Service, USDA

Animal and Plant Health Inspection Service, USDA

**Editors**

**William R. Goldner**

**Ann Marie Thro**

**John W. Radin**

**Contents**

> 1\. Executive Summary

5 I.  Introduction (Ann Marie Thro, CSREES, USDA)

> 5\. The Purpose of the Workshop
>
> 5\. The History and Objectives of the Workshop
>
> 7\. Michael Fernandez, Pew Initiative on Food and Biotechnology
>
> 8\. II. Overview of the Current Economic and Regulatory Situation
>
> *Moderator: Dan Jones, CSREES, USDA*
>
> 8\. Alberto Jerardo, Economic Research Service, USDA
>
> 9\. Sally McCammon, APHIS-BRS, USDA

12\. John Kough, Environmental Protection Agency 

13\. Mary Ditto, Food and Drug Administration, HHS

  16. Panel and audience discussions (A. Massey, Facilitator)

> 21\. III. Regulatory Challenges:  Experiences from the Perspective of
> Public
>
> Researchers
>
> *Moderator: John Radin, ARS, USDA*

21\. Dennis Gonsalves, ARS, USDA

23\. Ralph Scorza, ARS, USDA

25\. Alan McHughen, University of California-Riverside

26\. David Clark, University of Florida

27\. Panel and audience discussions (A. Massey, Facilitator)

> 32\. IV.  Regulatory Challenges:  Views from the Perspective of
> Private Business
>
> Enterprises
>
> *Moderator: Bill Goldner, CSREES, USDA*

32\. Keith Redenbaugh, Seminis

34\. Neal Gutterson, Mendel Biotechnology

36\. Terry Stone, Scotts

37\. Les Pearson, ArborGen

41\. Panel and audience discussions (A. Massey, Facilitator)

##  46. V. Approaches to Serving Public Needs for Other Regulated Small-Market 

##  Products

##  46. A. A Look at Existing Models

*Moderator: June Blalock, ARS*

46\. Bob Holm, IR-4 Program

48\. Sarah Linde-Feucht, Orphan Drug Program, FDA

##  51. B. Exploration of Possible Models to Serve Public Needs for Small-Market

##  Biotech Crops

> *Moderator: June Blalock, ARS*
>
> 51\. A Biotech Crop Trait Program (Steven Strauss, Kent Bradford,
> Keith
>
> Redenbaugh, David Tricoli, Roger Wyse)
>
> 53\. Models for Regulatory Relief (Jeff Wolt, Carole Cramer, Gary
> Lemme,
>
> Steven Pueppke)
>
> 55\. Panel and audience discussions (A. Massey, Facilitator)

##  62. VI.   Breakout Discussion Group Results

64\. VII.  Recommended Next Steps

65\. VIII.  Actions

66\. IX.  Acknowledgments

67\. X.     Appendix A: Biographies

74\. XI.    Appendix B: Workshop Participants

78\. XII.   Appendix C: Workshop Agenda

***Workshop Steering Committee***

**National Center for Food and Agricultural Policy (NCFAP)**

Sujatha Sankula, Director of Biotechnology Research

**Langston University**

Marvin Burns, Dean, School of Agriculture and Applied Science

Kanyand Matand, Researcher, Forage Grass

**United States Department of Agriculture (USDA):**

**Cooperative Research, Education and Extension Service (CSREES), USDA**

Ann Marie Thro, National Program Leader, Plant Breeding and Genomics,
Plant and Animal Systems Unit

William R. Goldner, National Program Leader, Small Business Innovation
Research, Competitive Programs Unit

Eldon Ortman, IPA -- National Program Leader, Plant and Animal Systems
Unit

Edward Kaleikau, National Program Leader, Plant Genome, Competitive
Programs Unit

Daniel Jones, National Program Leader, Biotechnology, Plant and Animal
Systems Unit

**Agricultural Research Service (ARS), USDA**

John Radin, National Program Leader, Plant Physiology and Cotton

June Blalock, Coordinator, Technology Licensing Program, Office of
Technology Transfer

**Animal Plant Health Inspection Service (APHIS), USDA**

Sally McCammon, Science Advisor

**Committee Chairs**

Ann Marie Thro and William Goldner, CSREES, USDA

**Workshop Facilitator**

Dr. Adrienne Massey, Massey and Associates

***Executive Summary***

**Public Research and the Regulatory Review of**

**Small-Market (Specialty) Biotechnology-Derived Crops**

November 8-9, 2004

Specialty crops, which include vegetables, fruits, nuts, flowering
plants, nursery stock and other horticultural products, produce
approximately 50% of US agricultural crop value (\~\$45 billion/annum).
A decade after the introduction of genetic engineering (GE) into U.S.
agriculture, however, it is clear that the biotechnology revolution is
bypassing specialty crops. Relatively few GE specialty crop varieties
have been submitted to regulatory agencies for clearance, and most of
those that have been approved are not available in the marketplace
today. Only one -- a disease-resistant papaya -- is a commercial
success, and it was developed not by the private sector, but by public
researchers. The number of products in development has declined rapidly
over the last five years, and is approaching zero. Thus the outlook for
change is bleak, unless those factors suppressing interest in GE
specialty crops are identified and reversed.

It is widely understood that large investments of capital in
small-market crops may be unprofitable, because of limited sales. A
substantial fraction of development costs of GE crops goes to meeting
the requirements of the U.S. regulatory agencies to demonstrate safety.
Can the regulatory requirements be met by some different approaches that
reduce costs but maintain safe products and effective regulation?

This two-day workshop was convened to discuss how the public research
sector, the regulatory agencies, and the private sector can work
together to facilitate the regulatory review of specialty GE crops. The
workshop's objectives were (1) to identify major sources of cost and
uncertainty in the development of GE specialty crops and submission for
approval; (2) to identify research that can help meet these requirements
effectively and at minimal cost, without compromising the integrity of
the regulatory process; and (3) to learn about existing programs that
facilitate commercialization of other regulated small-market products
and recommend a model that would be useful for GE specialty crops.

**Regulatory Agencies**

There are three regulatory agencies in the United States that oversee GE
crops: the United States Department of Agriculture's (USDA) Animal and
Plant Health Inspection Service (APHIS) through its Biotechnology
Regulatory Services (BRS) Division; The Environmental Protection Agency
(EPA); and Health and Human Services' Food and Drug Administration
(FDA). APHIS-BRS protects agriculture and the environment by evaluating
genetically-engineered (GE) products that present a potential plant pest
risk (including DNA from a plant pest, such as cauliflower mosaic
virus), and oversees field testing. The EPA has responsibility for GE
plants that raise pest management or pesticide issues protects the
environment and food safety of GE plants that contain pesticidal
proteins (such as the *Bacillus thuringiensis* delta-endotoxin \[Bt\]),
and FDA assures that food and feed derived from GE plants is safe and
wholesome (nutritionally, allergenically, and compositionally)

The processes that each agency has developed for regulatory review vary
according to each agency's mandate and the intended use of the product.
To consider deregulation of a plant product, APHIS-BRS requires
submission of data to demonstrate that release of a GE plant into the
environment will not present a plant pest risk. This data submission
usually occurs after several years of field. The EPA will approve GE
plants with pesticidal traits only when there is a finding of reasonable
certainty of no harm. This determination depends on input from expert
advisory panels and from public comments. Again, extensive data must be
submitted showing specificity of the pesticidal trait for the intended
target pest (or if toxicity is broader, no meaningful exposure of other
species), and no harmful residues of the pesticidal substance or its
metabolites in food. The FDA evaluates data on the characteristic
components of the food or feed in the form in which the product will be
eaten to ensure that new products are safe as the foods that are
currently on the market.

All of the agencies review products on s case-by-case basis. Each of the
agencies depends on input from experts and provides opportunity for
public comment. Reviews evaluate differences between the properties of
the GE products and their conventional counterparts.

**Identifying Economic Barriers**

Speakers from the public sector described their experiences with GE
specialty crops. The GE papaya resistant to papaya ring spot virus --
currently the only commercial success -- was developed in the public
sector, with the private sector contributing no-cost licensing of the
proprietary tools for generation of the GE plants. The process of
obtaining regulatory approval was relatively straightforward. Another
example, GE plum trees resistant to the plum pox virus, has been
developed in the public sector and is currently being considered for
deregulation. In both these cases, the major barriers to deployment were
related not to U.S. regulatory agencies, but instead to industry
structure and market needs. From inception to public release of the
papaya required 20 years (only 7 of which were needed for field trials
and regulatory approval). The GE plum is now (in 2004) at 13 years since
inception of the project. During that time, preferred varieties and
market needs change and researchers risk producing something that is
obsolete when finally released. The situation is exacerbated in the
floral industry for the same reasons. Although the regulatory process
can be improved, there remain structural impediments in the specialty
crop industries that limit the number of appropriate targets for use of
biotechnology.

The other important economic barrier identified by all participants is
overseas regulation. Most of these specialty products have export
markets, and the lack of regulatory standardization around the world
creates tremendous costs, inefficiencies, and uncertainties.

Characteristics of an improved and more efficient approach to
regulation, which would maintain or even improve safety of GE products,
are as follows:

-   Traits evaluated across appropriate groups of plants (e.g., leafy
    vegetables) with the same trait, rather than event-by-event.

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-   A clear and consistent regulatory pathway, because breeding programs
    take a long time, especially for fruit trees.

-   Distinction between products shown by experience to be relatively
    benign, and those that are more likely to present safety issues.

-   Evaluation of GE products basing risk analysis on phenotype.

Although there are significant barriers to commercializing GE specialty
crops, they are not without their advantages. Because they are grown on
small areas, it is easier to maintain segregated product streams without
admixtures, and to track the products, than for major commodity crops.
Therefore the product being sold can be more reliably tailored to the
needs of different markets and different regulatory systems.

**Models for Overcoming Economic Barriers**

Two functioning models were examined: The IR-4 Project, which aids in
registration of pesticides for use on specialty crops; and the Orphan
Drug Program, which stimulates private-sector development of drugs for
rare diseases. Both address needs that would not be filled in the normal
course of events, and both have been very successful.

The mission of IR-4 is to provide safe and effective pest management
solutions for specialty crop growers. Funding comes from USDA (CSREES
and ARS), the land grant university system, and the commodity and crop
protection industries. The total value of the IR-4 Project is \$25-30
million. This project receives and prioritizes requests for data to
support extending the registration of existing chemicals to uses on
specialty crops. Funds support field trials using the pesticides in
question, and residue analysis in laboratories certified for good
laboratory practices. Data are then submitted directly to EPA. This
approach is highly successful because it is a fully cooperative
partnership between academia (and ARS) and the crop protection industry.
Of the 24 insecticides that EPA is currently considering for use on
specialty crops, IR-4 has developed data for 23.

The Orphan Drug Program, housed in FDA, focuses on developing products
that demonstrate promise for diagnosis and treatment of patients with
rare diseases or conditions (affecting fewer than 200,000 people in the
U.S.). It is broader than IR-4: its three main functions are
administering the Orphan Drug Act, managing a grants program for
clinical research on rare diseases, and managing the humanitarian use
device designation program. Numerous economic incentives are available
for private companies to develop these drugs, and the Program
facilitates the evaluations, including difficult problems of running
useful clinical trials when the patient population in very small. Before
the Orphan Drug Act established this program, fewer than 15 drugs were
approved for rare diseases. Twenty years after its passage, 256 drugs
and biologics have been approved for rare diseases.

Facilitating approvals of GE specialty crops is different from
pesticides or orphan drugs, so the rationale developing an
organizational structure to address this issue needs to be considered
carefully. Such an entity might reduce both the costs and the
uncertainties of meeting regulatory standards. Efforts targeted to
consumer benefits (output traits) would be very likely to influence the
climate of consumer rejection, but no business plan has been developed
that envisions a profit from such traits in specialty crops. Having a
facilitating organization could help. Because of the wide
diversification of specialty crop industries, an extraordinary degree of
partnership, cooperation, and broadly based support would be necessary
to make this effort successful. What is needed includes the following:

-   Streamline knowledge of what is required for regulatory decisions,
    so that development efforts can focus on that.

-   Develop a network of laboratories within the public sector, somewhat
    analogous to the network of IR-4 research laboratories, but centered
    on product and molecular characterization and efficacy testing for
    regulatory clearance.

-   Pursue products that have a clearly evident public need so as to
    better empower regulatory action. 

-   Engage nongovernmental organizations as allies in development of
    small market opportunities that serve the public good.

-   Leverage regulatory knowledge across the public sector; develop
    public sector specialists in biotechnology regulation who can work
    with the proposed new entity.

-   Leadership from stakeholders.

**Recommendations from the Workshop**

Extensive discussions among the participants, both in plenary sessions
and in breakout groups, led to adoption of three major recommendations
for action.

> \(1\) Develop a plan, based on existing or new models, for an
> organization to facilitate the development of GE specialty crop
> products up to the point of regulatory approval.
>
> [Action]{.underline}: A steering committee was formed, consisting of
> volunteer participants from stakeholder groups (commodity and trade
> organizations) and university scientists, with participation also by
> USDA staff members. The committee will develop a concept paper for
> distribution to a broad group of stakeholders.
>
> \(2\) Develop a research plan to identify needed data for regulatory
> consideration.
>
> [Action]{.underline}: This recommendation will be among the first
> tasks to be addressed by the proposed organization once it is
> developed and implemented.
>
> \(3\) Prepare white papers for publication in internationally
> circulated peer-reviewed journals, assessing what is known about
> transgenic crops and the associated science.
>
> [Action]{.underline}: Volunteers from the workshop participants formed
> a committee to identify important topics for white papers and to
> suggest who might be best positioned to author them.

**Public Research and the Regulatory Review of**

**Small-Market (Specialty) Biotechnology-Derived Crops**

#### 

November 8-9, 2004

##### *PROCEEDINGS*[^1]

I.  ***Introduction to the Workshop***

**Workshop** **Purpose**

The purpose of this workshop was to discuss how the public research
sector, the regulatory agencies, and the private sector can work
together to facilitate the regulatory consideration of specialty
(small/niche market) biotechnology-derived crops.

**Workshop Objectives**

*Ann Marie Thro, National Program Leader, Plant Breeding and Genomics*

*CSREES-USDA*

The urgency of our purpose in this workshop is conveyed by an article on
"emergent issues" in biotechnology and agricultural research policy, by
Fred Buttel, a sociologist at the University of Wisconsin.  Buttel
believed that "the adoption of industry agendas for biotechnology
research will provide new ammunition to  \... critics of public
agricultural research, thereby creating unsavory publicity for the
system."  Buttel wrote that eighteen years ago.  Today, there are indeed
groups who have found ways to use biotechnology, in particular
transgenic crops, to paint a negative picture of agricultural research. 
 

As suggested in editorials in both Scientific American and Nature
Biotechnology in the summer of 2004, transgenic crop varieties are
needed from public research and small businesses, varieties that provide
a range of different benefits, in different crops; varieties that solve
problems for the environment, the economy, or individuals, or that
create new opportunities. However, before a broader offering of
transgenic crops can be presented to the public, they must be approved
through a trusted regulatory process.    

In 2002, the National Center for Food and Agricultural Policy (NCFAP)
published a report (Gianessi et al, 2002.) on projected pesticide
savings if all approved and pending transgenic crops were adopted.   In
2003, NCFAP observed to USDA that poor market acceptance for transgenic
crops appeared to be causing attrition among the pending opportunities
for environmental benefit identified in their 2002 report.  They
suggested a workshop to highlight benefits from transgenic crops in
USDA's research pipeline. 

In April 2004, at a planning meeting for such a workshop, the Steering
Committee pointed out that the concern raised by NCFAP applies also to
projects of USDA's state partners, the 1862 and 1890 land-grant
universities; and to small businesses.   To meet a need of all these
entities, the Steering Committee suggested a more focused workshop, on
navigating and funding the regulatory process, with special reference to
small-market crops that face a significant disparity between costs of
meeting regulatory requirements, and potential returns from a small
market.  While the focus was narrowed, the advisory committee was
broadened, to include representatives of the additional partners, and a
third USDA agency, our host today, APHIS. 

Before listing the workshop's objectives, it may be helpful to review
what are [not]{.underline} the objectives.

-   Intellectual property and freedom-to-operate concerns are set aside,
    to be discussed in other fora.   The organizers appreciate that
    there are groups working on these questions, such as PIPRA, which is
    represented at this workshop.  

-   Market acceptance issues are also, to some degree, taken out of the
    discussion, by focusing on crops intended for the U.S. market.   We
    are keenly aware that international aspects are important.  One of
    the outcomes of this workshop may be follow-on activities to address
    these.

-   We are further aware that the workshop may give rise to ideas that
    will be useful to the continued evolution of the regulatory process
    itself.  However, this also is not the purpose of the workshop. 

-   The workshop is not intended to suggest that small market size
    justifies concessions in the scientific standards of the regulatory
    process.

Workshop objectives include:

 

-   Identify current regulatory requirements that are major sources of
    cost; or of uncertainty, which creates costs;

-   Identify researchable questions, the answers to which would help
    meet those requirements effectively and at minimal cost;

-   Consider existing models that have enabled other small-market
    products, also subject to regulation, to complete the requirements
    necessary to come to market;

-   Propose one of these models, or a new model, for small-market
    transgenic crops.

Anticipated achievements are:

-   The target for the workshop is a set of recommendations for a
    concrete, do-able, fund-able model, one that will allow the
    regulatory process to work as intended for specialty crops, and
    thereby achieve market access for a broader range of approved
    transgenic varieties. 

-   The ultimate targeted outcome is a wider range of public-goods
    benefits than can be provided by major-market transgenic crops and
    private investment alone. 

Literature cited:

Buttel, F. H.  1986.  Biotechnology and agricultural research policy: 
Emergent Issues.  pp. 312-347.  In:  K. Dahlberg (ed.).  New directions
for agriculture and agricultural research.  Totowa N.J.  Rownard and
Allanheld. 

Editorial.  2004.  Untitled.  Nature Biotechnology, Sept 2004, Vol. 22
p. 1055

Editorial. 2004. The Green Gene Revolution.  Scientific American, Aug.
2004, p.8. 

**Impacts of Biotech Regulation on Small Business and University
Research: Possible barriers and potential solutions**

Background synopsis of a workshop held June 2004 and

organized by the Pew Initiative on Food and Biotechnology (PIFB) and
APHIS, USDA

Michael Fernandez, Director of Science, PIFB

This workshop focused on policy questions concerning the regulatory
burden and small-business and university research. The motivation for
the workshop came from the ongoing review of the regulatory structure
governing the use of biotechnology in food and agricultural production,
and the concern that a regulatory burden set too high may stifle
innovation, particularly in small businesses and universities that have
less capacity and less experience in dealing with regulatory agencies
and systems. Proceedings from this workshop (Fernandez and Smith, 2005)
are available on the website of the Pew Initiative on Food and
Biotechnology, at:

http://pewagbiotech.org/events/0602/.

**II. *Overview of the Current Economic and Regulatory Situation***

Moderator: *Dan Jones, National Program Leader, Biotechnology,
CSREES-USDA*

> **Specialty Crops**
>
> *Alberto Jerardo, Economist,*
>
> *Economic Research Service,*
>
> *United States Department of Agriculture*

Specialty crops, which generally consist of vegetables, fruits, nuts,
and other horticulture products. In 2003 these crops had a total sales
value of about \$50 billion, contributing about 25 percent of the total
U.S. agricultural production value. Farm sales value in relation to
other crops represents about 50 percent of total crop value in the
United States, and in terms of trade, about 45 percent of agricultural
imports and 24 percent of agricultural exports are specialty crops. Many
of these imported specialty crops are off-season fruits and vegetables.
These numbers indicate that specialty crops are not "small market" if
viewed collectively.

The farm sales receipts of these horticulture crops total about \$50
billion, representing 47 percent of all crops produced in the United
States. Some individual vegetable crops are even larger than tobacco,
which is one of the major field crops. Fruits and melons represent about
\$11.5 billion in farm sales receipts, and the share in total crops is
10.8 percent. One other large group is nursery and greenhouse crops,
consisting of floriculture and Christmas trees, which represents about
\$15.2 billion, about 14 percent of all crops and second only to
vegetables as a group.

Of the major vegetable crops in gross sales value by farms, potatoes
(all types) lead the group at \$2.6 billion, which represents about 15
percent of all vegetables. Lettuce is about \$2.1 billion, which is
about 13 percent of all vegetables in gross sales value. Tomatoes for
fresh market and tomatoes for processing represent almost \$2 billion
and about 12 percent of total vegetable farm sales receipts.

Among fruits and nuts, the largest crop is grapes, representing \$2.6
billion with about \$1.5 billion worth of grapes made into wine; grapes
represent 18 percent of all fruit and nut sales. The second largest crop
is almonds, which is the number one U.S. export nut product. Other major
crops are apples, oranges, strawberries, and melons. Other major
specialty crops include nursery and other greenhouse crops at \$9.5
billion, which includes vegetable transplants that are grown initially
in greenhouses. Floriculture is the next largest crop, which represents
about \$5.1 billion.

Market price depends on a number of factors that can be condensed to
four: supply, demand, competition, and quality. High yielding varieties
and good weather increase the supply and depress prices at the farm
gate, especially of commodity products. Competition increasingly comes
from overseas producers, whose cost basis may be lower than in the U.S.
Demand is also shifting, with increasing consumption occurring outside
the home (now about half of all meals in the U.S.). In response, U.S.
farmers must reduce input costs (for example, by planting seeds of
improved quality or using more efficient production practices), or they
must produce unique materials or materials with quality traits that set
them apart from commodities and bring a higher price. Good weather,
competition, and shifting consumption patterns are beyond the control of
the farmer. The quality of plants and seeds and the quality of products
are where biotechnology can make a difference.

As an example of individual crops and how the cost of the seeds or
transplants relates to total variable cost, in Michigan, potatoes are
used for manufacturing foods or making potato chips. Out of the total
\$2,392 in variable costs per acre, \$275 is the cost of the seeds,
which is 11 percent; but pumpkin seeds represent 3 percent of variable
costs for that crop because pumpkin farmers use only seeds, not plants.
In contrast, for blueberries, the percent of variable costs is much
higher because blueberry farmers use transplants (not seeds), even
though those plants are viable for a number of years.

**Regulatory Considerations of Small-Market Biotechnology-Derived
Crops**

*Sally McCammon, Science Advisor*, *Biotechnology Regulatory Services*

*Animal and Plant Health Inspection Service*

*United States Department of Agriculture*

The United States Department of Agriculture's Animal and Plant Health
Inspection Service (APHIS) formed Biotechnology Regulatory Services
(BRS) in 2002. Prior to that, APHIS had an organization called
Biotechnology, Biologics, and Environmental Protection that was
disbanded in 1998 with many of its functions integrated into other parts
of APHIS. However, because of subsequent increased national and global
interest in biotechnology and biotech regulation, APHIS reconstituted
its organization and did this based on an internal review process. The
stated purposes for establishing BRS were to keep pace with the evolving
technology and to assure that the resources were dedicated and capacity
increased to address the multiple issues that had arisen. APHIS-BRS was
to enhance the science basis of the APHIS regulatory program and ensure
that the regulatory program would be both rigorous and reasonable.

A variety of traits are being introduced into plants. These include
agronomic improvements in pest protection such as *Bacillus
thuringiensis* (Bt) protein-mediated insect resistance and virus
resistance; yield improvement; herbicide-tolerant crops; environmental
adaptations such as drought and salt tolerance; product quality
improvements; and pharmaceutical proteins.

Three major agencies review these products- APHIS, the Environmental
Protection Agency (EPA), and the Food and Drug Administration (FDA).
APHIS is responsible for overseeing the field testing and release of
plants into the environment as well as ensuring that the products do not
present agricultural and environmental safety issues. EPA reviews
pesticidal products to ensure environmental and food safety, and FDA
assesses the safety of the whole food. Which agencies review a
particular product depends on the intended use of the product. For
instance, a viral-resistant trait in a food crop will be reviewed by all
three agencies. Herbicide tolerance in a food crop will be reviewed by
APHIS-BRS and FDA, with EPA overseeing the use of the herbicide.
Herbicide tolerance in an ornamental crop will be reviewed by APHIS-BRS,
with EPA overseeing the use of the herbicide. Modified oil content in a
food crop will be reviewed by APHIS-BRS and FDA, whereas modification to
an ornamental flower crop will be reviewed only by APHIS-BRS.

APHIS-BRS regulates these products under the Plant Pest Act of 2000.
Plant variety development goes through several stages---from the
laboratory through early field testing and line selection, variety
development and finally into commercialization. APHIS-BRS regulates
primarily in the field testing, pre-commercialization stages.

The products reviewed by APHIS-BRS are called regulated articles and
have some plant pest attribute: the vector may be a plant pest, such as
[Agrobacterium]{.underline}, a gene or regulatory element may be
inserted from a plant pest such as cauliflower mosaic virus, or a gene
may be inserted into something that is a plant pest. APHIS-BRS evaluates
the potential to be a plant pest risk and whether it could have weedy
characteristics. Through its permit and notification process, APHIS-BRS
oversees importation, interstate movement, field testing, and confined
cultivation. (In the case of field trials, APHIS must be notified of
pending open-air tests of regulated articles). The permitting process
has a 120-day review, and the streamlined notification process takes 30
days, if the product qualifies. In both cases, State concurrence is
obtained before APHIS approval is granted. Sites are inspected and field
data reports are required at the end of the field trial.

As the new variety nears the end of development, the developer may
petition APHIS-BRS for non-regulated status, which usually happens after
several years of field testing. The petition evaluations are to be
completed within 180 days, but can take longer if more data are needed.
An extension process exists for those products that are similar to ones
that have already gone through the regulatory petition process.

Comprehensive scientific regulatory review occurs at this stage. The
various steps for evaluating the applicant's petition for determination
of non-regulated status include scientific review, development of a
draft environmental assessment (EA), and opportunity for public comment
on both the EA and the petition itself. APHIS-BRS usually requests
additional data or answers, and applicants may also withdraw and
resubmit applications. APHIS-BRS has never denied a petition, but 25
petitions have been withdrawn for a variety of reasons. For instance, a
small company may withdraw a petition if it realizes that its product is
unlikely to be successful in the marketplace.

When an evaluation is conducted, APHIS-BRS looks at the biology and
genetics of the plant, the nature and origin of the genetic material
used, and possible effects on other organisms in the environment or on
other agricultural products. The kinds of data required in a petition
include crop biology and taxonomic description, genotypic differences,
phenotypic differences, field-test reports from all the releases that
have been conducted under permit or notification, any relevant
experimental data or publications, and any unfavorable data. To evaluate
a submission, APHIS-BRS looks at the potential for creating plant pest
risk including disease and pest susceptibilities, expression of gene
products, weediness, agriculture cultivation practices, effects on
non-target organisms, effects on other agricultural products, and
potential for gene transfer to other organisms.

Since 2000, APHIS-BRS has granted 63 petitions. A total of 98
applications were submitted and 9 are pending. Two petitions have been
granted to universities - to Cornell University for a virus-resistant
papaya and to the University of Saskatchewan for a herbicide-tolerant
flax. Currently, the Agriculture Research Service has submitted a
petition for evaluation of a plum that carries plum pox virus
resistance. Since the first field test in 1987, more than 10,000
authorizations have been given at more than 39,000 sites. Each
authorization for field testing can be for more than one plant line
(event) and for more than one site of planting.

Whether using the permit process or the notification process, the same
issues must be addressed\--that the plant will be confined to the field
test and that it will not persist in the environment. For notification,
the field-testing confinement protocols must be available if an
inspection is conducted.

APHIS-BRS field test databases include information from for-profit as
well as nonprofit organizations such as academic or public institutions.
Nonprofit organizations have conducted field tests of small-market
(specialty) horticultural crops such as cucumber, grape, grapefruit,
peppermint, melon, persimmon, petunia, and pineapple. In comparing the
kinds of traits that have been evaluated by nonprofit organizations
versus for-profit organizations, quite a few virus-resistant,
bacteria-resistant, and fungus-resistant plants have been tested as well
as a much wider variety of agronomic properties by the nonprofit sector.
The for-profit sector has developed more of the herbicide-tolerant and
insect-resistant traits for commodity crops. In addition, a wide range
of phenotypes have been tested for product quality traits by nonprofits.

To answer the question as to whether there has been an increase or
decrease in the numbers of field tests by public institutions, there has
been no decrease in the number of field tests conducted by nonprofits.
(The nonprofits include foundations as well as academic and
public-sector institutions.) However, looking at the specialty crops,
there is a dramatic decrease in the number of field tests being
conducted. For example, from 1998 through 2003 the number of
notifications, sites, acreage, and phenotypes for lettuce peaked in
2000; only two tests were conducted in 2003. Strawberries show the same
pattern, with very small numbers of field tests being conducted and none
in 2002 and 2003. Melons show the same pattern, with a lot of work being
done in melons in the late 1990s but none by 2003.

In the near future, APHIS-BRS will be reviewing all aspects of its
regulatory process. Although the focus of this workshop was not on
regulatory changes, the information and uncertainties discussed will
help APHIS-BRS clarify what must be addressed through guidance
documents, in everyday communications, and in the regulatory structure.

The APHIS-BRS biotechnology Web site, www.usda.aphis.gov, offers much
information on the system developed during the past 15 years. In
addition, a U.S. Government Web site, www.usbiotechreg.gov, presents the
approvals done by the entire U.S. government regulatory system, 'event
by event,' and shows how each regulatory agency-APHIS-BRS, EPA, and FDA
has evaluated each of those events that are now available for commercial
production.

> **Assessment of Biotechnology Products:**
>
> **Protein Plant-incorporated Protectants**
>
> *John Kough, Senior Scientist,*
>
> *United States Environmental Protection Agency*

The United States Environmental Protection Agency (EPA) is responsible
for the assessment of biotech products that will deployed in the
environment. Protein plant-incorporated protectants (PIPs), are what the
EPA calls the pesticidal traits incorporated into plants. PIPs are among
biotechnology-derived products that have the potential for development
for specialty crops. The EPA works under laws that include the Federal
Insecticide-Fungicide-Rodenticide Act for the safety of residues of
pesticides that may occur on treated food. It also works under the
Federal Food Drug and Cosmetic Act and a number of other acts, including
the Endangered Species Act, with which all the regulatory agencies must
be involved.

PIPs are defined as both a pesticidal substance and the genetic material
necessary for producing that pesticide in a living plant. The genetic
material is essential to the plant for it to express the pesticidal
protein, but the basis of the risk assessment is the hazard of and the
exposure to the pesticidal substance itself. The data the EPA uses to
assess the safety of PIPs are based on the fact that these proteins have
a recognizably different characteristic from conventional chemicals; for
example, proteins have a predictable metabolic rate.

The EPA is part of an international effort to standardize the data
requirements used to assess PIPs. One of the important characteristics
is a description of the genetic material delivered to the plant,
including the biology of the plant. The inheritance and stability of the
introduced traits are also important, and the EPA also reviews and
characterizes the expressed protein and analyzes expression levels in
the plant.

Regarding dietary safety of the introduced proteins, because these
proteins have been designed to control pests, they have some expressed
toxicity. The required data are designed to ensure that that toxicity is
specific to the target pest. This test is conducted by looking at a
single, acute oral toxicity test at a very high dose---from 3 grams to 5
grams per kilogram of body weight. The test substance is pure protein,
and because of the difficulty of extracting adequate amounts of material
from the plant itself, the material is usually produced in an alternate
organism such as a yeast or bacterium. To ensure that the material is
the same as that expressed in the plant, a number of tests are
conducted, including amino acid homology between the expressed protein
and any possible known mammalian toxin. Food allergenicity is another
issue that is especially cogent for dietary exposure to new proteins;
this area is still in the early stages of assessment in terms of
scientific understanding, but the data used are based on amino acid
sequence homology. The protein's stability is also examined by exposing
it to intestinal fluids to determine that it breaks down rapidly, as
would be expected for the majority of dietary proteins. Stability for
processing is also tested, which would minimize the chances of exposure.
Because of known toxicity to some environmental organisms, the tests for
ecological effects review a range of surrogate species. A scientific
rationale for approval could also include a demonstration of no
reasonable expectation of exposure of non-target species to the toxin.

Endangered species are important to consider when looking at
environmental exposure. It is difficult to address the safety issues
because it is illegal to test endangered species directly. Information
on related species can be used in the risk assessment, and if adverse
effects are seen in that surrogate species, the next step in a risk
assessment is to look at whether an exposure component must be
considered. This was done for the Bt corn deployments with special
concern for exposure to the Karner blue butterfly. Information from the
nontarget testing and exposure that was examined for the Monarch
butterfly showed no significant interaction of the Bt corn plant,
especially the pollen, with the endangered species.

Decisions made by the EPA on the registration of protein PIPs focuses on
making findings of reasonable certainty of no harm. The EPA depends on
input from scientific peer review in the form of scientific advisory
panels of experts and from public comment on rules and regulations. Some
of that input comes from workshops and public meetings on issues of
special focus for the EPA. The relevant EPA Web site is
[www.epa.gov/pesticides/biopesticides](http://www.epa.gov/pesticides/biopesticides).
The EPA has been especially forthcoming in presenting all the data it
receives. Those data are put on the Web site, which allows the public to
examine the data concurrent with EPA review. The decisions and
rationales are shared openly with the public and with interest groups as
the process moves forward.

> **FDA's Policy for Evaluating Bioegineered Foods**
>
> *Mary Ditto, Consumer Safety Officer*
>
> *United States Food and Drug Administration*

Each of the Federal agencies involved in regulating the safety of foods
in the United States, USDA, EPA, and FDA has a unique role. USDA
oversees safety for cultivation, EPA oversees the safe use of
pesticides, and FDA oversees the safe use and proper labeling of foods
and food ingredients. In 1986 the U.S. government announced a policy,
the Coordinated Framework for the regulation of products derived from
the new recombinant DNA technology, or biotechnology, which stated that
foods derived through biotechnology would be regulated under existing
law as other foods.

FDA's statutory authority derives from the Federal Food Drug and
Cosmetic Act (FFDCA). Under the FFDCA, FDA has broad authority to
regulate the safety and wholesomeness of foods except meat and poultry,
which is the USDA's responsibility.

Whole foods are regulated under the postmarket adulteration provision of
the FFDCA. It is the legal responsibility of the producer to market safe
and wholesome foods. The FDA can act if something is not safe and can
take action when something is illegal.

In 1958 Congress gave the FDA authority for premarket review of food
additives. The definition of a food additive, that is anything which by
its intended use is added to food, is very broad, but an exemption for
premarket review was created for those additives generally recognized as
safe (GRAS). Congress recognized that many substances intentionally
added to food do not require a formal premarket review by FDA to assure
their safety, either because their safety had been established by a long
history of use in food or because of the nature of the substance and the
information generally available to scientists about the substance are
such that the substance simply does not raise a safety concern.
Substances such as proteins, carbohydrates, and oils that are normally
found in food and are normal components of food would usually fall into
the category of "generally recognized as safe" (GRAS), which means they
would be exempt under the food additive provisions of the law. FDA
believed that many of the foods being developed with biotechnology would
contain such components that are normally found in food.

Under the FFDCA, FDA is also responsible to ensure the proper labeling
of foods. A food should be identified by its common or usual name.
Additionally, representations made on a food label should be truthful
and not misleading.

Next are described the policy and procedures that apply to bioengineered
foods. The 1992 policy (Statement of Policy: Foods Derived From New
Plant Varieties, May 29, 1992; 57 FR 22984) provided guidance to
industry on both scientific and regulatory issues. This guidance may be
used by all plant developers irregardless of the method used to develop
the new plant variety. FDA evaluates the objective characteristics of
the food rather than the fact that a new method was used to produce the
food. New foods should be as safe as the foods that are currently on the
market. The policy encourages developers to consult with FDA about new
plant varieties developed using new production techniques including
recombinant DNA methods.

FDA instituted consultation procedures in 1996 (revised in 1997), which
clarified the interaction between the agency and developers. While the
consultation process is voluntary; the requirements of the FFDCA to
market safe and wholesome food is mandatory. Under the law, the
requirement for premarket review for food additives may be applicable to
substances "added" to a bioengineered food that do not meet the criteria
for the exemption for premarket review under the GRAS provisions.
Although the process of consultation is voluntary, FDA believes that the
program is effective and that all bioengineered plants intended for use
as food that have gone to market in the United States have been reviewed
by the FDA beforehand. It is unlikely that a producer would be able to
go to market without first having completed a consultation with FDA.

FDA evaluates food derived from bioengineered crops on a case-by-case
basis. While there are no required set of tests that every producer must
pass, every producer must evaluate the safety of their product and be
able to conclude that their new variety is as safe as varieties that are
currently in the marketplace. Given current technology, producers use
certain tests routinely because they are the best tests to answer a
particular question, but the FDA remains flexible in evaluating the
information a producer provides. The discussion between the producer and
the agency may be iterative. FDA will respond to a producer's submission
by letter which will be posted on the agency's Internet site once a
consultation is completed.

In evaluating potential safety and nutritional issues a
multidisciplinary approach is taken, and a producers may expect to
answer questions that address agronomic and quality characteristics;
genetic, chemical, and nutritional analyses. Included is an example of
the flow charts found in the 1992 policy. You will see that a producer
answers a series of questions, and depending on the information about
the new variety the producer may windup in the box that says "No
concerns" or "consult FDA."

The safety evaluation addresses both the intended modification that has
been introduced into the new variety and it also addresses potential
unintended modifications that might arise as a result of the genetic
engineering. In the case where the intended modification introduces a
new substance into the plant (usually a protein) information about the
identity and function of the introduced substance, the source of the
introduced DNA, digestibility, dietary exposure and potential for
altered nutrition would be presented. As to whether there may be
unintended modifications a genetic analysis to show stability of the
insert is helpful (usually both by segregation and molecular analysis)
as well as compositional information, especially that focusing on
important nutrients, antinutrients, and toxicants.

So a typical consultation would include information about the host or
starting plant describing the taxonomy and identity, its history of safe
uses as food, whether any harmful constituents are present in the host
and any important nutrients made by the plant.

Information about the donor or source organism for the DNA would
typically address taxonomy or identity, history of safe use as food, any
harmful constituents, the identity and function of the introduced
material (expression product). For the new variety a description of the
inserted genetic material is typically presented. Additionally, the
method of transformation, activity of regulatory sequences, the presence
of extraneous open reading frames, the number of inserts and insertion
sites, and genetic stability are discussed.

Some of the varieties that have completed consultation with the FDA
include corn, cotton, canola, papaya, radicchio, flax, cantaloupe, and
squash. The majority of traits that have been introduced are agronomic
rather than "value-added" traits. Agronomic traits included pest
resistance and herbicide tolerance. The "value-added" traits modified
the oil content of seed oil plants canola and soybean.

FDA posts on the Internet a list of those products for which a
consultation has been completed. The list contains summary information
about the new variety that includes the name of the crop and the
intended modification. FDA's letter to the producer and FDA's memo are
available from this site.

There are on-going initiatives at FDA. FDA s utilizing the Biotechnology
Subcommittee of the Food Advisory Committee to address questions that
are pertinent to the safety of foods derived through biotechnology. The
subcommittee as met to discuss allergenicity and molecular analysis. The
National Academies Institute of Medicine did a report on unintended
effects of genetically engineered foods on human health. The agency
continues to assist in foreign capacity building in this area. We are
preparing guidance to address allergenicity and the early food safety
evaluation of new proteins expressed in bioengineered plants.

Additional information may be found at FDA's Internet site. Go to the
Center for Food Safety and Applied Nutrition's (CFSAN) homepage
([www.cfsan.fda.gov](http://www.cfsan.fda.gov/)) and under "program
area" choose "Biotechnology."

> **Panel Discussion**

DR. KEITH REDENBAUGH (Seminis, Inc.): Sally, you mentioned your
determinations and then adding new transformation events to those
determinations. In your experience, how long has it taken to add to a
determination?

DR. MCCAMMON: Up to now, the extension process has taken about as long
as the original determination, but there is flexibility in the way that
system was set up for us to reexamine how we use the extension process.

DR. KATHY SWORDS (Gero-Simplot Company): For John: There are some
beautiful natural-resistance genes coming on the forefront that will be
utilized transgenically. How does the EPA intend to regard the
natural-resistance genes that may be coming from endogenous sources
relative to Bts, which have familiarity?

DR. KOUGH: If it is from natural solanum-type genetic background, they
would not be considered introduced genetic traits because they are part
of the traditional breeding accession.

DR. JOHN STILES (Integrated Coffee Technologies): What about importation
of genetically modified crops like a first importation? Would it go
through the same regulatory system? Would the USDA care? If it was not
going to be grown here, what would happen?

DR. MCCAMMON: The regulations are embedded in our traditional plant
protection and quarantine regulations. So if it comes into the
country---even if it will not be released into the environment---a
permit will be needed. We are working with the North American Plant
Protection Organization to determine what, if any, kind of evaluation
might be needed regarding environmental exposure. If it actually is to
be released in the environment, anything that comes into this country
must comply with the same regulatory requirements as anything developed
domestically.

DR. GREG JAFFEE (Center for Science in the Public Interest): If you look
at the databases on the review process from all three agencies and you
average how long it has taken to go through the review process, the
average time of each of the three agencies is not egregious when you
look at the data from 1992 or 1994 to 2003 or 2004. But if you break up
the data around 2000 and look at the review times before 2000 and the
review times after 2000, you see things take a lot longer now to go
through the review process at all three agencies. Why might it be that
it now takes longer to get products through the review process than it
did pre-2000?

DR. KOUGH: The bottom line is that post-2000 there was a dramatic upturn
in the demand for the expertise of the people who work on biotechnology
related to Starlink and other issues. A limited number of people conduct
these reviews, and you cannot put one person in two places at the same
time. There has been an effort in all the agencies to hire more people
or get contracting money to get back to the speed at which we were
working before in the review process.

DR. MCCAMMON: The APHIS has added several public participation
processes, which require more time. The clock does stop if we send back
a deficiency letter, so it may take much longer for an applicant to
address the deficiencies because we may be asking different kinds of
questions than we were earlier based on more biosafety questions coming
up.

DR. JIM COOK (Washington State University): One of the genes for
resistance to stem rust in barley has been cloned and transferred into
barley. Would what you said in response to the question about potato
apply here---that moving it in by that method would not require approval
under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)
other than whatever approval would be required under traditional
breeding?

DR. KOUGH: The only qualifier I would add is that, because it is
transformation, there are issues related to the marker gene that is
used. If you just move the gene in without any foreign nonhost genetics,
that would be akin to traditional breeding.

DR. KATRINA CORNISH (Yulex Corporation): I wonder if Sally would expand
on something she said---that the field test, both the permits and the
notifications, require State concurrence. How do you go about getting
that, how much does that stall the process, and how variable is this
among the States? Are there certain States where you would definitely
not want to even attempt it at this point?

DR. McCAMMON: I cannot think of any reason why we would not attempt it,
but I want to stress that the APHIS regulations are embedded in a long
tradition of the USDA of already established work with the States in a
variety of ways through our history of plant protection and quarantine
work. We have good relationships with the State departments of
agriculture. Developing a cooperative system regarding biotechnology was
not a foreign process that we had to introduce to the States.

Whenever a field test is going to be conducted, particularly for
permits, the State will get a copy of the application. We have had to
work on the issue of confidential business information, and some of the
States have personnel that are cleared to look at that and some States
are not. For concurrence, most of the States are used to the system now
so we have not had too many problems. In some States, when the issue
becomes controversial, it does take a bit of time, but that is a natural
result of working with one's partners.

UNIDENTIFIED QUESTIONER: What is the current status when the regulation
of a native gene is changed? Does that have any different regulatory
review if the promoter is changed or the expression of a gene is
suppressed, or is that treated like a completely foreign gene by the
three agencies?

DR. JOHN CORDTS (APHIS-BRS): Some of those discussions are still ongoing
in the Agency, but most of our reviews are still very comprehensive.

DR. JIM COUGHLIN (toxicology consultant): What has happened to the
January 2001 *Federal Register* notice about premarket notification?

DR. DITTO: We received more than 100,000 comments on that rule, and as
we read through them and talked to our legal counsel, we realized that
there are many issues about trying to require a mandatory premarket
notification program on products that are whole foods. Given the number
of other issues that came up after that rule was issued, the resources
that were involved, and the legal questions that were raised, we have
put that on hold and are proceeding under our consultation procedures.
The proposal is still out there, but you have not seen much activity
directly on it. However, we did make certain efforts to carry out other
parts of what we said we would do in terms of increased transparency and
engaging with other agencies and with the National Academy \[of Sciences
(NAS)\]. We have committed to finalize guidance and to produce new
guidance, and those activities are ongoing.

DR. COOK: Those of us in the land grant university network are getting
messages from the commodity groups that we support to go forward with
the research full steam ahead but do not put it into commercial use
until it is accepted in the marketplace. Do you know how many such
efforts are under way? Sally showed a peak two or three years ago and
now none. Are these on the shelf or have they been abandoned as
projects, and do we know how many are in the pipeline and on the shelf
within public-sector efforts?

DR. MCCAMMON: The ARS might have a much better idea about how to answer
your question. However, generally, I think the climate now is "wait and
see," and that includes academia and small business. A lot of these
particular products like the squashes and the melons weredeveloped by
small businesses, and those businesses have eliminated them from their
portfolio and are therefore not investing any more time or money,
perhaps because of the resources it takes to manage public perception
and dealing with the regulatory process are beyond what a small business
can withstand.

I also remember hearing that preferences change rapidly for some of
these small-market crops. If it takes 3 to 5 years to get something to
market from inception, the preference for that particular product may
have come and gone. So you have to time your product development with
the timing of market preference.

DR. KOUGH: One other thing that may account for the rising and fall off
is that a number of public institutions were using technology that was
proprietary and then found out that they would have trouble going
forward with it.

DR. TED BATKIN (Citrus Research Board): Are you looking at the
introduction of new genes? What about proteins that will downregulate
genes that are moved in the plant? Do you consider those the same in the
regulatory process as the addition of an external gene?

DR. KOUGH: That is a little vague. If changes would be expected to
affect the nutritional quality, that would definitely need to be
considered. Without more specifics on downregulation of the traits, it
is difficult to answer. If you downregulated something that was known to
be involved in a toxic phenomenon, like changing the glycoalkyloids in a
potato plant or altering the level of ER proteins known to be related to
allergens, those could need to be examined as part of the compositional
analysis for the food.

DR. NEAL GUTTERSON (Mendel Biotechnology): Regarding the EPA's view of
resistance genes, my understanding is basically that they regulate
natural plant function. So if one were to put in a transcription factor,
a kinase gene and another copy from potato back in potato, how would the
EPA view that?

DR. KOUGH: Other than the possibility of something related to the
regulation of that gene, it would be considered an inherent trait of
that plant.

DR. CORNISH: A question for the whole panel: How far along have the
regulatory rules come with distinguishing between food and farm and
industrial transgenics? Transgenic tires are not quite the same thing as
having a transgenic intravenous drug, and it seems they should not have
the same rigor in the rules that apply.

DR. MCCAMMON: The APHIS and the FDA have been grappling with this issue
for almost 3 years. We have a joint guidance document to deal with the
farm plants. We have worked with the FDA because the FDA has all the
expertise and the procedures in place for evaluating pharmaceutical
products, but the interface occurs from needing to decide how to treat
the field test in the environment of industrial pharmaceutical products.
At this point, we have put in place quite a few new field-testing
requirements for growing pharmaceutical products. The APHIS has said we
are not going to allow deregulation of these as they go to
commercialization, so we are looking at processes for commercializing
under Federal oversight as the product is being grown. Now the FDA has
discussed looking at the farm as a facility.

The APHIS recently came out with an amendment to our regulation saying
that if you grow an industrial-type plant product, it must adhere to the
same requirements for pharmaceutical growth. All of these expand and
expound on in much more elaborate detail the kinds of confinement
measures that we require for growing traditional biotech products for
food and feed purposes, but the main attribute of all of them is
confinement. It is only an elaboration of the details of how to achieve
that confinement. It is much more prescriptive for the pharmaceuticals
and industrials than it is for the field testing of food products.

DR. DITTO: We talked about regulation of the final product and that
joint guidance included everything pharmaceutical from animal drugs and
human drugs, human biologics, animal biologics, and medical devices.
From the FDA perspective, we are talking about how to produce a safe and
effective product and here is a unique way to do so. We recognize that
there are some unique issues. The USDA has responsibility for reviewing
the confinement of field trials and changes its regulations often. One
of the issues that people often do not realize is that, if people want
to put the production remainders into animal feed, anything that goes
into animal feed must be brought to the FDA's Center for Veterinary
Medicine, which regulates animal feeds.

DR. JOHN RADIN (ARS): A gene that is available and accessible through
conventional breeding procedures is far preferable because it escapes
virtually all regulation, whereas if biotech procedures are used, it can
be subject to a long procedure. Technologies now exist for removing
foreign DNA after its usefulness is over. Would that then make the
product equivalent to a conventionally bred variety?

DR. KOUGH: It is possible that would fit under conventional breeding.
Since nothing like that has come forward, it is either being done
currently or no one has asked our opinion.

DR. MCCAMMON: This brings up the broader issue of the baseline. What is
the comparator? The 2002 NAS report began the foray into the arena that
traditionally bred or nongenetically engineered plant varieties had some
of these same issues. In the late 1980s and early 1990s, nobody said
that these kinds of impacts would not occur with traditional breeding,
but that you would use this as your comparison when you were evaluating
the products of genetic engineering. Out of this came the concept of
familiarity that we do have a lot of familiarity with the crop plants
that are being developed and that these kinds of processes, breeding for
disease and pest resistance, have occurred for the past 100 years. We
have never said that significant effects are not occurring with
traditional plant varieties. If we are going to change that paradigm, it
would be helpful to do so in a conscious way.

As regulations are developed and even as some of these products are
being evaluated, the scientific community has to engage in an ongoing
basis. Otherwise, the balance of perspectives will not occur. We will
not have the benefit of your expertise and your desire to develop the
kinds of things you think are beneficial.

DR. DITTO: We did put out in 1992 a document that dealt with new plant
varieties and we thought that, however the new variety was derived,
there are certain questions you should be prepared to answer to know
whether you are bringing a safe product to market. We have depended on
plant breeders who do traditional breeding to do some of that vetting,
and there have been examples where some things have come to market that
really were not as safe as they should have been. They were discovered
and removed from the market. We must recognize that this new technology
raises some unique issues related to how you could get the trait in the
plant.

DR. ALAN MCHUGHEN (University of California, Riverside): Although
regulatory overview looks at the product and does a reasonable job of
doing so, the trigger is still process. If I am a genetic engineer and I
transfer a soybean gene into a new variety of soybean, and there is
nothing new and no foreign DNA, I still have to go through regulatory
review and have the regulators say, "Yes, this is not new. It's okay. Go
ahead." But if I did the same thing with conventional breeding, I could
bypass that entirely. This is one of the problems we have fundamentally,
and this has been mentioned by both of the NAS reports---in 2002 and the
recent one in 2004---that the trigger is not justified scientifically.
Sooner or later we will have to address that. For example, the XA21 gene
going into rice is produced using both conventional and transgenic
technology. Recombinant DNA technologies are virtually abandoned
everywhere except China because the conventional version is a lot easier
even though it is an inferior final product.

DR. THRO: There are vocal groups that are gifted in public relations
that disapprove of transgenic crops because they simply disapprove of
any kind of human intervention, so using a gene from the same species
would not be of interest to them. That does not mean that it is not a
good thing to pursue, because there are many consumers who probably
would be pleased, and there are good biological reasons for doing it.
But keep that wrinkle in mind.

DR. JERARDO: Organic fruits and vegetables constitute a large and
growing sector of the specialty crops market. A transgenic crop is not
considered organic so that part of the market might be excluded in this
case.

***III. Regulatory Challenges:***

***Experiences From the Perspective of Public Researchers***

Moderator: *John Radin*

*National Program Leader, Plant Physiology and Cotton, ARS, USDA*

> **The Papaya Story: Experience with Regulatory Issues**
>
> *Dennis Gonsalves, Center Director,*
>
> *Agricultural Research Service*
>
> *United States Department of Agriculture*

Hawaiian papaya is affected by papaya ringspot virus; a virus that is of
worldwide importance.   Work was started in 1978 to develop control
measures for papaya ringspot virus in case the virus migrated into Puna
district of Hawaii where 95% of Hawaii\'s papaya were being
grown.   Cross-protection work started in 1978 and the transgenic work
started in 1985; in 1987 a team was assembled to push forward the
transgenic work.

          The new concept of pathogen-derived resistance was
used.   Investigators believed that transgenic papaya expressing the
coat protein gene of papaya ringspot virus would be resistant to that
virus.  At the time, it was assumed that the coat  protein  gene  would
need to be translated.

          In May 1992, 95 percent of Hawaii's papaya was being grown in
Puna (53 million pounds), when the virus finally arrived.  By 1994 much
of the Puna papayas showed significant infection; by 1998 the yield was
down by half due to the virus, and the remaining fruit was of very poor
quality. By 1991, however, the research team from Cornell University ,
University of Hawaii, and Upjohn Company  had developed a genetically
engineered papaya that  was  resistant  to papaya ringspot virus under
greenhouse conditions.  The  transgenic line, called 55-1,  was then
micropropagated, and field trials were started  on the island of Oahu
in April 1992.  Following the APHIS regulations, a 1995 field
trial  which  was conducted in Puna  on Hawaii island  showed  that  the
technology was working nicely.   Using material from the first small
field trial in April 1992, Dr. Richard Manshardt  developed
the    \"SunUp\' and  "Rainbow" cultivars  that  were  subsequently
commercialized in May 1998.  The seeds were produced and released in May
1998, and in 1999 farmers began to reclaim their papaya farms.  In a few
years, much of Puna where the virus had been very bad several years
before had been transformed into lovely papaya fields once again.   The
\"Rainbow\" papaya is now the dominant transgenic papaya grown and sold
in Hawaii.

          **Commercialization.**  The application was submitted in
December 1995, and by November 1996 the papaya had been deregulated by
the APHIS.  By August 1997 the "Rainbow" papaya was exempted by the EPA
for tolerance levels.  In September 1997 the FDA had completed
consultations.   By  April 1998 the licenses  to  sell the genetically
engineered papaya  had been obtained  by the Papaya Administrative
Committee, a USDA Marketing Initiative.  In May 1998 seeds were
distributed to the growers.  From 1991 when the transgenic papaya was
first developed, it took about seven years to test, deregulate, and
distribute the seeds of the bioengineered papaya variety.

          **Funding.**  Much of this work was conducted  using funds
from special USDA grants targeted for Hawaii and the Pacific Basin
islands.  From 1981 to 1984 investigators received \$70,000.  From 1984
to 1987 investigators received \$94,000.  Specific funding came for this
project in 1988 through 1992---about \$112,000 during those 4 years.

          **Deregulation.**  Through the course of evaluating the
transgenic papaya, investigators knew by genetics that there was
one  functional  gene insert.  Much of the information utilized in the
deregulation application had been developed as a matter of course in
characterizing the product.  Investigators were asked if
the  transgenic  papaya could be a weed; papaya had been grown for 100
years in Hawaii, but the virus  was discovered in Hawaii in 1943. 
Papaya was not a weed before the virus came so it would logically not be
a weed now; experiments were not needed to prove this point.  As to
whether the  transgenic  papaya would cross to other  wild Carica
papaya, the argument was made that papaya  was originally  imported into
Hawaii and no wild papaya exists there.  Investigators reported a
positive experience with all three regulatory agencies.

          **Deregulation in Japan.**  Japan is very strict, but the
regulations are very clear as to exactly what is required.  Much more
extensive data are required, along with border sequences and
allergenicity.  The Foreign Agricultural Service provided a \$33,000
grant  through the Hawaii Papaya Industry Association  to  partly
 support the work necessary for this submission to the Ministry of
Health Labor and Welfare, which was  done in April 2003.   The ministry
subsequently requested more information.   The revised package will be
submitted in 2005.

         Biotechnology is the application of technology, and technology
has to be timely.  With the papaya work, the rationale was to solve a
problem as quickly as possible  and  to do whatever was necessary to
help the industry.  Regulations change with time, public sentiment, and
political pressures, but the impact of a transgenic product is affected
by its timely deployment.

> **Regulatory Challenges: Virus-resistant Stone Fruit**
>
> *Ralph Scorza, Research Horticulturist,*
>
> *Appalachian Fruit Research Station,*
>
> *Agricultural Research Service,*
>
> *United States Department of Agriculture*

         

In November 2000 an article appeared in *American Fruit Grower* titled,
"Biotech, Fight Diseases, Stay Healthy: Looking for fruit loaded with
cancer fighting agents and that ship well?  Just wait a few years." 
Four years later, what does the fruit industry have to offer to fruit
growers?  The "Rainbow" and "Sun-Up" papayas are tremendous
achievements, but that is all fruit breeders have to show growers after
four years.

       Fruit breeders are interested in this work because they want to
make improvements in traits that would otherwise not be made via
traditional breeding; disease resistance not available in the germ
plasm, new colors, new flavors, and neutraceuticals, and they would like
to improve traits in existing cultivars.  There is tremendous potential
for the fruit industry that relies on vegetatively propagated materials
in high-value varieties.  For example, 95 percent of pears in North
America are from three varieties; changing one of those varieties---for
example, making 'Bartlett' pears resistant to disease---could have a
significant impact on the market relatively quickly.  Almost the entire
production of sour cherries is 'Montmorency', and more than 50 percent
of the world's production of apples is concentrated in five varieties.

          The timeline below illustrates the full extent and timeframe
for activities leading to the development the gene transfer of plum pox
virus resistance, including:

-   Pre-project developmental work (regeneration and transformation
    technologies developed, isolation of the gene to be used for
    resistance, etc.).

-   Years 1 and 2---Starting out as the breeder getting a new gene into
    a program. Undertaking transformations, plant regeneration,
    molecular analyses for gene expression, plant proliferation, plant
    acclimatization, and plant propagation.

-   Years 2 to 5---Testing for virus resistance in the containment
    facility at Fort Detrick, Maryland, a USDA facility; gene expression
    studies; studies of the resistance mechanism.

-   Years 6 to 13--- Field testing by conducting multi-environment,
    multi-plum pox virus isolate field trials in 3 European countries
    where the virus is endemic; productivity and fruit quality tests,
    transgene expression tests, hybridization tests for transferring the
    resistance, and risk assessment studies.

-   Results: The transgenic clone is highly resistant to plum pox virus,
    as tested for more than 8 years in three field tests in three
    different countries.  The mechanism of resistance is now known and
    can be transferred through hybridization.  Quality and productivity
    are so good that this plum could be a variety in its own right.

-   Year 13---Deregulation and intellectual property issues are
    addressed. Progress in these areas to be followed by variety
    introduction, adoption by growers, and acceptance by consumers.

At the initiation of the project over 13 years ago a "state of the art"
transformation vector to produce transgenic plants was employed. In the
13 years that it took to get a product close to market the regulatory
climate has changed in terms of regulatory issues and consumer
perceptions. This vector is no longer the most desirable in the sense of
the marker and antibiotic resistance genes that it carries. Fruit
breeders need long-term stability in the regulatory arena so that the
genetic elements that they use now in their transformation work will
have the greatest chance for regulatory approval a decade or more from
now. 

A survey of 32 stone fruit breeders worldwide found that few breeders
are using or considering using transgenics.  The reasons have to do with
lack of consumer acceptance, insufficient resources of money and
laboratory space, insufficient knowledge of the useful genes, and legal
and intellectual property constraints.

         A strain on resources was evident in the course of developing
plum pox virus resistant genotypes.  For example, regulations require
that all the prunings from the experimental trees have to be burned, and
all the fruit has to be harvested and destroyed.  A sentinel tree
program is used to monitor gene flow. A laboratory program was
necessary. Traditional breeding does not require much of a laboratory
program if any.  These costs that impinge on the program definitely are
considered by fruit breeders as difficulties in starting out in this
area.  Tree fruits in particular take up a lot of land long term and
require a lot of labor, so the decision to utilize transgenic technology
in a tree fruit breeding project cannot be taken lightly. It is a costly
and long term commitment.  If the fruit breeder determines that this is
the best approach, the regulatory issues must be addressed early in
project development and must be an integral part of the testing program.

          The current status of the plum pox virus resistance program is
that initial discussions with the APHIS occurred in October 2003, more
information was gathered from field testers in other countries, an
application for non-regulated status was submitted in August 2004, and
it looks like that process is going through and that a letter will
arrive soon from the APHIS.  Interactions with APHIS have been very
positive.  Constructive talks have set the stage for moving forward to
get these varieties out to serve the industry and consumers.

          In summary, here are the fundamentals of what is needed to
support fruit breeders:

-   A clear regulatory pathway

-   A stable regulatory pathway because tree fruit breeding programs
    take a long time

-   An economically feasible regulatory pathway

-   Regulations that promote public confidence and good science

-   Input from the scientific community as well as the public

          Publicly funded researchers can provide information to
facilitate regulatory considerations.  To provide this information,
publicly funded researchers need to know what information is relevant,
and funding is needed to get this information, especially in the long
term because of the long-term nature of tree fruit crops.  Mechanisms
are needed for efficient sharing of information between researchers and
the regulatory community, because some of this information is not going
to be published.  There needs to be a way to share this information
outside of the normal peer-reviewed publication process.

> **Regulatory Challenges: Sulfonylurea (SU)-Tolerant Flax**
>
> *Alan McHughen, Biotechnologist,*
>
> *University of California, Riverside*

Herbicide tolerance did not originate with genetic engineering; plants
have natural resistance to at least some herbicides. During 20 years in
Saskatchewan, we developed a number of new varieties, including a
conventionally bred new flax variety that was a somaclonal variant. That
flax variety has since became a major variety that has been grown on
millions of acres around the world without further regulatory oversight.
The original application for it was 30 pages long; the genetically
engineered version was many pages longer, 75 percent of which was
immaterial to any increase in confidence in the safety of the product
and was merely "jumping through hoops." A self-fulfilling vicious circle
occurs because the public knows about the intense regulatory scrutiny of
transgenics and thus believes if the regulators are so stringent with
them, transgenics must be hazardous.

Agronomic performance is needed; farmers will not buy a transgenic
product if it does not perform well, regardless of its wonderful new
attributes. In addition, proximate analyses must be performed for
conventional and transgenic products, anti-nutritive factors must be
reviewed to make sure those factors do not escalate out of control, and
the product must be genetically distinct and genetically stable.

It is important to know how the new product is biologically different
from the status quo, whether it carries enhanced fitness (the ecological
question that portends a chance of weediness), the difference between
the managed ecosystem (a farm) and an unmanaged ecosystem (everywhere
else), how to control unintended spread, and the benefits of the new
product. Often a new variety can be grown with fewer pesticides or with
less water, or it has positive nutritional attributes; these benefits
must be part of the regulatory system because evaluation of the new
product must be made relative to what is being grown currently.

In an analysis of the risks associated with genetically engineered foods
compared with the risks of other forms of breeding, we looked at
different methods of plant breeding---different types of recombinant
DNA, different forms of induced mutagenesis, and ordinary crossing. The
purpose of the analysis was to predict the likelihood of getting an
unintended effect, a measure of potential for hazard. Genetic
engineering cannot be segregated from all other forms of plant breeding,
but currently the regulatory structure does just that throughout most of
the world. It is not scientifically valid to trigger regulation based on
a method or a process.

Foods with novel substances or altered levels of usual compounds should
be scrutinized regardless of the method of breeding. A new modified
food, whether genetically engineered or not, whose composition is
similar to conventional versions may need little or no safety
evaluation. If a food is genetically engineered and is identical to the
conventional version, it does not need any more regulation than the
conventional version.

Limited resources should be directed to the things that must be known as
opposed to the things that are not necessarily needed to make a safety
evaluation and develop a mitigation strategy if one is necessary. For
similar but nonrecombinant DNA plants---for example, Xr21 for disease
resistance in rice and resistance in sulfonyl urea-resistant canola---if
the genetically engineered version and the conventional version pose the
same risks, they should be regulated the same way. Whether that is
superficial overview or deep scrutiny, both of those plants need to be
regulated the same way; that is the basis of scientifically sound
regulation, and that is what the public needs to know. If the trigger
for regulation is based on the method of breeding, then an objective
assessment is being applied to a subjective ideological foundation.

> **Challenges for Biotech Applications in Ornamental Crops**
>
> *David Clark, Associate Professor,*
>
> *University of Florida*

         High-cost, intensive agriculture includes many issues, such as
shipping and handling, transportation, and consumer issues.  Consumers
have very high expectations of ornamentals because the ultimate consumer
expects an unblemished product.  Petunias are the model system for use
in state of the art experiments on biotechnology of floriculture crops;
although they represent sales of only \$200 million a year wholesale.
 Petunias have been engineered for several potentially valuable traits
for floriculture crops, including ethylene insensitivity to increase
shelf life of flowers.  

          A flower-specific promoter from *Arabidopsis* hooked to the
isopentenyl transferase gene that makes cytokinins from *Agrobacterium
tumefaciens* inserted into petunia has also been shown to result in the
production of larger fruit larger and bigger flowers.  Other biotech
solutions for floriculture include internal growth regulators (for
flowers and for turfgrass), flowers that can be produced with reduced
amounts of chemicals, and leaves that stay green longer.  One unintended
positive side effect has been the acquisition of tolerance to the fungal
pathogen Cercospora, which was uncovered while engineering plants to
have leaves that stay greener longer; Cercospora will completely
defoliate a normal plant, whereas the stay-green plants will contain the
fungus but hold their leaves.

          Floral scent can be engineered by knocking out or
over**-**expressing genes involved in floral volatile synthesis. 
Ornamental crops are not subject to the same regulatory agencies as
edible crops, but if humans smell the plant, does that mean that
ornamental producers must adhere to additional regulations intended for
crops normally consumed orally?  If a single gene is knocked out, and
tests show that the only result is removing one scent-related chemical,
how will this be regulated?  Databases of genes are currently available
and are being mined, and additional genes are being engineered at the
rate of about one per week in our laboratory alone.  This means that
there are potentially several newly available technologies, but there
are still questions that linger with regard to how the end product will
be regulated.

          Associated with the large number of transgenic possibilities
are some negative aspects of the floriculture industry that do not help
with the concept of releasing new biotech floriculture crops.  The
genetics used across the industry are highly fragmented, and the
turnover of new varieties is rapid.  The average life expectancy of an
ornamental cultivar on the market is 3 to 6 years.  It takes 4 to 6
years to develop a biotech variety, so by the end of that development,
the genetics are obsolete.  This problem is amplified in ornamental
crops because consumers may like one color this year but another color
may be in vogue next year.  The markets are small:  Royalties on a new
variety amount to as little as \$1000-\$5,000 per variety per year. 
This combination of challenges makes it difficult for the floriculture
industry to prioritize fiscal goals with regard to biotechnology.  A
recent survey of some of the bigger growers around the country asked
what they would like in a biotech crop; about 100 people gave about 80
different answers.  Everyone wants his or her own problem solved, and it
is difficult to get a consensus on what is important.

          Breeders in academia have difficulty getting competitive
Federal dollars for working on a floriculture crops because the small
size of the crops and potentially small returns on investments make them
seem insignificant.  Some good researchers are doing science on some of
these floriculture crops, but many are working on these crops as side
projects.  Industry initiatives provide about half of the support in our
laboratory, and direct industry relationships provide about another
half, so academic research on floriculture is highly dependent on the
industry.  Some recent Federal initiatives have been discussed and are
being implemented, but they still only represent a small input to the
overall funding available for research on floriculture biotechnology. 
From the business aspect, justifying research and development
investments is where much of the technology is stopped in the ornamental
industry, and companies with small profit margins are not prepared to
handle the high hurdles and the high expectations of the regulatory
process.

          It is difficult to define the concept of how much value is
added to an ornamental crop compared with agronomic crops.  For example,
calculating the value of a better smelling rose is impossible because of
the subjective nature of "better smelling."  The ornamental industry is
also scattered in the sense that many growers have multiple crops, so
one particular crop is no more important than the other.  Combined, it
appears that all of these costs are on the brink of being too expensive
to justify the investment, so growers in the ornamental industry are
getting scared off.  There will always be industry problems, and
biotechnology-based solutions likewise will abound.  The question for
the ornamental industry is whether biotechnology will play a part.

> **Panel Discussion**

DR. LAWRENCE KENT (Danforth Center): When you look at the costs of
putting together a regulatory dossier for deregulation, a major cost
element in some cases is the protein purification for feeding studies.
In the case of pathogen-derived resistance strategies, one can get
around that cost or not incur that cost. Is that relevant in the cases
of virus-resistant products and did it hold true when you dealt with the
Japanese regulatory system?

DR. GONSALVES: The U.S. regulations did not require animal feeding
studies, and that was the same with Japan.

DR. SCORZA: We do not produce protein so there would not be anything to
test other than perhaps the marker genes, but we have not heard about
that so far.

DR. GUTTERSON: For a small company to contemplate the issues of the
regulatory process is not a trivial process, and several of you have
been through that process. We heard earlier this morning that it seems
awfully daunting to master that. Would you do it again? Is there another
solution to having academics handle the regulatory process?

DR. GONSALVES: In the land-grant universities, you look at something,
and if it is worthwhile doing, then you go ahead and do it.

DR. SCORZA: In our case, we really wanted plum pox virus resistance
because it is an extremely serious disease. It entered the United States
and Canada a few years ago and was eradicated, but it is currently a big
problem in Europe. We did not have any sources of resistance at that
time, so this was the only option if we wanted to be prepared for the
potential of this virus appearing, which it eventually did.

DR. MCHUGHEN: If small businesses and public institutions do not do it,
who is going to serve those smaller markets? The big companies have
their clientele with the big crops. It is important for those of us in
the public sector to get the system working to show that there are
benefits to public research and public development of new cultivars of
other new food products. We have to do it, even if it is terribly
frustrating. If we do not do it, the public will not benefit from this
technology to the extent that it should.

DR. CLARK: I would certainly do it again. We are supposed to be the
unbiased source of knowledge.

DR. FERNANDEZ: Alan, at the beginning of your talk you asserted that
more scrutiny from regulatory agencies makes people nervous, because
they think that products that receive such additional scrutiny require
it. That is a debatable proposition at best. In any of the surveys we
have conducted on that kind of question, it seems to show the opposite.
The more the FDA is involved, for example, the more confidence that
gives people in the end product. Do you really think that less
regulation would lead to more consumer confidence?

DR. MCHUGHEN: No. What I advocate is more effective regulation. We need
targeted regulation across the board. If we regulated in a targeted
manner, it would probably amount to the same degree of regulation we
have now, but it would be more targeted to those products that truly
pose risk. That will eventually build greater public trust and
confidence because we will be able to tell the public that the
regulation is science-based, that we are looking at the hazards, and
that we are regulating based on the hazard of a particular product
regardless of how it was made. It takes time to build consumer
confidence, but then the public will see the products coming through,
and presuming there are no disasters, that trust will eventually
develop.

DR. FREDDIE HAMMERSCHLAG (USDA): You have released and are producing two
varieties of papaya. Do you expect that the resistance is going to hold
up, and is there work under way to release other varieties with other
mechanisms of disease resistance? Having released these papaya in
Hawaii, the public has apparently accepted them; do you think this
acceptance will lead the way to other acceptances of transgenics in
Hawaii?

DR. GONSALVES: Based on the mechanism, I expect the resistance to hold
up because the viruses in Hawaii are generally uniform. We do have other
products in the pipeline. I do not think Hawaiian people are any
different from people of the mainland. My observation is that if you
have something that is good and well priced, consumers will buy it. I do
not think the public cares that much, and they basically trust the
government. My own experience is that we have had no public loss of
confidence. A lot of people make a lot of claims about the papaya
contaminating organic papaya, but that is not the opinion of the general
public.

DR. COOK: What is the status of regulation of coat-protein-mediated
resistance as a PIP?

DR. GONSALVES: A recent meeting should result in some kind of ruling
that will come out soon.

DR. SCORZA: We are going through the APHIS process, and some initial
discussions in general meetings with the EPA have concluded that if no
protein was produced, it may fall under a different regulation. We are
waiting to see.

DR. KOUGH: There was a recent meeting, and the intent is to address the
issue of exempting the viral coat-protein-mediated resistance. It is
still in discussion at this point. We have had other examples of virus
resistance without expression of a protein. That type of information
came in before there was any understanding of interfering ribonucleic
acid, and we went through the process and registered the viral replicase
in potatoes with minimal data.

DR. COUGHLIN: I was at General Foods and Kraft for many years waiting
for approvals on irradiated foods because the FDA decided 30 years ago
to regulate the process and not regulate the finished products. Mary
mentioned the magic phrase of GRAS, generally recognized as safe. I
spent some time working with the International Food Biotechnology
Council during the 1980s, and we did not want to see a replay of what
happened to irradiated foods. Could we talk about the possibility of
scientific review by academic panels that might be able to self-GRAS
some of these things? GRAS is 45 years old. We could home in on the
techniques used to self-GRAS other kinds of foods.

DR. MCHUGHEN: There are many opportunities with GRAS, but to apply GRAS
you have to first identify something new in the product. If you have
genetically engineered corn that has a novel protein in the roots, for
example, the corn oil from that corn is identical in composition to
conventional corn. So is it proper to call that corn oil GRAS? I do not
think so because that is misleading to members of the public who may be
familiar with the concept of GRAS. Where there are truly different
components in the oil---for example, the high oleic soybean---that does
require some regulatory oversight and a determination of safety for
specific purposes.

DR. GUTTERSON: The land grant institutions have a mission and you are
particularly mission-oriented people in solving problems, but I worry
that the average academic is not going to want to spend the time and
effort to do the regulatory work required to understand that process.
Even if we solve the cost side of it, for the land grant institutions to
carry out that mission will require greater support somewhere in the
institutions.

DR. GONSALVES: Until you are able to test a lot of these things in the
marketplace, it is difficult to look at it from any aspect except
academically.

UNIDENTIFIED QUESTIONER (University of California): I was intrigued by
your comment that we need a regulatory system to support public
confidence. During the recent debates in California about ordinances, a
common refrain that came from activists was that the FDA regulation was
only voluntary. The impression was that if the regulatory system were
required, there would be a higher level of consumer confidence. What
would you envision in a regulatory system that improves confidence?

DR. SCORZA: When we have regulations, we should not appear to try to get
rid of regulations because they are inconvenient. We have to identify
the important issues and the regulations to address these important
issues, and we should not regulate issues that are not important. We
have to be comfortable that what we are doing make sense and that the
regulations we are using will make a safe product. It would inspire
confidence if we really targeted what we want to regulate and show the
reason why we want to do that.

DR. MCHUGHEN: It is also important to keep in mind that regulating
simply to mollify public anxiety will actually jeopardize public
confidence because mistakes will be made. The Cartagena Protocol on
Biosafety, which was signed by more than 100 countries, is designed to
ensure the sanctity of and promote and preserve biodiversity worldwide.
This protocol was sold to the public at great cost because the public
wants to preserve and promote biodiversity, but the protocol does this
by regulating living modified organisms (LMOs) ---what the international
community calls genetically modified organisms (GMOs) ---and
scientifically there is no connection. Of all the damage that has been
done to biodiversity in the world, none has been caused by GMOs.
Eventually, when the environmental damage continues and the attacks on
biodiversity continue, in spite of the implementation of the Cartagena
Protocol, the public will understand that they spent a huge amount of
money and other limited resources supporting this protocol, but the
damage is still occurring. Public confidence in that regulatory system
will plummet. We do not want to see the same thing happen here.

UNIDENTIFIED QUESTIONER: Please describe the kinds of media attention
that you received on the products that you dealt with or are dealing
with and how you feel about being equipped to be able to address that
kind of media scrutiny.

DR. GONSALVES: You would think the papaya case was "untouchable" because
of the people being helped in Thailand, but Thailand is now under
ferocious attack by Greenpeace. All I can tell you now is that in Hawaii
and now in Thailand, there are major attacks on this papaya.

DR. SCORZA: Within the United States, any time I talk at a public group
about this plum there has never been a single negative comment. We had
an interesting meeting at the APHIS last year during which we were
talking, among other things, about this plum. Several environmental
groups were present, and they were quite interested because they felt
that this virus was a new virus in the country, an exotic disease. In
fact, this new plum and use of this type of technology could stop the
invasion of this virus, such as the Dutch elm problem and the chestnut
blight. The environmental groups believed that if the disease got into
the wild species of prunus, it would destroy forests, bird sanctuaries,
and habitat. That was something I had not thought of, so our public
comments gave a new light to what we could be doing.

DR. STEVEN STRAUSS (Oregon State University): The ornamentals are in
floriculture where there is almost limitless genetic
diversity---hybridization, radiation, and cloning. The high-powered
genetic work is very good at generating the diversity that industry
wants. Some of these species do establish in the environment to some
extent, although some are quite sterile and not adaptive. How would
regulators consider the environmental impacts, given the incredible
genetic diversity and genetic experimentation that goes on all the time
in that industry?

DR. CLARK: Right now we do not have the ability. I was giving a talk at
the international meeting of the American Association of Botanical
Gardens and Arboreta, and someone said that approximately 60 percent of
all exotic invasives in this country were brought in through botanical
garden introductions. We must keep our eyes open in terms of what those
people are doing, but all that genetic diversity adds layers of
potential difficulties.

DR. ERIC SACHS (Monsanto): We have developed various technologies and
brought them into reality as commercial products through the regulatory
path, but people were concerned about how well we answered questions
from public interest groups. As the technologies are brought forward and
as we focus on addressing some of the regulatory hurdles, it is very
important to talk about what is done by developers and in particular in
the universities and other interests that are developing these
technologies to address the questions that linger in the public arena.

DR. GONSALVES: As we were developing the papaya, we had "farm days." I
spoke at high schools. When the papaya was released, it was a major
media event. People knew what we were doing. You have to look very
carefully at the kind of education you are going to give people.

DR. SCORZA: Regarding the challenges for the researcher in going through
the regulatory hurdles, one of the biggest difficulties is figuring out
how to get this information to the public. That is a huge challenge: You
have a product, and now you want to see it accepted. An important aspect
of that is partnering with the commercial interests. This issue is
important because we need those partners. Who will those partners be,
and who has the money to do those kinds of things?

DR. CLARK: An example with Monsanto: I give lots of talks to master
gardeners with a demographic of 90 percent women. I also take groups of
7-year-olds through our greenhouses and show them transgenic plants.
Some of the most positive responses I have received for biotechnology
are from products like Round-Up Ready Soybeans in the Midwest. Farmers'
attitudes are changing, and they do not plow their fields any more.
Instead, they stick the seeds into the ground, which has the potential
for reducing erosion and the flow of silt into the Mississippi River and
down into the Gulf of Mexico. The Gulf of Mexico is very important for
the people of Florida, and everybody asks me why they have not heard
about these positive developments or seen any of these data. We must be
able to publicize the positive data that people want to hear about.

DR. MCHUGHEN: As public educators, we have to be careful not to sell
Monsanto's products, and overwhelmingly the products currently available
in agriculture belong to Monsanto or Dupont. We run into that criticism,
and I am sometimes accused of being a front man for industry and taking
money under the table. That is not fun to put up with that when I am
dedicated to the public good and try to provide education. I find most
people do not really want to be educated, but they want to be able to
trust regulators to tell them if a product is safe. A very noisy
minority, but nevertheless a minority, of people do not trust regulators
and believe they are in the pockets of industry. My job is to provide
information to people, whether they like the technology or the product
or not.

***IV. Regulatory Challenges:***

***Viewpoints From the Perspective of Private Business Enterprises***

Moderator: *Bill Goldner, National Program Leader, Small Business
Innovation Research, Competitive Programs, CSREES-USDA*

> **Regulatory Challenges: Horticultural View**

*Keith Redenbaugh, Associate Director of Regulatory Affairs,*

*Seminis Inc.*

Seminis is the world's largest vegetable seed company, with sales of
about \$500 million a year; Seminis sells vegetable seeds in about 128
countries. This discussion uses Seminis as an example to illustrate the
costly worldwide safety data requirements.

The cost of developing biotech products has not changed much in recent
years, but launching a transgenic biotech product will cost between \$3
million and \$5 million. The cost increases as time goes on and as
approvals are sought on a worldwide basis; for example, Monsanto spent
about \$65 million to develop its Round-Up Ready Soybean.

The EPA has never finalized its view on viral coat proteins. From
sitting through the FIFRA Science Advisory Panel workshop, it appears
likely that the EPA will decide to require registration, but will
provide certain exemptions. In my view, this is going in the wrong
direction by increasing the regulations and making it more difficult to
launch biotech crops.

Almost all the fruits and vegetables and many of the ornamentals are
exported to other countries, so a biotech crop cannot merely go through
the U.S. regulatory agencies. The developer must also look at the
regulatory entities in other countries such as Mexico, Japan, Korea,
Australia, and New Zealand. Europe has a unique process that is very
complicated and time consuming; Europe is once again approving food use
of transgenic products and has not yet ended the moratorium on approvals
for environmental release for field planting.

In 1998 Seminis had a total of 25 USDA field trial notifications. In
1999 there were 58 notifications, the peak year and the largest total
number of notifications. In 2000 there were 40 notifications and much
activity in new crops. In 2001 the number of notifications decreased to
20. In 2002 there were only 10 field trial notifications. This is the
genetic engineering activity of the world's largest vegetable seed
company. Four notifications occurred in 2003, and in 2004, there was a
nonsignificant increase to seven notifications or permits. Particularly
for the virus resistance and the herbicide tolerance, these traits
worked quite well; if Seminis were doing plant breeding and these
varieties were developed through normal breeding methods, they would all
be products because the technology worked. However, because of the
issues of regulatory costs and market acceptance, Seminis has shelved
these valuable potential products.

For fruit and vegetable research activities, all organizations working
with these crops show a peak in 1999 and a steady decrease until 2004;
it has about bottomed out at about 20 notifications from a high of 120.
In 2000 a lot of companies and organizations were involved in developing
biotech fruits and vegetables. Almost none of these companies is working
hard now at developing biotech fruits and vegetables. Some products have
become commercial, such as the papaya, the sweet pepper in China, and
the Seminis squash; Monsanto's insect-resistant potato was but is no
longer commercial. Many organizations were working on biotech projects
with sweet corn and tomato but are no longer doing so.

Unexpected issues along the way have caused problems: Horticultural
crops have small acreage but huge potential liability, high regulatory
costs, biodiversity issues with gene flow, coexistence with organic
farmers, labeling issues, and market acceptance (which appears to be a
more significant issue than consumer acceptance).

Ways in which public research agencies could help include:

-   Creation of a public biotech crop trait program to help get
    approvals for biotech crops.

-   Working on freedom-to-operate issues (as the Public Intellectual
    Property Resource for Agriculture is doing); a recent meeting
    focused on a freedom-to-operate transformation vector that could be
    used widely.

-   Capacity building in developing countries---putting in place
    capacity systems that will help them commercialize, which is
    especially needed in African countries.

Solutions for the United States and Europe include developing fewer, but
highly valuable, alleles such as consumer traits, with a focus on fresh
market opportunities, and using biotech genes already commercialized in
agronomic crops, such as Bt and herbicide resistance. Dr. Redenbaugh
concluded his presentation by stating that the industry is not moving
ahead strongly because of the problems and barriers created that have
encouraged industry to scale back significantly their investment in
biotech crops.

> **Regulatory Challenges: A Technology Company Perspective**

*Neal Gutterson, Chief Operating Officer,*

*Mendel Biotechnology, Inc.*

Mendel Biotechnology is a research and development company that was one
of the first plant functional genomics companies working on *Arabidopsis
thaliana* in 1997. The company's overall mission is to create value
through the knowledge of plant pathways and, in particular, plant
transcription factor function. Mendel commercializes technologies
through seed and germplasm customers with direct market access via
biotech traits, through chemical companies with direct market access via
chemistry, and through collaboration and research services that develop
long-term value. Although the company intends to commercialize products
as well, this is a longer term prospect. Mendel's basic mission was to
identify plant regulatory genes, discover and patent function, and then
commercialize those that appeared to have high value. This has been done
in *Arabidopsis*; all *Arabidopsis* transcription factors have been
characterized, an extensive database was built, patents were filed on
about 1,500 transcription factors (about 80 percent of the transcription
factors in *Arabidopsis*), and genes have been licensed to a number of
partners.

Significant costs are associated with this regulatory framework, which
does not contribute to safety, and those costs have had a significant
impact on Mendel's business. When Mendel was started in 1997, the
founders' vision was that in 10 years a tremendous number of different
crops would be transgenic products; that is not the case. Vegetables,
for example, are not an area on which Mendel focuses significant
commercial attention because of the lack of likelihood of commercial
development in the near term. Therefore, Mendel's primary business
focuses on crops that are already transgenic such as corn, soybean, and
cotton.

Dr. Gutterson's interest in event-specific regulation started at a
meeting in Monterey, California, about 2½ years ago that focused on
specialty crops. Much analysis has been conducted on the *Arabidopsis*
and cereal genomes with respect to dynamics of genome variation
evolutionarily. Event-specific regulation is an unnecessary regulatory
requirement that is not scientifically valid as a contributor to safety.
Genomics studies during the past five years have revealed that both
within species and among species, even in different families, there is
enormous diversity of gene positions without effect on safety;
polyploidization lies at the heart of this, and more than 60 percent of
all plants have a polyploid lineage. For example, some corn varieties
are as different genetically from each other as the mouse genome is from
the human genome.

The premise of event-specific regulation is the idea that insertion of a
novel DNA element into a plant could alter plant biology in unexpected
ways, i.e., insertional inactivation of an endogenous gene or activation
of that endogenous gene, an altered expression pattern of the introduced
gene or other molecular changes that in theory can have safety
consequences that can be elucidated by molecular characterization.
Regulations call for extensive analysis of each new event. Is this
scientifically valid? And, if the answer is unclear, what additional
work can be done to address that? The regulatory agencies could get
involved in funding additional work in genome characterization that
would help clarify this issue.

Extensive background information with mutation as a tool for crop
development suggests that mutations are not inherently an impediment for
developing safe products. Genome dynamics indicate that gene location is
not an important consideration for crop performance. The creation of
mutations has been a long-standing practice in breeding, and there are
more than 2,000 crop varieties derived from mutagenesis; so mutagenesis
per se will not necessarily create a safety problem. Evidence indicates
that mutations do not create problems when developing novel varieties,
in a way that would justify characterization at the molecular level.
Once a trait has been demonstrated, it should be sufficient to conduct
additional characterization of new varieties at the phenotype level. The
failure to detect problems to date, and the likelihood that most
insertions through transgenesis are not problematic, is linked to the
large amount of genetic redundancy in plants.

Regarding grass genome dynamics, closely related edible grass species
and even cultivars within species have genomes with different gene
positions for individual genes that might be considered alleles. Much of
this work has been conducted in maize, rice, and sorghum. There are
tremendous differences in gene context, and a noticeable lack of
micro-colinearity, between homologous chromosomes in rice, sorghum, and
maize. The zein regions of the maize, rice, and sorghum genomes also
show significant differences.

Recommendations:

-   The event-specific process should be eliminated entirely.

-   There is no evidence for relevance of insertion position for a
    transgene in the regulatory process.

-   The focus should be on phenotype, as it is for breeding. Testing
    once a trait has been established in a crop should be sufficient in
    subsequent events with that same construct in that same crop.

-   There is no basis for penalizing transgenesis methodology relative
    to breeding methodology.

-   Research funding should be directed toward analysis of genome
    dynamics in other crops, to further support these conclusions.

> Finally, no evidence exists for a safety benefit from what today is a
> very expensive process of event-specific characterization. Further
> research would be useful to understand genome dynamics in a couple of
> other families; given what has been learned about the conservation of
> function in different plants, crop-specific as well as event-specific
> regulation could be reduced when similar crops are being created with
> the same constructs.
>
> **Regulatory and Commercial Considerations**

**for Small-market Biotechnology-derived Crops**

*Terry Stone, Directory of Biotechnology and Regulatory Affairs,*

*The Scotts Company*

The future is in small market crops and they are the way to obtain
consumer benefit and greater consumer acceptance. Specialty biotech
crops tend to be the focus of universities, the ARS, and small startup
companies; as large companies are not generally interested in
small-market crops. Because they are grown on smaller acreages, there
exists a greater ability to manage production at different steps along
the path to the marketplace. Market risk can be reduced through approval
in countries with reliable regulatory systems. Real consumer benefit may
enhance public acceptance; for example, a lawn that needs to be mowed
only once a month is an important use of technology that is a consumer
benefit, a quality of life benefit, and an ecological benefit.

The U.S. regulatory framework is based on familiarity and history of
safe use. Regulatory agencies provide oversight and guidance before and
after commercialization. The Monarch butterfly issue that came with Bt
corn was a good example of how post-market regulatory authority
demonstrated the ability to gain additional data on the safety of Bt
corn to the Monarch butterfly. Thousands of field releases each year
show essentially no unintended effects. Regulatory approval comes after
very extensive risk assessment, scientific review, a great deal of
public input, and agency decision-making. Dozens of products have been
commercialized since 1996. Hopefully, the process of revision in the
regulatory system will lend greater certainty to the process and enable
some of these products to get to market through either the public or
private sectors.

Before entering the regulatory process, universities and the ARS and
other public organizations should consider the following:

-   Where will the resources for product development and regulatory
    approval come from?

-   Are the industry commodity groups and other stakeholders fully
    behind development and commercialization of the product?

-   Are they prepared to support the product domestically and
    internationally?

-   Are the channels understood to determine where country regulatory
    approvals will be needed or the product channeled from?

-   Can channeling from certain markets be successfully implemented?

-   Is the organization prepared to deal with media inquiries,
    unintentional releases, or legal challenges?

Universities and the ARS and other public organizations also should
consider the following science and regulatory questions:

-   Are there wild weedy relatives, threatened or endangered species, or
    other cumulative environmental impacts to consider?

-   Are there resources to develop the molecular expression and other
    safety data either in-house or through a third party?

-   Are there resources to develop dossiers and coordinate with
    oversight and other stakeholder agencies before and after regulatory
    approval?

-   Are there resources to implement a plan to appropriately steward the
    product?

-   Are there financial resources for a prolonged regulatory review?

-   Can an economically viable product be safely commercialized
    considering the above?

The APHIS should establish a threshold for adventitious presence because
that can greatly increase the likelihood of the product being
economically viable and safely commercialized. Regulation varies
tremendously from country to country. This is not just a science-based
process. The extent to which the APHIS and other regulatory agencies in
the United States are focusing on science is laudable, but the reality
is that it is a political process, fostered in part by public interest
groups who do not care about the science but have an agenda of their
own. That reality affects the kinds of data, information, and ways to
communicate and causes a great increase in cost that has ultimately
reduced the realization and the benefits to society of the technology.

Changes in regulatory policy occur slowly. Inevitably there will be more
regulatory requirements, although perhaps coupled with more flexibility.
Researchers at the ARS, universities, or other public agencies should
find ways to develop the data packages required to move a product
through the regulatory process. A small company cannot afford to develop
all of the data required to move a product through. If this can be done
at a university through public funding, there is a much greater
likelihood of seeing the product on the market if it is then handed off
to a small company, because that is where their strength lies.

The benefits and safety of biotech crops are well documented, yet
regulatory requirements are increasingly complex. Public research
agencies can be leaders in ensuring a strong regulatory regime and
developers and advocates of biotechnology-derived plants. This is not a
private industry function; it will have to come from public
institutions.

**Les Pearson, Dawn Parks, Maud Hinchee**

**ArborGen**

**Perspectives on the Application of Biotechnology to Forestry**

**Overview:** Forestry products are the third most valuable commodity
after oil and gas. Trees supply the bulk of the fiber for pulp, paper,
packaging and building needs. Some 5,000 products are made from trees.
Three billion people depend on wood for fuel so we must harvest wood.
But forests also are an essential component of our ecology. They provide
wildlife habitat, help control erosion and purify water, they sustain
the world's environment by emitting oxygen and sequestering carbon
dioxide, and their beauty is unquestioned.

The challenge of foresters today is to maintain the natural
characteristics of forests while meeting society's need for products
produced from trees. It is therefore essential that our forests are
managed sustainably for ourselves and future generations. During the
20^th^ century, wood consumption tripled around the world and continues
to grow. The most practical way of preventing this increased demand from
further impacting our natural forests is to increase productivity of
managed tree plantations.

Silviculture is the agriculture of trees -- how to grow them, how to
maximize growth and return, and how to manipulate tree species
compositions to meet specific objectives. Silvicultural research
increased loblolly pine plantation productivity from an average of 10-20
tons per acre 40 years ago to 90 tons per acre today on the most
productive sites. Advancements in site preparation and selective tree
breeding have been the primary contributors to this significant
increase. Biotechnology will be another important tool in the
sustainable silviculture "tool kit" for stepwise improvements in
productivity per acre.

As biotechnology helps to preserve natural forests, it also will give a
new role to trees -- roles such as pollution cleanup and restoration of
threatened species. It has long been said that people who fail to see
the big picture "can't see the forest for the trees." In this case, it
is important that we not lose sight of trees' potential by focusing
solely on the forest. By improving plantation trees, we can help sustain
forests.

**How biotechnology can reduce the impact on natural forests:** Today,
managed tree plantations provide only about one third of the world's
need for wood and wood products. The rest comes from other sources,
including natural forests. Clearly, if tree plantations produce more,
natural forests will have to produce less. For example, in the southeast
United States, loblolly pine is the major pulp species and has about a
25-year rotation. A five-year reduction in time to harvest would have a
tremendous impact over time on total cellulose production per acre.
Genetic research, including tree biotechnology, holds promise to produce
faster-growing trees and to increase the cellulose content of individual
trees.

Biotechnology can also reduce threats to tree health. Research is
showing promise to introduce traits that are resistant to pests and
pathogens that weaken or kill trees. Improvements through tree
biotechnology may also improve weed control, enabling young trees to get
a head start over nutrient-robbing weeds. Trees with these traits will
improve the competitiveness of the United States forestry industry in
the international market for forest products and they will improve
productivity of lands intended for pulp production.

**Other potential benefits of tree biotechnology:** Tree biotechnology
promises many other benefits beyond increased productivity. These
include:

-   Restoration and preservation of heritage trees. Research is under
    way at several institutions, including the State University of New
    York and the University of Georgia, to develop disease-resistant
    varieties of important and desirable tree species that are
    threatened with extinction due to diseases and pests. Biotechnology
    provides the best hope to save and restore species such as American
    chestnut, American elm, flowering dogwood and various oak species,
    which have been so important to our culture and the beauty of our
    cities and woodlands.

-   Clean-up of toxic waste and Superfund sites. It may be possible
    through biotechnology to develop trees capable of absorbing specific
    toxins from the soil. This has the potential to reduce by millions
    of dollars the amount of money spent on cleaning up toxic sites. The
    University of Georgia is among several institutions conducting
    research with trees for phytoremediation.

-   Improvement of water quality. Just as trees can be improved to
    absorb toxic metals, they also can be modified to absorb excess
    nitrogen, which contributes to water pollution and algal bloom in
    waterways. Rutgers University is pioneering research in this area.

-   Biofuels. The U.S. Department of Energy is researching the potential
    for trees to provide clean, sustainable fuels. One possibility is to
    convert the cellulose in wood to ethanol for use in automobile
    engines. Biotechnology can play a vital role in producing wood
    better suited for the production of ethanol, which can reduce our
    reliance on foreign oil.

-   Improved lignin content for pulping. Biotechnology can reduce the
    amount of lignin in trees intended for paper manufacture. Lignin, a
    natural polymer found in wood, must be removed in the pulping
    process. Trees that have less lignin or more extractable lignin are
    more readily pulped, allowing mills to reduce the chemicals and
    energy required to remove lignin and purify cellulose (the basis for
    paper, packaging and many absorbent products) from wood. The mills
    are expected to better achieve their ambitious environmental
    objectives while also reducing their costs and inputs.

-   Better lumber. Biotechnology may also produce straighter trees, with
    fewer limbs, which results in more and better lumber.

Continued research in tree biotechnology may address and solve other
issues, such as why some woods resist rot and others do not or why some
species are susceptible to insects and others are not. Through this
continuing knowledge will come many advancements that will maximize the
value and efficiency of trees.

**Deregulation:** Commercialization will require that biotech trees go
through a regulatory process to assess risks and benefits. The framework
under which the Animal and Plant Health Inspection Service (APHIS) has
assessed the risks and benefits of agronomic crops such as soybean, corn
and cotton is effective and protective. This is evidenced by the fact
that more than 10,000 trials have been field tested since 1987 and more
than 60 biotech products have entered into commerce without adverse
effect on human health or the environment. This science-based approach
allows for the assessment of risk on a case-by-case basis for a
particular trait in a particular crop of interest. This approach is
equally applicable for many of the new products under development
including trees. The significant knowledge base that already exists for
tree species must be considered in the regulatory process.

Many products developed in new species are likely to be produced by
small companies or academia that are staffed and funded to produce the
science, but are generally unprepared for the regulatory requirements
and funding to achieve regulatory approval. If regulators are able to
advise companies far enough in advance on what data will likely be
required, companies can focus resources and attention accordingly.
Without knowing the requirements, small companies are disadvantaged and
could divert valuable resources to develop data that will not be
required for deregulation. Unlike large biotech companies, most small
companies and academic labs do not have the luxury of a regulatory
expert on staff to work through the regulatory uncertainties that could
lead to delays in commercialization. In the case of trees, the
significant understanding of their basic biology and management
practices could obviate the need to initiate certain types of studies
for biotech trees that would be redundant. In the Venture Capital or
academic grant funding world of today such delays may result in lost
funding, and great products could stall before they see the light of
day.

**The role of public research:** Several institutions, including
ArborGen, have made significant progress in introducing and testing
genes that improve wood volume gains as well as in improving the lignin
content and composition. ArborGen's trees are currently in multiple
field tests to determine trait performance and to ensure overall tree
performance in plantation operations. ArborGen has multiple field test
sites aimed at testing trees in the geographies and environments in
which industrial forestry is practiced for these species. Some of the
trees currently under evaluation will be selected for further product
development and future commercial sale.

Small companies are focused on the work and data to bring their product
to market. Scientific familiarity about the product and the trait is
learned through the scientific research, laboratory work, greenhouse
experimentation and field trials that will be needed for customer
acceptance as a product is brought closer to market. Small companies
must rely on public research to assist with regulatory approval by
developing broad scientific principles and providing baseline data. For
example, in long lived species, age-to-age correlations that support
early data used as predictors of performance in older trees are
important for a timely product approval. While much research has focused
on understanding the relationships and correlations between early ages
and mature stages, more research is needed. Small companies are unlikely
to be able to afford conducting this additional research, over and above
what is necessary for product development, but that is required for
deregulating their products. This type of data can best be generated by
public institutions.

For many tree species, the potential to use backcrossing to introduce a
trait into different germplasm is not practical because of
self-incompatibility. Asexual propagation of elite trees will most
likely be the basis for delivering high performance elite trees for
plantation forestry. A single approval for multiple genotypes containing
similar introduced genes, referred to as a trait by species approval,
would streamline the regulatory approval process. The broad
applicability of this approach would benefit small companies and
academics in particular. This approach is already supported by data that
demonstrates the consistent performance of transgenes across a wide
range of parental genotypes, for example through the extensive crossing
of transgenic annual crop species to a wide variety of different
cultivars. Public research could extend the knowledge base that would be
required to realize this approach.

Other areas that would benefit from public research include the
development of management practices that will address potential risks
and understanding how transgenic plants compare in fitness to their
natural counterparts in their normal settings.

Public research could develop the foundation for decisions regarding
gene flow. These decisions should be made on a case-by-case basis based
on an understanding of the potential ecological impacts. For example,
extensive work is under way to make the American chestnut resistant to a
devastating exotic pathogen for which there is no natural resistance. In
this case it seems highly desirable for pollen to flow freely to allow
the spread of this trait to natural stands and promote the restoration
of this species.

**Summary:** In summary, tree biotechnology will have many environmental
and societal benefits. Faster-growing trees, developed through
biotechnology, will contribute significantly to sustainable silviculture
by diminishing the demand for wood harvested from old growth and natural
forest stands. Many other benefits are possible, as well. These include
restoration of heritage tree species such as American chestnut and
American elm; clean-up of toxic wastes and nitrogen absorption;
biofuels; and lignin modification to improve the production of paper.
Biotechnology will help the forestry industry advance its goals of
providing wood products for society while protecting the natural forests
that provide beauty and essential ecological benefits. Public research
will develop the baseline data and fundamental principles that allow for
further development of biotech by small companies and academics.
Uncertainties in the type of data required for regulatory assessment
force companies to focus on those products that provide the highest
potential market and return. While the technology for many products that
benefit society exists, they may be significantly delayed or may never
reach the market if the costs associated with deregulation are
prohibitory.

> **Panel Discussion**

UNIDENTIFIED QUESTIONER: In your realistic presentation, you talked
about the costs and hurdles, and there are regulatory costs, public
acceptance costs, and market acceptance costs. You hinted that you might
want to elaborate more on the difference between consumer acceptance and
market acceptance. You left the impression that public or market
acceptance questions may be more constraining than the regulatory costs.

DR. REDENBAUGH: My observation over the years has been that consumers do
not care and, at least in this country, do not have a lot of concern. If
the FDA, the USDA, and the EPA have given their approval, then a product
is considered fine for the consumers.

As we have tried to launch some biotech vegetable crops, the various
commodity groups have said they do not want to be "next." They think the
technology is great and will solve some problems, but they do not want
their product to be the next biotech "test." Therefore, we are faced
with having to lobby within the industry to convince them that these
traits are going to be valuable. The problem is that most all the traits
have been ones that benefit farmers, and the farmers want these traits
as long as the processors and shippers/packers will take them. The
farmers would like to have these new traits because it helps them, but
the shippers/packers and the processors see nothing in it for them other
than trouble and problems. Until they start to see some benefits, they
will be resistant. I do not see that changing until it becomes evident
to them that they can benefit from the technology, which they can do if
beneficial consumer traits can be so labeled. A failed example of this
would be Calgene's FlavorSaver tomato, which I worked on; it benefited
the consumer, and the grocery stores liked the product because they
could charge more for it, so they were willing to accept it.

MR. STONE: One of the things we learned over the years is that prior to
attempting to get a product into the regulatory system, we must ensure
that it is wanted by the industry and that they are willing to support
it all the way through the process because the trait is seriously
valued.

DR. GREG CONKO (Competitive Enterprise Institute): Keith and Neal talked
about the regulatory framework not being based on science that is
event-specific regulation or process rather than product regulation.
What, if anything, are you doing to talk to the political level opinion
leaders above the regulatory establishment to create a political
environment in which the regulatory agencies could feel comfortable
making appropriate science-based changes?

DR. GUTTERSON: Mendel Biotechnology is a small functional genomics
company, so we do not have the resources to address that political
level. One of the great strengths in the United States is the confidence
in the regulatory agencies. Five years ago, event-specific regulation
was important because there was much we did not know, but today we do
not need to do that anymore. This more technical message is best
addressed at that level for a company like Mendel. Perhaps other
companies can address the political agenda at a higher level.

DR. REDENBAUGH: The U.S. regulatory system is not preventing us from
launching products. It is expensive and time consuming, but it is
predictable and doable. If that were the only issue before us, we could
be launching products without much difficulty. It is the broader
worldwide requirements that we have to meet, because most of the fruits
and vegetable seeds that we produce, even if they are grown only in the
United States, end up in the export market; so we need to deal with all
the export regulatory issues. The primary issue is market acceptance of
these products, and without traits for the market or consumers, there is
a real push back at this time. That is why Seminis is involved neither
in lobbying at a political level to try to bring about changes within
the U.S. system nor in other countries' regulatory processes.

DR. PEARSON: As a small company, ArborGen does not have the resources or
the staffing to do those things, even though we realize they are
extremely important.

MR. STONE: The avenues are being pursued through the Biotechnology
Industry Organization and others; it is a slow process. There has to be
real incentive for a decision-maker or opinion leader within the
government to drive a particular agency to do something they are not
already doing or are not determined to do. For example, establishing
thresholds is really important and has been going on for a number of
years. Our World Trade Organization case is an example of how government
is trying to influence biotech acceptance, not just domestically but
internationally.

DR. MCHUGHEN: Market acceptance and public acceptance are grossly
overblown when we consider that anywhere in the world where consumers
have been allowed access to biotech products, those products have been
embraced. The primary consumer for the industry is farmers, and 85
percent of farmers have embraced this technology; that is close to
saturation. I do not buy the argument that consumers do not want these
biotech products; I think they do.

Through one of their subsidiaries several years ago, Monsanto had a Bt
potato on the market, and I still know people who are jealously guarding
their Bt potatoes and grow them every year because of the Bt capability.
Monsanto should give that technology to some small company and let them
run with it and take that chance. There is a market for it; maybe that
market is not big enough to make money for Monsanto, but it has to be
big enough to make money for a smaller company.

DR. GUTTERSON: There is no doubt that the technology has been embraced
by farmers, especially in processed food crops such as soybean and
maize. We had an aggressive program in transgenic strawberries, but we
could not enlist Driscoll Strawberry Associates, Inc., and other major
companies that are breeders to incorporate it because they had concerns
about consumer acceptance. They know their market and there is
definitely an issue there. If Safeway were not concerned about it,
Driscoll would not be concerned about it, so it is not as simple as
farmers adopting the technology.

DR. REDENBAUGH: In the case of the Bt potato from Monsanto, the reason
why that was pulled from the market was because McDonald's and McCain's
frozen processor said they would not accept any Bt varieties. The market
was speaking. Consumers had no idea about this, but Greenpeace was out
to stop it; the last thing McDonald's and other companies want is to
have Greenpeace or other activists protesting. There was no benefit for
McDonald's or McCain's, so they said they did not want to have it---a
good example of the market pushback.

We were developing herbicide-tolerant lettuce and were working with the
IR-4 Project on the registration of the herbicide on lettuce. We started
running into opposition from some of the markets in the lettuce
industry. They were not so sure they wanted this product and started
making noise against it, and we realized it was going to be an uphill
battle. If the markets do not want these products, the developers have a
very difficult time launching them. That has happened to us with lettuce
and with tomatoes, which has affected our development of these products.

DR. GUTTERSON: Much of it comes down to companies that protect their
brands, which is a huge consumer asset. Gerber's, which was a subsidiary
of Syngenta-Novartis at the time, walked away from baby foods containing
transgenics. The Driscoll brand is such a prize with consumers.

DR. MCCAMMON: I would like to discuss the event-by-event evaluation and
what we should do with it. The regulatory agencies want to be able to
assure the public and the political powers that what the applicants
bring to us or say they are doing is what they really are doing. So, if
you take genes out of one background and move them into another, how do
you know exactly what genetic material you have extracted and that you
are putting exactly that into your recipient? That conundrum started
this whole process on the molecular level. Added to that is that, with
extremely powerful technologies, we get in a "fractile" mentality---How
much detail should you provide to characterize what you have taken out
of something? Part of the regulatory process is to make sure that if you
say you have just done a deletion or added a promoter, then that is
exactly what you have done.

We have heard that it is extremely expensive just to ensure that there
is only one copy and that you know exactly where that copy is located.
Do you have any comments on the issue of copy number?

At what level do we start evaluating the phenotype---on morphological
external characteristics or at the molecular or biochemical level?

DR. REDENBAUGH: We go way overboard in our analyses on this. I have seen
thousands of transformation events and different crops that we really
should be able to regulate on a gene-family-by-crop basis and not on an
event basis. We do this with getting approvals of chemicals---one
chemical on all the leafy vegetables, for example. We do not look at
each leafy vegetable individually; we put them together and do the
analysis all at once. We are going way overboard with this. We can do
the same thing with genes: If you have a construct and you know what you
are putting into lettuce, for example, and you put it into 20 different
lettuce varieties, you should not have to go through the entire process
20 times and examine all the data 20 times. That is overkill.

The insertional mutagenesis problem is overblown. We have not seen any
real problems, and if a problem did occur, we would catch and eliminate
it during the breeding process.

If you look at the important nutrients in a crop, at the phenotype, and
at the behavior in the field and if you do all the typical things that
we have done, you will be able to catch anything. We overregulate even
in the United States on this event-by-event basis, and I see no
justification to continue with that sort of regulation and oversight.

DR. GUTTERSON: Regarding copy number, it is appropriate to ask whether
copy number contributes to safety and what difference it makes. There
are many genomes with multiple copies of genes all the time. There are
complex gene families that exist in genomes. One gene more or less does
not have a major impact. That level of variation exists in the edible
crops we eat everyday. Five or ten years ago we did not have that
background, but we do now. We know that copy number determines to some
extent the level of penetrance of a phenotype. The phenotype
works---that is what breeders do---and the same model should be applied
to transgenics as is applied to breeding: standard practices and
standard growth cycles in the field for phenotype.

DR. PEARSON: The history from the data on unintended effects is that it
will not be a major contributor, so looking at the phenotype and
following it through field testing needs to drive the process.

MR. STONE: It comes down to safety. If you have been able to demonstrate
that your trait is safe, if the original event is fully characterized,
and if subsequent events use the same trait phenotypically, you will not
see anything new. The issue for industry relates to outside of the
United States. At least some of the data are going to need to be
generated. At the very least, there should be a confirmatory expression
linking back to the original package. We should be able to notify the
APHIS of this information, and in the end it should be not much
different than the acknowledgment that is used for field trials today.
Companies will need those data for international approvals, and the
APHIS can request those additional data if they are required.

DR. DEBORAH DELMER (Rockefeller Foundation): At the Monterey meeting a
few years ago, there was a suggestion that the public sector, as a
group, should do one big project to try to change market acceptance. The
trick would be to pick the right project. Is there any merit to that
idea?

DR. REDENBAUGH: The 'Rainbow' papaya is a good example. It is a good
idea, but what is really needed is something for consumers to be able to
buy, handle, look at, and taste to see that it is safe and good. Seminis
is interested in developing consumer products, but that is a long-term
prospect for us, perhaps 10 years away from having something that is of
real value to consumers. Perhaps those in the public sector have some
traits that they think they could put out sooner.

UNIDENTIFIED QUESTIONER: Terry made the point that it is essential to
establish contamination, gene flow, and adventitious presence
guidelines. In thinking about the risks to companies of getting
involved, it sounds like the lettuce growers are saying yes or no as a
group; perhaps that is because they are concerned that any contamination
of their seeds would cause trouble domestically and perhaps
internationally. If we could agree nationally and internationally on one
number for adventitious presence, would that allow niches to develop in
all of these small-market crops that then perhaps would open further
doors?

MR. STONE: Despite everything we are doing to be able to isolate our
production and prevent seed contamination, as long as you understand the
threshold or the target, you can develop a management plan to reach it.
Then it comes down to a cost situation---whether you can do that at a
cost that still makes your product economically viable. Assuming you
can, then you can bring that product to market in those areas where you
are able to financially afford to isolate it so that it will not go
anywhere else. For small markets, that is probably the number one
barrier to being able to move forward.

DR. REDENBAUGH: In Europe, they are working to establish these
thresholds, which may be anywhere from 0.5 percent to 0.1 percent. The
seed industry is saying that that level for many crops is impossible and
that 5 percent is more reasonable, but it is not going to be 5 percent
in Europe. The United States could benefit from this as well, although
it is not quite as important for most agriculture. It will become
important to have thresholds established for organic products, which
currently do not have thresholds. The organic industry has thresholds
for chemicals that have long been established, but they have been
resistant to putting in place any thresholds for biotech components.

## *V.A. Approaches to Regulatory Realities:* 

## *A Look into Existing Models*

*Moderator: June Blalock, Technology Licensing Program Coordinator, ARS,
USDA*

> **IR-4, What We Do... Provide Safe and Effective**
>
> **Pest Management Solutions for Specialty Crop growers**

*Bob Holm, National Director,*

*IR-4 Program, Rutgers University*

The IR-4 Program's mission is to provide safe and effective pest
management solutions for specialty crop growers. "Pest management
solutions" encompasses chemical controls, biopesticides, biological
controls, and plant biotechnology. "Specialty crops" means minor crops
or small-market crops.

Specialty crops include most vegetables, fruits, nuts, herbs, spices,
flowers, nursery plants, landscape plants, turf, and Christmas trees.
They are high-value/low-acreage crops that make up about 40 percent of
U.S. agricultural production, or \$45 billion in sales. A total of 23
States derive more than 50 percent of their agricultural crop sales from
"minor" crops. For example, in New Jersey, more than 90 percent of the
crops grown in the State are specialty crops, and more than half of
those are ornamental crop species.

The IR-4 Project is a publicly funded organization that has been around
for 41 years. It exists because of the lack of economic incentive for
the agrichemical industry to develop products based on small-market
specialty crops. Funding comes from the USDA, the CSREES and the ARS,
the land grant university system, and some commodity and crop protection
industry support. This year the IR-4 budget, along with a number of
other USDA programs, was cut 10 percent. The land grant system provides
infrastructure support in the form of laboratories and office space. For
every Federal dollar that goes into the IR-4 Project, there is a
matching State dollar. The crop protection industry partners fund the
out-of-pocket costs. The program also receives in-kind support in the
form of analytical support, message development, and analytical
supplies. The total value of the IR-4 program is \$25 million to \$30
million.

Field trial and residue analysis sites for the IR-4 Project are located
around the country. The national headquarters is at Rutgers University,
New Brunswick, NJ. The Northeast Region headquarters is at Cornell
University, Geneva, NY, the North Central Region headquarters is at
Michigan State University, Lansing, MI, the Western Region headquarters
is at the University of California, Davis, CA and the Southern Region
headquarters is at the University of Florida, in Gainesville, FL. ARS
components are located around the country and headquartered in
Beltsville, Maryland. The backbone of the IR-4 Project is 30 field
research centers located around the country that conduct the good
laboratory practices (GLP) trials that are required for the EPA to
register crop protection chemicals. This system has approximately 125
full-time staff members.

The IR-4 Project is a stakeholder-driven organization that receives and
acts on approximately 500 requests per year from growers, commodity
groups, and the land grant university system but not from the
agrichemical industry. A stakeholder workshop is held every September to
prioritize requests, and about 200 stakeholders help in this task;
approximately 100 projects are taken on per year, and about 700 field
trials are conducted per year in the food use area. A similar amount of
work is conducted in ornamentals.

IR-4 develops the protocols and runs the field trials and then conducts
the analytical work and submits the registration packages to the EPA,
all within 30 months or less. After that, it usually takes about 12
months to get EPA approval, and the manufacturer adds the use to the
label based on the tolerances; then the crop protection tool is
available for growers.

The key to IR-4 is being able to form partnerships with a number of
different groups. Congress often cites the IR-4 Project as a model
interdepartmental organization that works among different governmental
and nongovernmental agencies. A strong partnership has been developed
with the EPA and has been expanded with a technical working group in
recent years. The program is experimenting with innovative approaches
such as electronic submissions to the EPA, which projects about a 25
percent cost savings in doing so.

In the work plan this year, there were 49 products that the EPA is
considering for registration in different classifications, and IR-4 is
working with 82 percent of that total base. Working with public health
products, such as mosquito control products or vector control products,
is not in the program's charge; removing those four products from the
total of 28 insecticides, IR-4 is working with 23 of the 24 insecticides
being considered for registration this year. Prior to the Food Quality
Protection Act (FQPA), IR-4 was averaging 100 clearances per year;
however, in the past 4 years, the program has averaged more than 500
clearances per year, and for calendar year 2004, they expect to approach
700 clearances.

IR-4 also works with other regulatory agencies; for example, IR-4 has
developed partnerships and alliances with the California Department of
Pesticide Regulation during the past 4 years and has also worked with
Health Canada's Pest Management Regulatory Agency (PMRA) under North
American Free Trade Agreement (NAFTA). Working with Agriculture and
Agrifood Canada for a few years has helped develop an IR-4 program in
Canada. This partnership has greatly expanded the number of joint field
trials, and some NAFTA petitions are now being reviewed by the PMRA.

Without the crop protection industry (chemical, agrichemical, and
biopesticide companies) working with the IR-4 Project and providing the
chemistries, IR-4 would not exist. The program alerts the crop
protection industry about market potential and sharing submissions.

The IR-4 Project works with herbicide-tolerant crops. The success of
RoundUp Ready Soybeans has been a curse in disguise for specialty crop
growers because the crop protection industry is not developing new
herbicides for broadleaf crops, which includes most of the vegetable
crops. There have been no new herbicides, and some of the older products
are still on the market, despite being under regulatory concern, because
many of them are B2 carcinogens.

Glufosinate-tolerant sweet corn may be the only success story. A residue
program was conducted. The glufosinate gene is a marker gene for Bt so
it is already in commercial corn, although it is not registered for that
use. It shows good insect and weed control, but none of the processors,
including Del Monte, wanted to touch the corn so it has become a niche
market. A lot of Bt sweet corn is being grown in the Northeast; roadside
stands are likely filled with Bt sweet corn. The IR-4 Project hopes to
have registration in 2005.

The other IR-4 project is glyphosate-tolerant lettuce, a partnership
among Monsanto, the IR-4 Project, and Seminis that was supposed to have
been fast-track-submitted in 2001. Residue trials were conducted, but
consumer-driven concerns about the product forced its cancellation.
California lettuce growers can spend \$500 to \$1,000 an acre to
hand-hoe their leafy vegetables. Consumers who buy the packaged mixes do
not want to see any weeds, but there are no weeds because someone has
either hand-hoed them or picked out the weeds by hand. Two shots of
RoundUp will completely control all the weeds, a technology that will
save the growers \$400 to \$500 an acre. Glyphosate-tolerant lettuce
will probably sit on the shelf for a long time.

The mint industry used its money to develop a glufosinate-tolerant mint.
Mint is a sterile clone that has to be vegetatively propagated, so there
is no outcrossing. All parties agreed except the producer of
glufosinate, Bayer Crop Science; IR-4 guidelines state that if the
manufacturer will not put the use on the label, IR-4 will not do the
work. This success story is not wanting from a marketing or consumer
consumption standpoint, but Bayer Crop Science was concerned about the
consumer liability issues.

Transgenic minor crops have potential, but it is unknown whether
herbicide tolerance and insect disease resistance will actually be
valuable in the marketplace.

> **The Orphan Drug Program at FDA**

*Sarah Linde-Feucht, Medical Reviewer,*

*Orphan Drug Program, FDA*

The Orphan Drug Program focuses on developing products that demonstrate
promise for the diagnosis and treatment of patients with rare diseases
or conditions. Its three main functions are administering the Orphan
Drug Act, a grants program, and the humanitarian use device designation
program. The Orphan Drug Program is organizationally independent from
the Product Review Division and interacts with all the review divisions
within the FDA. Organizationally, the Orphan Drug Program is located
within the Office of the Commissioner, so it acts as a mediator,
facilitator, and diplomat to help the sponsors and researchers of these
drugs navigate the regulatory process.

An orphan product is a drug, biologic, device, or medical food that is
used in the diagnosis and treatment of patients with rare diseases. Rare
diseases are defined as those that affect fewer than 200,000 people in
the United States; products are called orphans because they are not
developed by the pharmaceutical and medical device industries because of
economic and regulatory barriers. There is poor return on investment
because the product would be used in only a small population, thus
making it unattractive to the big pharmaceutical companies to invest in
research and development to bring that product to market.

Researchers face significant obstacles in clinical trials for orphan
diseases. Sometimes the trials do not fit the gold standard of the
randomized, double-blind, placebo-controlled trial that is preferred in
patients before going through the approval process; researchers may have
to use historical controls or other unconventional clinical trial
designs. Because the diseases are rare, the total number of patients
that can be expected to enroll in a clinical trial may be too small to
power the study to obtain meaningful data. The Orphan Drug Program works
with researchers and with the FDA's Product Review Division to help
construct these clinical trials to obtain meaningful data, although
likely not in an optimal number of patients. Other challenges include
the small patient population that is likely to be spread out over a
large geographic area, the heterogeneity of the disease, the likelihood
that few clinical experts in these diseases exist, and problems in
acquiring the product and ensuring manufacturing consistency. In
addition, a small company that may take on an orphan drug or medical
device may be faced with not only limited resources but also limited
experience in dealing with the regulatory process.

Before the Orphan Drug Act, fewer than 15 drugs were approved for rare
diseases, resulting in patients with these diseases having few treatment
options. Sometimes drugs used to treat other diseases were used off
label for patients with rare diseases, but data to evaluate efficacy
were not available for those off-label uses. In 1983 the Orphan Drug Act
was passed, creating incentives for orphan drug development. The
original intent of the act was to study some of these drugs for use in
rare diseases. Tax credits for clinical research were believed to be the
greatest incentive that could be provided to researchers and industry to
encourage the study of these drugs. The tax credit is 50 percent of the
clinical research costs, which is a significant incentive that can be
used for 3 years back and 20 years forward, creating a valuable
commodity for companies that get sold to another company in later years.
Other incentives built into the Orphan Drug Act include 7 years of
marketing exclusivity from the date of approval, marketing application
fee waivers, grants for research, and assistance from the Orphan Drug
Program.

**Exclusivity.** Once an orphan drug receives approval from the FDA to
go on the market, the company has 7 years of marketing exclusivity,
which offers some additional protection compared with patents. For
example, a use patent on a product may protect it for 20 years, but it
may take 15 years to bring that product to market, leaving only 5 years
on the patent. If the product has received orphan drug designation, the
company has 7 years of marketing exclusivity, another 2 years of
protection. In the case of patent protection, the person holding the
patent is responsible for defending the integrity of the patent; under
the marketing exclusivity available through the Orphan Drug Act, the
Secretary of Health \[Department of Health and Human Services\] will not
approve another drug for this orphan indication during those 7 years.
One other benefit of the Orphan Drug Act exclusivity is that products
that are considered unpatentable are now protected, for example certain
biologic products like gene therapy, blood, and drug products whose
development time is long.

**Prescription Drug User Fee Act (PDUFA) fee waiver.** Having an
application reviewed by the FDA for marketing approval requires a
significant financial investment. If an application includes clinical
data, it will cost \$672,000 (in FY 2005) to file an application with
the FDA; if the application is for a generic drug evaluation so that
clinical data are not required, the cost is \$336,000. Other fees called
establishment fees and product fees are paid yearly by companies to have
the FDA conduct inspections. All those fees are waived if the drug is
designated as an orphan drug.

**Process of orphan drug designation.** The application to the Orphan
Drug Program must contain information about the disease, the rationale
of why this drug would be useful in this disease, and an estimate of the
prevalence of the disease (which must be fewer than 200,000 people). The
Orphan Drug Program reviews each application, conducts some of its own
research, and makes a decision based on the original application or that
application plus additional requested information. Once the drug is
designated as an orphan drug, it is then eligible for the aforementioned
benefits.

The grants program administered by the Orphan Drug Program funds
clinical research in rare diseases. The budget for the FY2004 grants
program was approximately \$13 million, which provides seed money for
some of these researchers. Around 10 to 15 new grants are awarded each
year out of the approximately 100 applications received, and the Program
manages an ongoing 60 to 70 active grants at any one time. Currently, 38
products on the market have been funded in part by these grants. Much of
the grant money supports improving the knowledge base in rare diseases,
so even if the grant does not directly contribute to a product going to
market, the advancement of knowledge in that area is a success of the
program.

Twenty years after the Orphan Drug Act passed, 256 drugs and biologics
have been approved for rare diseases (compared with 15 before the Orphan
Drug Act). More than 1,600 drugs and biologics hold orphan drug
designation; although those have not come to market yet, they may be in
the pipeline or may have advanced the knowledge and in some ways the
treatment of rare diseases. In addition, the growth of the biotech
industry in part may be related to the Orphan Drug Act---nearly 50
percent of all biologic products that have been approved are orphan
products; Genentech, AmGen, and Genzyme are examples of companies whose
first approvals were orphan products. Orphan Medical is a company whose
sole reason for existing is the development of orphan products.

The Orphan Drug Program is effective because of the financial and
economic incentives, the marketing exclusivity, fee waivers, tax credits
and grants, the regulatory assistance that the office provides, and the
"status of status"---development of these orphan products is assisted
because sponsors and researchers can get inside the FDA and know that
they have an office that can advocate for them.

## *V.B. Approaches to Regulatory Realities:* 

## *Exploration of Possible New Models*

Moderator: *June Blalock, Technology Licensing Program Coordinator,
ARS-USDA*

**\
**

> **Biotech Crop Trait Program:**
>
> **A Proposal to Establish a Public Biotech Crop Trait Program (BCTP)
> to Assist in Regulatory Approval for "Minor" Biotech Crops**
>
> *Kent Bradford, Keith Redenbaugh,*
>
> *Steven Strauss, David Tricoli, and Roger Wyse*
>
> *(Presented by Steven Strauss, Professor, Oregon State University)*

Cost associated with R&D, particularly with regulatory approvals, is an
important reason that commercialization of biotechnology, especially
genetically engineered crops, have been limited almost exclusively to
high-acreage commodity crops. The decline in production of new biotech
varieties, as enumerated by previous presenters, results in a reasonable
conclusion that regulatory costs and uncertainties are at the core of
that reduction. If more output crops with direct consumer benefits were
on the market, consumer acceptance would increase; many of these output
crops will come from small-acreage vegetable, fruit, and ornamental
crops or some niches within the commodity crops.

The continuing stream of achievements in the science of crops inspires
technical confidence. There is no shortage of innovation in products
that are important and have significant value for consumers and the
environment, but bottlenecks in the system are preventing these niche
crops from getting through to the market. In addition, U.S. agriculture
is under siege from imports, with major concerns from agricultural
producers about how they can stay competitive with foreign products. One
way to stay competitive is to have superior technology that increases
the value and reduces costs. The United States leads the world in
agricultural biotechnology, but if the U.S. regulatory system is so
difficult to deal with, that lead in science will be meaningless. It
would be a shame not to be able to use this new technology to help U.S.
farmers compete in world markets.

Some kind of public-private partnership is needed. The IR-4 Project
boasts an incredible success record for registration of pesticides for
minor crops; perhaps this strategic model is relevant to the biotech
problem. A viability assessment is needed. The first year of such a
program in biotechnology might be a feasibility study that would include
a more strategic look at the issues, how the organization might work,
what it might work on, and whether there is enough here to go forward
given the current environment. The second year would involve developing
a business plan for how this program might operate. A feasibility study
would involve talking with a lot of the key stakeholders to determine
whether they believe this model can be successful and to find out
whether the USDA would support it; leaders would be sought to get behind
this program and champion it. The business plan would enumerate what
such a program would do and not do and would include extensive
discussion of liability risks, particularly in light of the acrimony
about biotechnology and the existence of lawsuits. It also would include
a recommended budget level, suggestions for where the money would come
from, an estimate of staffing requirements, and a listing of the
crop-gene-trait targets and priorities that make sense to work on now
and in the near future.

If such a program were to be implemented in biotechnology, some kind of
governing body would need to meet at least annually with all the
stakeholders to advise on the priority targets. Having key crop
stakeholder partners is essential, which is similar to the IR-4 Project.

The incredible diversity in minor crops makes it difficult to imagine
that the current regulatory scheme (event-specific regulation) could
ever produce maximum value. Therefore, classes of traits encoded by
genes in crops---perhaps groups of crops like the leafy
vegetables---might be able to get regulatory treatment all at once;
further investigation of how to group these crops is needed. Dialog with
regulatory agencies will be needed. Some of the key regulatory questions
would be:

-   What is considered reasonable design of feeding studies that get at
    the critical safety information as cost effectively as possible?

-   Is event-specific research needed?

-   How can that question about event-specific research be answered for
    broad classes of crops or broad transformation methods?

-   Are there certain kinds of vectors or markers that regulatory
    agencies might exempt to make the path to market easier and faster
    for future biotech products? (As a public-based effort, all this
    regulatory information would be publicly available.)

Regarding intellectual property, there should be strong linkages with
some of the efforts that are now developing to help identify technology
packages and licenses to facilitate moving forward. Outreach and
communication are critical in biotechnology and must be conducted
carefully and independent of the developer, actively communicating the
quality of the data and why the product is believed safe based on the
high-quality data. Post-commercial market surveys will enhance
understanding of the value and the impact of a product. Particularly in
the early years, funds would need to be found in addition to
public-sector support. Specialized grant funds could be sought to
support general issues such as a new transformation platform, good
techniques for confinement or tracking the movement of organisms,
compositional variation, a database of natural variation among
conventional varieties, and the best ways to give the desired levels of
expression control stability.

Much of this work would be conducted outside the biotech program through
contracts, but some would be done in-house. Staffing needs would include
a technical/scientific staff, and facilities would include a laboratory
and offices. The budget for such a program would start at approximately
\$5 million a year, which is about one-fifth of the IR-4 budget.
Proximity to a university with active research on minor crops would be
ideal. Expected clients include university scientists and breeders.

Public-sector leadership as well as investment in an IR-4-like program
could be a major effort in moving biotechnology forward, acting as a
critical bridge among scientific advances (which continue to be
impressive), application, and public acceptance for many crops.

> **Models for Regulatory Relief**

*Carole Cramer, Gary Lemme, Steven Pueppke, Jeff Wolt*

*(Presented by Jeff Wolt, Professor, Iowa State University)*

>  
>
>           Big-market biotechnology has been quite successful in
> commercialization of input traits and this experience serves as a
> model for understanding regulatory hurdles and costs. This experience
> shows regulatory costs rise through time with any new technology as
> the regulatory process matures.  For the example of input traits, the
> controversies about the Monarch butterfly and Bt corn and the Starlink
> episode increased regulatory costs markedly as public interest and
> concern were raised and regulatory scrutiny increased.  Regulatory
> costs internationally also must be figured in, because
> near-simultaneous regulatory clearances for the import of these
> products into other countries must be in place for a product to be
> considered viable and marketable.  Whether this is true for
> small-market innovations is not yet settled, so the question of
> international regulatory clearance may need special consideration for
> specific small-market concepts that may come forward.
>
>            The costs for registrations include costs for
> science-driven processes such as molecular characterization data,
> protein characterization data, and efficacy and safety testing.
> Related to those processes are regulatory fees, regulatory management
> to obtain clearances, and management costs associated with issues of
> regulation and marketing outside the United States.  Experienced
> regulatory managers who have dealt with big-market products ranked the
> gross categories of costs using the example of a single-trait Bt
> registration. Their analysis shows that for a first-time registration,
> costs are incurred in the order (largest to smallest): outside-U.S.
> issues management, safety testing, regulatory management, regulatory
> fees, protein characterization, molecular characterization, and
> efficacy testing. This ranking does not change markedly with a
> bridging data package, other than for reduced regulatory fees.
>
>  
>
> As models for regulatory relief are considered for the small market,
> public-sector scientists need to expand their considerations from
> research activities (which remain important) to recognition of the
> additional importance of regulatory and issues management activities.
>  The lesson of big-market biotechnology is that success occurs largely
> through emphasis on these extra-scientific issues and activities.
>
>  
>
>           A number of tactics can be utilized within the public sector
> that can lead to an improved regulatory process and improved success
> in regulatory clearances for the small market: 
>
>  
>
>        Streamline the knowledge of what is required for regulatory
> decisions versus what is "nice to know."  This involves standardizing
> the regulatory process to the maximum extent possible, while still
> recognizing the desire to maintain case-by-case flexibility. The goal
> of streamlining is to decrease the costs incurred in developing and
> reviewing duplicative data.
>
>        Develop a network of laboratories within the public sector,
> somewhat analogous to the network of research conducted through IR-4
> but centered on the needs for the product and molecular
> characterization and efficacy testing that are needed for regulatory
> clearance of small market opportunities.
>
>        Leverage the regulatory knowledge across the public sector so
> that public sector specialist in biotechnology regulation can be
> developed.
>
>        Create a baseline of knowledge for understanding the process of
> data package development for small market products. 
>
>        Pursue products that have a clearly evident public need so as
> to better empower regulatory action. 
>
>        Engage nongovernmental organization as allies in development of
> small market opportunities that serve the public good.
>
>  
>
>           When the regulatory managers were asked what they considered
> the most important public sector activities needed to streamline the
> regulatory process and making it more effective, they noted the
> following possibilities:
>
>  
>
>        Develop the necessary data and justification for using tiered
> data package development.  Recognition of the level of information
> needed by regulators should be based on the risks and benefits posed
> by the opportunity. Such a tiered approach could eliminate unnecessary
> and  expensive data requirements while maintaining those that are
> necessary and should be maintained.
>
>        Participate more actively in government efforts to harmonize
> regulations.  Harmonization takes many years to accomplish, but
> aggressive and consistent participation can result in lowering some of
> the barriers that exist throughout the world.
>
>        Continue conducting basic studies.  For developers of the
> technologies, the same type of basic questions arise over and over
> again. These basic questions should be answered in the public sector
> and laid to rest.
>
>        Develop data and approaches that allow for predictable
> requirements.
>
>  
>
>           As a model of success, the IR-4 Project could be emulated
> for specialty crops.  Its diverse funding sources include both public
> and private-sector funding.  The activities and administration of IR-4
> are disbursed across regions, which helps in effective coordination of
> research.  IR-4 depends heavily on its administrative advisors and on
> the Commodity Liaison Committee for leadership.  The unique features
> of IR-4 that might be emulated for biotechnology are the
> administrative structure, the diverse base of support for funding and
> resources, the unique mix of dispersed and regionally focused
> activities (so not everything is vested in one laboratory in one
> region), and commodity group leadership.  Commodity group leadership
> will be especially important.  It allows bridging of the users of the
> technology with the IR-4 membership, maintains focus and direction,
> allows for clear communication with commodity groups, and garners the
> support needed for championing funding and continued budget support.
>
>  
>
>           A poll of regulatory managers provided examples of practical
> actions that the public sector could take to support small-market
> crops.  They suggested that basic research questions should be
> answered that would produce data on, for example, pollen flow, gene
> flow, adventitious presence, digestibility tests, and insect
> resistance management.  Also helpful would be to define when multiyear
> monitoring for non-target impacts might be appropriate, and the
> important end points in such an assessment.  Justification should be
> created for tiered data requirements that eliminate duplicative data.
>
>  
>
>           Suggestions to consider for establishing regulatory relief
> for small markets include:
>
>  
>
>        Continue to advance science-based understanding to gain global
> acceptance.  Small markets are not likely to be confined to the United
> States.
>
>        Generate and disseminate science to address broadly impacting
> issues.
>
>        Support streamlined systems of regulation that, for a given
> product, differentiate through a tiered system the knowledge needed to
> gain regulatory clearances versus what would be nice to know from a
> science-based standpoint.
>
>        Using a national model, develop regional and national networks
> for sharing expertise in data development and regulatory expertise.
>
>  
>
> **Panel Discussion**

DR. REDENBAUGH: Regarding orphan drugs, do you have situations in which
a developer of a drug does not have an interest in its use for orphan
purposes, and so another party comes along that wants to use that drug?
If yes, how do you deal with intellectual property issues and liability?
Does the original developer of that drug face liability issues when it
comes to an orphan drug use by another manufacturer?

DR. LINDE-FREUCHT: Our office does not deal directly with intellectual
property issues or liability issues, but here is an example. Sometimes
our researchers are using a commercially available product to study the
product for an orphan disease, and they may apply for the orphan drug
designation. They can go to the company with the orphan drug designation
and say, "The FDA thinks what we're doing is important. Maybe you do
want to consider changing the label." This is what we mean by "the
status of status." But the original company certainly does not have to
do it if it is not in their plan. If the researcher can prove through
clinical trials and through the data that this drug will work in an
orphan disease, even if the label does not get changed on that drug it
is still helpful to the rare disease patient group because the drug can
be used off label through the practice of medicine. If the drug is then
used in a patient with a rare disease and a bad outcome occurs, the
original manufacturer of that drug is not necessarily held liable. The
doctor who used it off label might be liable, depending on the
circumstances.

DR. COOK: Bob made an important point about the pipeline not being full
anymore with respect to herbicides for the control of broadleaf weeds
and, for example, horticultural and minor crops. That is just as true
for the small grains such as wheat and barley. In the Pacific Northwest
we are counting solely on two chemistries---the ALS inhibitors and the
ACCase inhibitors. This is very serious and puts a sense of urgency into
what we are talking about. What about the insecticides? Is it true there
as well that new chemistries are not coming into the pipeline because of
what has happened with Bt cotton and Bt corn?

DR. HOLM: No. We have been very fortunate since the FQPA because the
initial focus was on the organophosphates and carbamates, which are
insecticides, and then the focus was on two classes of carcinogens that
include a number of herbicides and fungicides. We have worked with a
wealth of new chemistries in the area of insecticides and fungicides,
and this year we have seen 15 new products from companies we are working
with; all but two of them are herbicides. The good news is that there
are other products in the pipeline that are insecticides and fungicides;
the bad news is that the herbicide discovery effort has been
dramatically decreased.

DR. GUTTERSON: Regarding the IR-4 models, Steve commented that this
program should not be seen as an overall advocate for biotechnology.
That raises a problem, because if the government is going to subsidize
this activity, it has to be assumed that a public good is associated
with it. How do we navigate that challenge?

DR. STRAUSS: That requires a lot more thought and consideration. Such a
program would need to be an advocate for biotechnology in the general
sense, but for specific products and whether they are the best
alternative, we would need to be careful not to look like a for-profit
company trying to develop a product.

DR. RADIN: We already have programs in place for the public sector to
conduct research and biotech risk assessment. There is a competitive
grants program funding of \$3 million, and the ARS has been somewhat
successful in getting funds for its in-house research. Depending on how
they are counted, those funds can be anywhere from \$6 million to \$29
million. Some of this money is encumbered, but we need a strategy to
make it as effective as possible. Are you suggesting we should look at
our existing funding programs and start immediately to deal with the
questions in the way you are advocating? Or are you looking at new
funding so that these programs can continue to do what they have been
doing?

DR. STRAUSS: We are looking at new funding. For one, the biotech risk
assessment program is very small considering the number of issues and
crops involved. Second, there is a powerful attraction to things that
are in significant commercial use now to produce the biggest impact for
the research. Small-market crops are just trying to get to market and
have an effect. The ARS programs are a little more pre-product oriented
and more science development than partnering to release new varieties
and dealing with the regulatory issues and science. It is a distinct
niche for those reasons and, therefore, needs distinct funding.

DR. WOLT: The programs we have in the area of biotech risk assessment
are quite oversubscribed; there is more demand for research than there
are funds available. Therefore, redirecting available funding would not
be appropriate for what Steve has outlined here today. We need to
recognize that the types of research needed for any model we adopt will
have to focus on the regulatory science, which is a different nature of
science than the types of science that are funded through currently
existing programs. It will need a different model and different funding
sources.

DR. REDENBAUGH: Does IR-4 shoulder any liability in terms of the
products that are registered? Have you ever been sued by someone who did
not use the product right or had problems?

DR. HOLM: No and no. We do not even start discussing a product unless we
run it by the crop protection companies and they express interest. We
submit the information, but we are not the registrant on it; the company
holds the liability and all the product information. If the company puts
the use on the label, they retain the associated liability.

DR. COUGHLIN: Instead of modeling the IR-4, could expertise be added to
the existing IR-4 centers to do biotech crops? There is expertise on
each of those four campuses, and if there were four small, minor biotech
centers that were extensions of what is already there, might that work?

DR. HOLM: It could work. We debated this within IR-4 and at the Pew
conference this summer. There is a fairly strong feeling among many of
our stakeholders that we should not get involved in expansion because of
the potential frailties of the backlash from either the consumer or
political systems. We do not want to jeopardize our current funding;
people have actually threatened me that if we get into this program, our
base funding could be threatened. We do a great service for the U.S.
public by helping provide a safe and effective food supply, and we do
not want to jeopardize that. We are willing and able to help serve as a
model and to advise. We could even do some contract analytical work
because we have the capability. There are a lot of other university
systems that are capable of doing that, too.

DR. STRAUSS: I can imagine contracting with either IR-4 or some of the
laboratories for much of that work while the biotech issue settles,
hopefully, over time and then reevaluate later.

DR, SHARIE FITZPATRICK (Forage Genetics International): Regarding the
models of IR-4 Project and the Orphan Drug Program, much of the original
costs have already been borne by the primary use. When we develop models
for programs, we should be aware that the budgets that have been
suggested by the speakers today need to be increased, because these
traits may be appropriate only in these small-market crops. They may not
have been cost-shared by larger uses. What levels of funding may need to
be brought to bear because of the uniqueness of these traits?

DR. LINDE-FEUCHT: Some of the products whose development we promote are
add-on indications to something that is already on the market, but there
are also a lot of novel compounds that are brought to market that go
through without being add-ons but with orphan drug designation. A
comment was made earlier about the importance of finding the balance
among the challenges, but you have to balance the cost of holding these
products to the same scientific standards with the cost of doing
nothing.

DR. HOLM: The cost to do an average residue study is about \$100,000 and
with the fee waiver from the EPA, it is about another \$75,000. If you
include in-kind contributions from the land grant system, it probably
costs about \$250,000 for us to add a tolerance or a use. We are relying
on the toxicology database and refer to it from the agrichemical company
that developed the use for our major market. So if the trait were
specific for specialty crop markets, then the cost would be much
greater.

Thirty years ago, IR-4 did one study and got one clearance; today we do
one study, and our average is seven clearances. If we had to do a study
on every crop, we would be working all our lives just to get through one
chemical. Over the years, we have developed with the EPA a crop-grouping
scheme. There are 19 crop groups with representative crops in each crop
grouping. In each crop group, if we do 2 or 3 of the representative
crops then we get up to 30 registrations. It makes a lot of regulatory
sense because we pick the worst-case situation. With leafy vegetables,
we pick spinach because the leaf will retain the most residue. The
Agency does its risk assessment on the worst case, and if that holds,
then everything else within that crop grouping should hold. There is an
opportunity in the plant biotech area to use that same type of process,
and it could be very cost effective to do so.

DR. WYSE: Have you thought about access to genes and the freedom to
operate around transformation systems? We will have to bundle all of
that to provide freedom to operate and that will mean bringing some of
the big players on board as partners very early on.

DR. STRAUSS: That is a really big issue. A big part of the cost of the
business plan would be getting serious about some of the legal issues.
What it would take to get freedom to operate? Would any of the big
players give freedom to operate with any of their technologies, or would
they see the liability risk as being too high? For example, is Monsanto
technology completely off limits for public-sector use? There may be
enough in the public sector to be successful, but that would be a
serious issue.

DR. MCCAMMON: The IR-4 Project is built on looking at pesticides, and if
that translates into transgenic plants, there is pesticide resistance in
an insect or disease resistance. But there is great potential for
products that are not related to pesticides. Has anyone parsed out the
costs of going through the regulatory system of food products versus
pesticide products? What about the incremental costs?

DR. WOLT: We have not tried to take on this idea of trying to parse out
where the costs may lie. Those costs are very inexact to begin with, and
the more we try to parse them out the more uncertainty develops. The
process of a Bt crop versus a small-market nonfood crop will be
different, but I cannot tell you what the differences in cost might be.

DR. KEITH REDDING (Monsanto): Post-commercial or post-approval
requirements also need to be considered, especially for EPA
registrations and now potentially for USDA approvals, for example, IRM
monitoring, surveying for resistance, and other types of data
requirements. Not only will you need some group to take responsibility
for it, but also there is cost in head count associated with that.

DR. WOLT: The lack of baseline information on which to base a decision
for monitoring or determine an approach to monitoring is the most
significant issue. Monitoring made a lot of sense on the top line, but
looking at it deeper, the question comes up about just what are you
trying to monitor---What type of change are you trying to see, whether
it is in the food supply or in nature? This is an area that needs a lot
of basic research before we encumber the regulatory process with a large
variety of monitoring approaches.

DR. STRAUSS: A number of the traits that are of consumer interest are
traits that result from changed regulation of genes compared with the
pesticide model of having new herbicide tolerances that require complex
monitoring and toxicology. It is part of the regulatory negotiation to
get those changes in expression of native genes recognized as
substantially equivalent or familiar, and get the product deregulated
early in the research process.

DR. KENT BRADFORD (University of California-Davis): The regulations also
affect the research. The discovery process is much more difficult
because as soon as we want to get out in the field, we have a separate
situation to deal with. We just grew three or four acres of mutagenized
tomatoes in the past couple of years without any problems. We have other
products that are coming through that are still in the discovery stage
that are using transgenics, and we expect to have a completely different
situation as far as looking at those products in the field.

DR. DELMER: A negotiation is going on with the Cartagena Protocol, and
the public sector is not getting a voice in this dialog. Those who are
interested should talk with Shawn Sullivan at CIMMYT, who is their
intellectual property expert and has a significant interest in the
public sector having a voice in this issue of liability and redress.
Second, there is some need for somebody to create a list of common sense
principles. For example, we have been considering nutritional
improvement in sorghum, but there are some issues with gene flow in
sorghum.

DR. STRAUSS: In the near term, the most important function of this
public-sector entity we are starting to imagine would be to provide an
effective public voice to interact with the world as well as the
national regulators about what the science says and does not say. I have
heard from several sources about this conspicuous absence at these
critical regulatory negotiations of public-sector scientists who really
know the science and technology. The activists are there, and they know
the outcome they want. The public-sector scientists are poorly
represented.

DR. THRO: There is a document on the document table describing an
international effort to get public-sector input into the Cartagena
Protocol. Pete Van der Meer from Netherlands may be spearheading that
effort.

DR. GUTTERSON: Academic institutions have offices of technology transfer
and their mission is to get technology out into the world. At UC you
have a system-wide regulatory individual who can provide that kind of
insight and support. Maybe there is a need for funding, especially for
these large system-wide opportunities, for that kind of expertise being
brought into the academic environment.

DR. ROUSH: I want to express skepticism that we will be able to get over
these difficulties by finding traits consumers like. Zeneca produced a
tomato paste in the United Kingdom (U.K.) that was inexpensive, which is
the primary quality we always hear that consumers want. They produced a
tomato paste in a larger container for the same price and that was not
successful. What consumers want beyond low price is often fickle. Given
the 7- to 10-year timelines, how can we judge today what consumers are
going to be enthusiastic about in the future? The core of people opposed
to this technology is not going to be swayed by what we think consumers
want. They are always going to be out there and we have to face that
issue. The crops have already delivered what people wanted: They have
reduced pesticide use enormously, which is something consumers have
asked for since the time of Rachel Carson. If we cannot sell them on
that and we cannot address these issues with that alone, we are in
trouble.

DR. REDENBAUGH: Some clarification on the tomato product in the U.K. It
was the best selling tomato paste in the U.K., and in 1998 Zeneca filed
a request for an environmental release to grow the tomatoes in Europe.
Up to that point they were growing the tomatoes in California and then
processing and shipping very cheap tomato paste halfway across the world
to the U.K., which was not financially profitable. In 1998 the
moratorium against approvals started with a rejection of Zeneca's
request to have this product approved for environmental use, so the
product died because it could not grow the tomatoes locally. At that
point, Zeneca decided it would let the product stay on the shelf until
the supply ran out, and at that point the product disappeared. But the
consumers liked the product. It was the best selling tomato paste under
both the Safeway and Sainsbury brands.

DR. RADIN: Can we simplify our problems by identifying those crops with
hardly any exports outside U.S. borders and focusing on those to learn
how to address the issues of a society that is willing to accept these
products?

DR. STRAUSS: That would be a sensible way to look at the early
priorities.

DR. COOK: It is not as simple as it might seem. We have the potential
for transgenic barley for resistance to root disease, but barley is
grown in rotation with wheat and wheat is exported. If there is any
carryover from barley in the next year's wheat crop, then there is an
adventitious presence.

DR. STRAUSS: That is why we must have adventitious presence rules soon
that are workable and sensible and agreed on nationally and
internationally.

DR. MCCAMMON: The APHIS cannot help with the problems of adventitious
presence because once we deregulate something, we are stating that it is
safe. Adventitious presence has already been allowed by the regulatory
system saying it is safe for its intended use. The major issues are
marketing issues, especially if a genetically engineered product is
mixed with a traditional or organic product. There is no line for safety
as far as adventitious presence of things that have not gone through the
system yet, and we cannot say it is acceptable for "a little bit" of
something to get into the environment if we have not completed our
environmental evaluation. It is going to be quite difficult to determine
a specific threshold below which something is safe and above which it is
not.

DR. JOSETTE LEWIS (US AID): Would it not be advantageous to all parties
to start looking at the regulatory issues much earlier in the
development of the technology, so that the burden is on the technology
developers as well as the regulatory agencies to have a serious and
possibly conclusive discussion much earlier? If this occurred and issues
were raised, the product could be developed differently by engineering
around the regulatory concerns. That means the regulatory agencies will
have to be more decisive at an earlier stage, but the technology
developers also will have to go into the process much earlier.
Addressing these issues earlier in the regulatory process would benefit
both parties.

DR. STRAUSS: We need to use scientific wisdom. If every transgenic
event, because it is transgenic, is considered an entirely unknown
environmental and health risk and yet breeders can do virtually anything
with conventional technology that we know will pose all kinds of risks,
then this technology in specialty crops will go nowhere. The regulators
need to realize that they can be a bottleneck, and they need to make
some scientific decisions or the technology will not go forward.

UNIDENTIFIED QUESTIONER: The regulatory and scientific concerns are only
part of the issue. The regulators are addressing the theoretical,
potential concerns that have been identified around these technologies.
Even after these technologies have been deregulated (by the USDA) or
concerns have been addressed by other agencies, those concerns never go
away in the minds of some people. As a scientific community and a
regulatory community, until we stand up and clearly state when an issue
is over and it is time to move on, we will continue to deal with it.

MR. STONE: The reality is that these issues do not go away. They
persist. I cannot imagine a university or IR-4 taking a product all the
way through and bringing it to the market and then getting international
regulatory approvals as well---for a specialty or a small-market crop.
It is not going to happen. There are issues that our regulators need to
make decisions about and provide guidance. If you do not, our scientific
community and our industry will not have a voice that will be recognized
satisfactorily by the public. We understand that once Biotechnology
Regulatory Services (BRS) deregulates they cannot set a threshold, but
what is the BRS doing with the Agricultural Marketing Service to ensure
that a threshold is being established? These are real needs and they are
not being addressed in a way that is helpful to the industry.

DR. JANET WHITLEY (FDA Office of Orphan Products): The Office of Orphan
Products Development and Orphan Drug Designation has a little known
program called Humanitarian Use Device Regulations, which may be
something to keep in mind. Humanitarian use devices are devices that
have a very small market, defined as less than 4,000 people in the
United States. The FDA allows the manufacturer to demonstrate safety and
probable benefit, lowering a barrier to entry and reducing the
regulatory hurdles. In return, the sponsors can bring their products to
market. This is a tightly controlled approval process that results in
approval that is not as complete as for an ordinary medical device.

## *VI. Breakout Discussion Group Results*

## 

On the second day of this workshop, four breakout groups were asked to
brainstorm solutions to surmount challenges and identify alternative
scenarios. Four issues were stated for discussion during the breakout
sessions:

## 

## Issue 1. Critical (priority) crops and traits to move through the regulatory process

***Summary of group responses:***

[Criteria for crop and trait selection:]{.underline}

-   Ready for development

-   Consumer health/nutrition

-   Significant \$\$ Value

-   Marketability/Commercial Partner

-   Only biotech solution available

-   Powerful market niche

-   Public sector as source

-   Intellectual property manageable

-   Biological safety

[Examples of Priority Crops and Traits:]{.underline}

-   Fireblight resistant apple/pear

-   Plum pox virus resistant plum

-   Anti-oxidant blueberry

-   Pierce's disease-resistant grape

-   Blight-resistant chestnut

-   Lignin-modified trees

-   Lignin-modified forage

-   Vaccines delivered through plants

-   Delayed ripening bananas

-   Non-allergenic peanut

-   Cucurbits w/ high carotene-lycopene

-   Methyl bromide replacement -- strawberry/tomato

-   Fungal-resistant potato

**Issue 2. Areas of research that could enhance and accelerate the
deregulation of small-market crops**

***Summary of group responses:***

-   Health-directed aspects of small market crops

-   Research directed to consumer attitudes

-   Ecological assessment of modified crops -- risk/benefit

-   Adventitious presence:

    -   IMPACT of pollen/gene flow

    -   Current level of "admixture" -- tracking

    -   Methods to prevent gene flow (optional use)

    -   Research to promote coexistence

-   Scientific meta-analysis of current products

    -   to improve process for small market crops

-   Research on "event-specific" regulatory issues

    -   Safety of transformation process

-   Allergenicity testing methods

-   Baseline composition analysis -- toxicological properties

-   Core vector/transformation systems

**\`**

**Issue 3. The appropriateness of existing models to overcome the
barriers and identify new models or propose changes to existing models**

***Summary of group responses:***

-   ASSUMPTION: There is a public good associated with application of

    -   biotechnology to small market crops.

-   QUALITIES OF THE MODEL (based on IR-4 concept):

    -   Regulatory compliance (expertise, implementation)

    -   Resources/\$\$ - sustainable funding

    -   IP support

    -   Regulatory research (both science and policy)

    -   Communication -- safety & policy

    -   Both new and previously regulated genes

    -   Accelerated approvals

    -   Economic incentives for partners

**Issue 4. Identification of next steps**

***Summary of group responses:***

-   Build a partnership with leadership from academia and the USDA

-   Develop support among Experiment Station Directors and within USDA

-   Seek funds to put together teams to focus on developing a proposal
    and plan

-   Build a constituency (e.g. commodity groups)

-   Meta-analysis of regulations in light of first 10 years of
    experience

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-   Identify research objectives

-   Establish a strategy for consultation with partners/industry

-   Pick a set of crops and traits

-   Prioritize research

-   Immediately gather and analyze existing data

-   Provide open access to information from both universities and the
    private sector

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```
-   Never give up!

-   Take a strong group position. Build a new structure to bridge where
    we are now and where we need to go.

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```
-   Develop an organization that can act as an intermediary between the
    research community and the regulatory agencies (such as the IR-4
    Project). It should provide expertise as IR-4 does, and researchers
    should get involved early with this organization. (IR-4-like groups
    can propose regulatory efficiencies.)

-   Educate researchers and funding organizations about needs.

-   Provide seed grants to facilitate approvals.

-   Develop regional or national projects within the CSREES, to support
    research which would pull together interdisciplinary groups and
    would provide a way to target/prioritize research on groups of
    traits, genes, and enabling technologies.

Points of consensus among the breakout groups included the development
of a draft program with similarities to the USDA IR-4 Project,
supporting small-market pesticide registration, and FDA's Orphan Drug
Program. The proposed biotechnology program may work to facilitate the
optimization of the processes required for specialty
biotechnology-derived crops to meet rigorous environmental and safety
reviews in the most cost-effective manner possible, thereby allowing
important new specialty crop cultivars to enter the market. All four
breakout groups noted that it is time for action.

Discussion uncovered a number of examples of transgenic plants sitting
on the shelf. Considerable investment has been made through the use of
public research and development funding to develop these shelved crops.
It would be useful to compile a list of those products, since there may
be a product that is ready to begin the regulatory process. Vicki
Forster \[Forster and Associates\] will send Dr. McHughen a list of the
products that have been approved; this list may be useful to the
steering committee. A publication coming out in the next few months may
provide this information.

***VII. Recommended Next Steps***

As suggested by the breakout groups:

-   Form a Planning Committee to move all efforts forward. Develop a
    plan for the new biotechnology support program which may be based on
    existing models (e.g. IR-4, ODP)

-   Draft white papers to assess what is known about transgenic crops
    and the science. A committee should be assembled to suggest white
    paper topics. Topics for white papers will help drive needed
    research. These papers should be sent to peer-reviewed journals so
    the international community can understand the breadth of
    information on which these conclusions are derived. The ongoing
    APHIS Safeguarding Review Committee could assist in distributing the
    white papers.

-   Develop a research program; the data needed may be separate from the
    white papers, which will be more global about making the regulatory
    process more efficient. This research program would focus on gene
    composition and the collection of other relevant data to support the
    current regulatory system. This program will have different
    constituencies and practitioners than the white papers.

***VIII. Actions***

Workshop participants were adamant about the need for action.
Consequently, two volunteer groups were organized to move efforts
forward, a White Paper Development Team and a Planning Committee.

**White Paper Development Team:** Volunteers to develop topics for the
white papers were Carole Cramer (Arkansas State University), Hector
Quemada (Western Michigan University), Kent Bradford (University of
California--Davis), David Williams (Chlorogen), and Neal Gutterson
(Mendel Biotechnology). Dr. Gutterson will be the chair. These
volunteers will communicate during the next 45 days to suggest topics
for the white papers and then will circulate topic suggestions. This
group is not expected to write the white papers.

**Planning Committee:** Planning Committee volunteers included, George
Acquaah (Langston University), Ted Batkin (Citrus Research Board), June
Blalock (USDA-ARS), Kent Bradford (University of California--Davis),
Marvin Burns (Langston University), Michael Dobres (NovaFlora, Inc.),
EPA (vacant), Bill Goldner (USDA-CSREES), Neal Gutterson (Mendel
Biotechnologies), Beth Hood (Arkansas State University), Kanyan Matand
(Langston University), Alan McHughen (University of
California-Riverside), Sally McCammon (USDA-APHIS), Eldon Ortman
(USDA-CSREES), John Radin (USDA-ARS), Nancy Ragsdale (USDA-ARS), Sujatha
Sankula (NCFAP), Ann Marie Thro (USDA-CSREES), and Jeff Wolt (Iowa State
University). Dr. Alan McHughen was named Chairperson of the Planning
Committee.

The Planning Committee determined that the following short-term actions
were needed:

-   Draft an appreciation letter to the three USDA administrators who
    provided financial support for the Workshop. (December, 2004)

-   Schedule a meeting with IR-4 Program Director, Bob Holm, to learn
    the nuances of the Program and determine if IR-4 model would be
    applicable to the issues facing regulatory consideration of
    specialty biotechnology-derived crops. (January, 2005)

-   Interface with the White Paper Planning Group to solicit recommended
    white papers, as appropriate.

-   Develop a plan of action to actuate the Workshop recommendations.

***IX. Acknowledgements***

Funding for the workshop was provided by: CSREES-USDA; ARS-USDA; Plant
and Animal Systems Unit, CSREES-USDA; Competitive Programs Unit,
CSREES-USDA and BRS-APHIS-USDA .

The Steering Committee expresses its gratitude to Dr. Adrienne Massey
for her excellent work as Workshop Facilitator. The Steering Committee
also acknowledges the important contributions of the following
individuals who made the workshop a success:

> Steven Strauss, Carole Cramer, Kent Bradford, Jeffrey Wolt, Gary
> Lemme, and Stephen Pueppke, for insightful development of potential
> program models as bases for discussion of the needs of specialty
> transgenic crops;
>
> M. Martin, M. Duryea, M. Burns, J. Cook, E. Ortman, K. Bradford, L.
> Kent, for serving as the breakout group leaders;
>
> Ted Blumenthal (NCFAP), for his support of the implementation of the
> Workshop;
>
> Andrew P. Wilson and Amy Rhodes (CSREES, USDA) for their assistance in
> recording the Workshop discussions;
>
> Donna R. Savage, M.Ed. and ELS, Science Writer, Intelligent Fingers,
> Kensington, MD.

***Appendix A: Biographies***

**Steering Committee**

**June Blalock:** June Blalock has been Coordinator of the Technology
Licensing Program at the U.S. Department of Agriculture (USDA),
Agricultural Research Service since 1993. Prior to joining USDA, she was
Associate Director of the Triangle Universities Licensing Consortium
(TULCO), where she had primary responsibility for licensing
biotechnology and biomedical inventions. She has held sales and
marketing positions at International Biotechnologies, Inc. and has
taught microbiology at the University of Maryland and at Goucher
College. Ms. Blalock currently serves as a member of the Expert Advisory
Committee for the Central Advisory Service on Intellectual Property
(CAS) of the Consultative Group on International Agricultural Research
(CGIAR). She also serves on the Advisory Board for the Agricultural
Biotechnology Support Project II (ABSP II) and as a member of the
U.S.-India Joint Working Group on Agricultural Biotechnology. She
represents USDA in negotiations related to the International Treaty on
Plant Genetic Resources for Food and Agriculture (IT) and in the U.S.
Government interagency working group on Access and Benefit Sharing (ABS)
pursuant to the Convention on Biological Diversity (CBD). Ms. Blalock is
a member of the Licensing Executives Society (LES), the Association of
University Technology Managers (AUTM), and the American Society for
Microbiology (ASM).

**Marvin Burns:** Dr. Marvin Burns received a B.S. in Agronomy from Fort
Valley State University, an M.S. in Agronomy from the University of
Wisconsin, and a Ph.D. in Plant Breeding and Pathology from the
University of Arizona. After receiving his doctorate, Dr. Burns served
as Head of the Department of Plant Science at Prairie View A&M in Texas
for four years. In 1978, he moved to Tuskegee University in Alabama and
served as Head of the Department of Agricultural Sciences for the next
10 years.

In 1988, Dr. Burns was a Visiting Professor at the University of
Delaware and in 1989, he was a Visiting Scientist in the Discovery Group
at American Cyanamid in Princeton, NJ. During both of these Visiting
Professor positions, Dr. Burns learned valuable biotechnology skills and
techniques that he later used to establish the first biotechnology
laboratory at Tuskegee University.

In 1991, Dr. Burns embarked upon a long and illustrious international
career when he became the Plant Breeder/ Pathologist with the RAV II
Extension and Research Project in Zaïre (now Congo) for two years. He
then moved to Cameroon where he served as the Plant Breeder/Pathologist
with the Root and Fiber Crop research program for two years. Dr. Burns
has also had short-term assignments in Guyana, El Salvador, Burkina
Faso, Chad, Zaïre, South Africa, Nigeria, Liberia and Rwanda.

In 1995, Dr. Burns left Tuskegee University to become the Associate
Administrator of Extension at Langston University. In 1997, he was named
the Acting Dean for Research and Extension and in 1998 was named the
Dean of the newly formed school of Agriculture and Applied Sciences,
where the E (Kika) de la Garza Institute for Goat Research is now
housed.

**Bill Goldner:** Dr. William Goldner has served as a National Program
Leader for the USDA-CSREES Small Business Innovation (SBIR) Program
since 1999. He is responsible for the Plant Production and Protection
(Biology and Engineering) and Industrial Applications program areas.
Prior to joining USDA, Dr. Goldner held positions as: an Associate
Biochemist at the Hawaiian Sugar Planters' Association (now Hawaii
Agricultural Research Center); a Research Scientist/Project Manager for
Union Camp Corporation (a major forest products company \[now part of
International Paper Company\]); and most recently as Technical Strategy
Manager for Applied Genetics in the Biotechnology Development Group for
the Global Agricultural Products Division of American Cyanamid Co. (a
major crop protection company \[now BASF\]). While at Union Camp and
American Cyanamid, he served for six years as an Associate Professor in
the Graduate Program in Plant Biology at Cook College, Rutgers
University.

Dr. Goldner's research background includes: plant carbohydrate
biochemistry; the physiology of woody plant growth, development, and
abiotic stress tolerance; plant breeding; accelerated genetic selection
of forest trees and agronomic crops; forest biotechnology; and
production horticulture. He has published several research articles and
received two patents, including one on the production of the anti-cancer
compound taxol. He is a recipient of the Union Camp Corporation
*Research Creativity Award* -- for work leading to implementation of
technology with striking commercial significance. He holds a Ph.D. in
Plant Physiology from the Pennsylvania State University.

**Dan Jones:** Dr. Daniel Jones is the National Program Leader for
Biotechnology with the USDA Cooperative State Research, Education, and
Extension Service in Washington, DC. He holds a B.S. degree in chemistry
from the University of Iowa and a Ph.D. in biochemistry from the
University of Michigan. He conducted postdoctoral research on protein
chemistry and structure at Georgetown University in Washington, DC and
at the Brookhaven National Laboratory in New York.

Dr. Jones currently directs the Biotechnology Risk Assessment Research
Grants Program and the Microbial Genome Sequencing Program at USDA. He
served previously as the Deputy Director of the USDA Office of
Agricultural Biotechnology where he developed biotechnology research
opportunity areas and priorities and provided executive secretarial
support for advisory, sub-cabinet, and senior staff committees
developing biotechnology policy. He also chaired several national
biotechnology workshops and testified before Congress on biotechnology
issues. Dr. Jones has published a number of papers on the research and
regulatory aspects of biotechnology, and he has given invited
presentations on federal biotechnology funding and policy options.

**Ed Kaleikau:** Ed Kaleikau received his Ph.D. in plant genetics from
Kansas State University and was a postdoctoral research fellow in plant
molecular biology at Stanford University prior to joining the U.S.
Department of Agriculture in 1993. Dr. Kaleikau served as Division
Director of the Plant Systems Division of the National Research
Initiative (NRI) Competitive Grants Program of USDA's Cooperative State
Research, Education, and Extension Service. In addition, he has served
as Co-Program Director of USDA's Biotechnology Risk Assessment Research
Grants Program, the NRI Agricultural Systems Program and the Initiative
For Future Agriculture and Food Systems (IFAFS) Plant Genome and
Bioinformatics Programs. He currently serves as National Program Leader
for several NRI competitive grant programs including: the Plant Genome,
Bioinformatics and Genetic Resources Program, the Plant Biosecurity
Program, the Functional Genomics of Agricultural Organisms Program, the
Applied Plant Genomics Program, and the joint USDA/NSF/DOE programs for
the Arabidopsis, Rice and Maize Genome Sequencing Projects. Dr. Kaleikau
has represented USDA on numerous National committees including the
U.S. - E.C. Task Force on Biotechnology Research, the Agricultural
Biotechnology Research Advisory Council, the National Genetic Resources
Advisory Council, and the National Science and Technology Council's
Interagency Working Group on Plant Genomes.

# **Kanyand Matand**: Dr. Kanyand Matand is a native of the Democratic Republic of Congo in Central Africa, where he was Leader of the National Peanut Breeding Program at the Congolese National Agricultural Research and Extension Service (RAV/SENRAV), where he conducted plant breeding research at the regional, national and international levels, collaborating with the International Crops Research Institute for the Semi-Arid Tropics (ICRISAT), India, to successfully introduce improved peanut cultivars into the crop production of the Congo. In 1999, Dr. Matand received a Ph. D. in Crop Biotechnology at Alabama A & M University, Huntsville, Alabama. He is currently an Assistant Professor at Langston University, where he established the Langston University Center for Biotechnology Research and Education (CBRE), a program for which he serves as Coordinator. Current research at the CBRE focuses on tissue culture and transformation of tall wheatgrass and genomics studies of peanut and goat. The Center also focuses on the training of Oklahoma high school science teachers and students in biotechnology through workshops and weekend academies. In addition to research, Dr. Matand also teaches courses in the Department of Biology.

**Sally McCammon:** Dr. McCammon serves as Science Advisor in the Animal
and Plant Health Inspection Service (APHIS). Currently, Dr. McCammon
heads the Office of Science for the Deputy Administrator for
Biotechnology Regulatory Services. In this capacity, she works to assure
the appropriate scientific basis for policies, regulations, and
assessment decisions in biotechnology. She has served in a variety of
policy and liaison roles for biotechnology and other initiatives
including as the agency liaison to the National Academy of Sciences for
reports on biotechnology.

Internationally, she is the U.S. head of delegation to the Organization
for Economic Cooperation and Development\'s (OECD) Working Group on
Harmonization of Regulatory Oversight in Biotechnology (Working Group);
was the alternate U. S. delegate to the Codex ad hoc Intergovernmental
Task Force on Biotechnology; and has represented the United States in
activities aimed at implementing the Biosafety Protocol, particularly
the BioSafety Clearinghouse.

She has been involved with regulatory review and biosafety operational
and policy issues and nternational biotechnology regulatory
harmonization for over fifteen years and invited speaker and participant
in numerous international and national meetings, workshops, and
symposia. She has also testified before Congressional committees and
sub-committees.

**Eldon Ortman:** Dr. Eldon Ortman retired in 2001 after a distinguished
career as the entomology Department Head and subsequently Associate Ag
Experiment Station Director at Purdue University. Dr. Ortman holds a
Ph.D. in entomology from Kansas State University. Since 2001, he has
held a shared faculty position at CSREES, USDA. He is a past President
of the Entomological Society of America and a Fellow of the American
Association for the Advancement of Science.

**John Radin:** Dr. John Radin is the Senior National Program Leader for
the USDA Agricultural Research Service in the areas of Plant Physiology
and Cotton at the Beltsville Area Research Center. He holds a Ph.D. in
Plant Physiology from the University of California, Davis. Dr. Radin's
research has involved water- and nutrient-use efficiency and crop
responses to environmental stress, especially heat and drought. He is
the author or co-author of 70+ refereed scientific research or review
articles and 10 book chapters.

His current responsibilities include: Technical Staff Advisor to the
Administrator of ARS; liaison to agricultural stakeholders, especially
to the cotton industry; determining goals and priorities for ARS
research within areas of responsibility (plant physiology, plant
biotechnology and biotechnology risk assessment/risk mitigation, and
cotton production and processing); and leading, coordinating, and
managing research in ARS to achieve those goals.

Dr. Radin is a Fellow of the American Society of Agronomy and is also a
Fellow of the Crop Science Society of America. He is a recipient of the
D.R. Hoagland Award for research benefiting agriculture, presented by
the American Society of Plant Physiologists (now American Society of
Plant Biologists)

### Sujatha Sankula: Dr. Sujatha Sankula is Director of Biotechnology Research, National Center for Food and Agricultural Policy. Sujatha Sankula joined the National Center for Food and Agricultural Policy (NCFAP) in 2001. Prior to joining NCFAP, she has held research positions at the University of Delaware and Louisiana State University where she worked on biotechnology-derived crops and their impacts on weed management and crop production practices and IPM approaches to pest management in various field crops and vegetables. 

A major focus of her research program at NCFAP is to evaluate the impact
of biotechnology-derived crops in the United States and elsewhere in the
world. Other research activities include exploration and analysis of
issues that confront biotechnology in agriculture and performance of
domestic and international education and outreach to promote an open and
honest dialogue between various stakeholders.

She has authored three book chapters, 15 peer-reviewed publications, and
40 abstracts and research reports. She coauthored a report on
"Comparative environmental impacts of biotechnology-derived and
traditional soybean, corn, and cotton crops" which was commissioned by
the Council for Agricultural Science and Technology. As a recognized
authority on biotechnology, Sankula has briefed the Environmental
Protection Agency, U.S. House of Representatives Committee on Science
and the U.S. Senate and House Agriculture Committees on the
environmental impacts of crops developed through biotechnology methods.
Sankula holds a Ph.D. in Weed Science from the Department of Plant
Pathology and Crop Physiology at Louisiana State University

**Ann Marie Thro:** Dr. Thro is the National Program Leader for Plant
Breeding and Genomics for the USDA - Cooperative States Research,
Education, and Extension Service (CSREES). In this capacity, she works
to provide leadership to focus federally-funded state research on plant
breeding, genetic resources, genomics, and transgenic plants. Dr. Thro
earned a Ph.D. and M.S. in plant breeding and genetics from Iowa State
University, a B.S. in Agronomy from Virginia Polytechnic Institute and
State University, and a B.A. in history and languages from Bryn Mawr
College. Prior to joining CSREES she served as Commissioner of the USDA
Plant Variety Protection Office; Coordinator of the International
Cassava Biotechnology Network based at CIAT (the International Center
for Tropical Agriculture) in Colombia; Assistant and Associate Professor
of Agronomy at Louisiana State University, and Technical Advisory to the
National Grain Legume Program in Gandajika, Zaire (now the Democratic
Republic of Congo). Dr. Thro has 12 years of experience as a field plant
breeder and has published 22 articles in refereed research journals. Dr.
Thro's interests include environmentally, economically, and socially
sustainable agriculture, with specific reference to the contributions of
plant breeding, genomics, and biotechnology.

**Facilitator:**

**Adrianne Massey, Ph.D., Principal, A. Massey and Associates**

Dr. Massey has been involved with scientific research, education,
workforce training and public policy for over 20 years. Before starting
her own company, she was Vice President for Education and Training at
the North Carolina Biotechnology Center where she directed the Center\'s
award-winning public education and workforce training programs from
1990-1997. She was hired by the Center in 1988 to develop and implement
projects that combined science, technology development, public policy
and communication. In this capacity she mediated consensus-building
activities among companies, environmental organizations, government
officials, public interest groups, ethicists, university administrators
and scientists.

From 1982-1987 she was on the faculty of the Zoology Department at North
Carolina State University where she taught and conducted research in
physiological ecology and evolutionary genetics. During that time she
was also an instructor for courses in tropical ecology offered by the
Organization of Tropical Studies in Costa Rica and Duke University.

In addition to publishing scientific articles on her research, Dr.
Massey was an invited contributor to the U.S. Congressional report,
*Field Testing Genetically Engineered Organisms: Ecological and Genetic
Issues*, sponsored by the Office of Technology Assessment, and to the
National Academy of Sciences report, *Applied Environmental Research
Opportunities*. She is co-author of the best-selling textbook on the
science, applications and societal issues of biotechnology, *Recombinant
DNA and Biotechnology*, published by American Society for Microbiology
(ASM) Press. Her second book for ASM Press, *Biology and Biotechnology:
Science, Applications and Issues*, a textbook for undergraduate
non-science majors, will be released in 2005.

Dr. Massey served as the Science Advisor for the PBS series,
*BREAKTHROUGH: Television\'s Journal of Science and Medicine,* sponsored
by Connecticut Public Television; was the original Director of the North
Carolina Environmental Technology Consortium; participated in the
international negotiations of the Biosafety Protocol; and has developed
interactive exhibits for science and technology museums. She has served
on a number of federal and state advisory panels on scientific research,
education and public policy and is a frequent lecturer on the science,
applications and policy issues of biotechnology.

**Presenters:**

Alberto Jerardo, Economist, USDA -- ERS: Since 2001, Alberto Jerardo has
been the floriculture and nursery crops analyst in the Specialty Crops
Branch, Market and Trade Economics Division. He is responsible for the
Floriculture and Nursery Crops Outlook report and yearbook. He also is
the ERS analyst of U.S. agricultural imports and is responsible for the
import section of *Outlook for U.S. Agricultural Trade.* Prior to his
current position, Andy was co-coordinator of *U.S. Agricultural Trade
Update.* He also authored the international macroeconomics section of
*Outlook for U.S. Agricultural Trade* and *U.S. Agricultural Update.*
Prior to joining ERS in 1989, Andy was an energy demand forecaster at
the U.S. Department of Energy. Andy has a Ph.D. in Economics from the
University of California, Riverside, 1982; an M.A. in Economics from the
University of California, Santa Barbara, 1976, an M.S. in Quantitative
Business Methods from California State University, Hayward, 1975; and a
B.A. in Economics from California State University, Hayward, 1973.

# **John Kough, Senior Scientist, EPA:** Dr. Kough is a Senior Scientist in the EPA's Office of Pesticide Program's Biopesticides and Pollution Prevention Division. Dr. Kough has been at EPA since 1990 working in the biotechnology programs in the Office of Prevention, Pesticides and Toxic Substances. In the Office of Pesticide Programs, he has reviewed the scientific data submitted for the plant incorporated protectants and many of the currently registered microbial and biochemical pesticides. Dr. Kough has presented EPA\'s position at numerous Scientific Advisory Panels on topics like product characterization, protein toxicity assessment and food allergenicity. He has also helped write sections of EPA's plant-incorporated protectants rule as well as policy on pheromone-based pesticides. Dr. Kough recently received EPA\'s Seifter Award for his role in the human health risk assessment of the products of biotechnology. Dr. Kough has published numerous papers on the regulation of biopesticides as well as his research interests of biological control and immunology. Prior to joining EPA, John was a research project director at IGEN, a biotechnology company specializing in developing monoclonal antibodies for several plant diseases. John received a B.A. degree in biology from Reed College in Portland, OR and a Ph.D. degree in plant pathology from Oregon State University. Dr. Kough received an NSF post-doctoral fellowship in Dijon, France where he researched the ecology and biocontrol of soil borne fungi. John was born in Uniontown, PA and raised in the Allegheny Mountains of southwestern Pennsylvania.

### Mary Ditto: Dr. Mary Ditto is a Consumer safety Officer for the United States Food and Drug Administration (FDA). She received her Ph.D. in Molecular Genetics and Cell Biology from the University of Chicago and did post-doctoral research work at the National Institutes of Health. She currently serves as a Consumer Safety Officer in the Division of Biotechnology and GRAS Notice Review, which is part of the Center for Food Safety, and Applied Nutrition in FDA. She has worked on biotechnology issues for several years.

**Janet Whitley:** Dr. Janet Whitley has been a reviewing scientist with
the Office of Orphan Products Development at the Food and Drug
Administration (FDA) since 2000.  At FDA she administers the provisions
of the Orphan Drug Act which facilitates development for medical
products for the treatment of rare diseases.  Dr. Whitley serves as a
project manager for international orphan drug policy development. 
Outside of FDA, Dr. Whitley is an adjunct faculty member at the
University of Maryland, University College where she teaches
Biotechnology and the Regulatory Environment.

# **Dennis Gonsalves:** Dr. Dennis Gonsalves is the Director, USDA ARS -- Pacific Basin Agricultural Center in Hilo, Hawaii. He holds a Ph.D. in Plant pathology from the University of California, Davis. From 1972-1977, he worked on viruses that affect citrus at the University of Florida, advancing from assistant to associate professor. He then joined Cornell University at the New York State Agricultural Experiment Station in Geneva, New York and worked there from 1977 to May 2002. While at Cornell, he worked on viral diseases of fruit and vegetable crops, with an emphasis on developing genetically engineered plants to control viral diseases. He became a full professor in 1986 and was appointed to one of the endowed Liberty Hyde Bailey Professor positions in 1995. While at Cornell, Dennis maintained close research ties with the University of Hawaii and led a team to develop and commercialize a transgenic papaya that helped to save the papaya industry from devastation by the papaya ringspot virus. The initial team consisted of Drs. Richard Manshardt of University of Hawaii, Maureen Fitch of ARS, and Jerry Slightom of Pharmacia-Upjohn with Steve Ferreira of the University of Hawaii playing a major subsequent role. For the papaya work, the initial team was awarded the Alexander Von Humbolt Award in 2002. Dennis recently received the 2003 American Society of Plant Biologist Leadership in Science and Public Service Award.

#  

# **Ralph Scorza:** Dr. Ralph Scorza is a Horticultural Researcher, USDA -- ARS Appalachian Fruit Research Station. He received his undergraduate degree in agronomy at the University of Florida. After a tour in the Peace Corps in the Amazon region of Brazil, working with tropical fruit production, he returned to the University of Florida and received his Ph.D. from Purdue University in Plant Genetics and Breeding under the guidance of Dr. Jules Janick. Following an assignment in Bolivia, where he worked for the University of Florida, Dr. Scorza was hired by the USDA as a stone fruit breeder at the USDA -- ARS Appalachian Research Station since 1980. He has released Sentry and Bounty peaches, now widely grown in the northeastern U.S., Earliscarlet nectarine, and, most recently, Bluebyrd plum. Dr. Scorza has developed new columnar growth habit peaches for high-density production systems and these are currently under test in a number of states.

In the mid 1980's Dr. Scorza initiated a tree fruit biotechnology
program at the Appalachian Fruit Research Station to supplement
conventional breeding for variety development. The program has developed
gene transfer systems for plum, grape, and pear. Aware of the potential
consequences of an introduction of plumpox virus into the U.S., Dr.
Scorza initiated a program to develop plum pox virus resistant
transgenic plums.

# 

# **Alan McHughen:** Dr. Alan McHughen is a Plant Biotechnologist at the University of California, Riverside. Dr. McHughen's research focuses on using biotechnology, especially the development of molecular genetic technology to develop improved crops contributing to more environmentally sustainable cropping systems. He is also interested in analyzing products of biotechnology for their effects on the environment and on health.

Alan McHughen is a public sector educator, scientist and consumer
advocate. After earning his doctorate at Oxford University and working
at Yale University, Dr. McHughen spent twenty years as Professor and
Senior Research Scientist at the University of Saskatchewan before
joining the University of California, Riverside. A molecular geneticist
with an interest in crop improvement, he has helped develop Canada's
regulations covering the environmental release of plants with novel
traits and US regulations governing transgenic plants. He served as
recent OECD (Organization for Economic Cooperation and Development)
panels investigating the health effects of genetically modified foods.
Having developed internationally approved commercial crop varieties
using both conventional breeding and genetic engineering techniques, he
has first hand experience with issues from both sides of the regulatory
process, covering both recombinant DNA and conventional breeding
technologies. He also served on the Canadian national expert committee
on variety registration (including several years on the executive panel
as Secretary of Oilseeds Subcommittee). As an educator and consumer
advocate, he helps non-scientists understand the environmental and
health impacts of both modern and traditional methods of food
production. His award winning book, 'Pandora's Picnic Basket; The
Potential and Hazards of Genetically Modified Foods', uses
understandable, consumer-friendly language to explode the myths and
explore the genuine risks of genetic modification (GM) technology.

# **David Clark:** Professor of Floriculture Biotechnology, University of Florida The research in Dr. Clark's laboratory is directed toward genetic engineering of floriculture crops for improved horticultural performance during production and post harvest handling. Dr. Clark's specific interests are in the areas of post harvest physiology, and molecular biology of ethylene biosynthesis and sensitivity in flowers. The main goal of his work is to utilize information gained from molecular and physiological experiments to help solve real-life problems in greenhouse-grown floriculture crops. He hopes to determine the commercial viability of genetically engineered floriculture crops by assessing the attributes and limitations of genetically engineered floriculture crops in commercial scale greenhouse experiments.

**Keith Redenbaugh:** Dr. Keith Redenbaugh is the Associate Director of
Regulatory Affairs, Seminis Vegetable Seeds. Dr. Redenbaugh has been
involved with agricultural biotechnology since the mid 1970's. At
Calgene, he worked with the FDA and USDA to establish appropriate
instruments for safety assessment and oversight of transgenic crops and
foods. He obtained regulatory approvals for the first transgenic whole
food, the FLAVR SAVR tomato. His efforts also led to FDA issuing a food
additive regulation for the kanamycin-resistant marker gene protein,
NPTII, a significant decision by the FDA. He also obtained for the
FLAVR-SAVR tomato what is still the only full commercial approval of a
transgenic crop in Mexico. Dr. Redenbaugh spent 1 1/2 years at Iowa
State University in the role of Biotechnology Industry Liaison, which
involved broad biotechnology interactions with industry and the public,
ranging from issues on fermentation, animal health, transgenic animals,
as well as plant biotechnology. In this role, Dr. Redenbaugh spent time
talking to farmers, students (both high school and college), and
community service organizations.

Currently, Dr. Redenbaugh is Associate Director for Regulatory Affairs,
Licensing and contracts at Seminis Vegetable Seeds. His responsibilities
include worldwide regulatory affairs, commercialization of biotech
plants, biotechnology stewardship, technology assessment, and
negotiating licensing and contracts for the R&D department.

### Terry Stone: Terry Stone is the Director -- Biotechnology and Regulatory Affairs at Scott's. Terry Stone obtained his Bachelor's degree from Southern Illinois University in invertebrate zoology and holds a Master of Science degree in Entomology from Mississippi State University and a Masters degree in International Business from St. Louis University. For 19 years he worked at Monsanto to develop and commercialize plants through biotechnology with resistance to insects and tolerance to Roundup herbicide. For the past 12 years he has worked in biotechnology regulatory affairs and helped to gain approval for a number of products including NewLeaf potatoes, Bollgard cotton and YieldGard corn. In 2001, he began leading an effort to gain the regulatory acceptance of specialty crops, including turfgrasses, developed through biotechnology. He left Monsanto in April 2003 to join The Scotts Company in Marysville, Ohio to focus on biotech-derived turf and ornamentals and currently serves as the Director of Biotechnology Regulatory Affairs. 

# **Maud Hinchee:** Dr. Hinchee has been the Chief Technology Officer at ArborGen since 2000, and before that she had spent many years at Monsanto, where she conducted research in the field of biotechnology. Some of her professional activities include being Managing Editor of The Plant Biotechnology Journal, and Managing Editor of Plant Cell, Tissue and Organ Culture. Dr Hinchee was on the Board of Reviewing Editors for In Vitro Cellular and Developmental Biology as well. She has authored five patents and over twenty scientific publications including a plant biology textbook.

**Les Pearson:** Dr. Pearson has been the Director of Regulatory Affairs
and Regulatory Science, ArborGen, LLC, since 2002. He is responsible for
regulatory oversight for ArborGen field trials. ArborGen is a world
leader in transgenic forest tree research. ArborGen conducted the first
field trials of *Eucalyptus* in the US and is currently the only entity
field-testing transgenic *Eucalyptus* and pine in the US and sweetgum
worldwide. Prior to joining ArborGen Dr. Pearson was the Biotechnology
Section Leader for Westvaco Forest Research (1998-2000), where he had
oversight of world's first field trials of transgenic pine. From
1989-1997 he was Senior Scientist DNA Markers / Project Leader Molecular
Genetics, Westvaco Forest Research. Les received a Ph.D. from the John
Innes Institute, Norwich, England in 1983, where he demonstrated the
relationship between DNA methylation and gene expression in plants. He
served as a Post-doctotal research fellow at the University of Georgia
from 1984-1989, where he studied gene expression of the actin multi-gene
family in soybeans.

**Robert Holm:** Dr. Bob Holm was raised on a small farm in Indiana and
received his B.S, M.S. and Ph. D. degrees (Biochemistry and Plant
Pathology) from Purdue University. Prior to joining IR-4 as Executive
Director in 1998, Dr. Holm spent 30 years in the crop protection
industry working for Diamond Shamrock Corporation as a Senior Research
Scientist; Mobil Crop Chemical as Research Manager; Rhone-Poulenc as
Director of Agrochemical Sciences and Field Research and Product
Development; and Valent U.S.A. Corporation, a Sumitomo Chemical Company
subsidiary, as Technology Vice-President. He has had extensive
experience with the development of crop protection tools on a wide
variety of major row crops as well as numerous specialty crops like
fruits and vegetables. Dr. Holm is a member of a number of professional
societies and served as Chairman of the Plant Growth Society of America
in 1978/1979. Five patents have been issued in his name. He has over 40
technical publications and book chapters in referred journals and has
given over 200 presentations at various professional and technical
society meetings.

# **Sarah Linde-Feucht:** Dr. Linde-Feucht is a Medical Officer at Office of Orphan Products Development at the US Food and Drug Admiistration. Sarah R. Linde-Feucht is a medical officer assigned to the Food and Drug Administration Office of Orphan Products Development. There, she directs the Humanitarian Use Device program and is the administrator for the Grants Program. Prior to her assignment with FDA, Dr. Linde-Feucht was assigned to the National Health Service Corps and served as the Director of the Shenandoah Valley Family Health Center, a community health center in Inwood, WV. Prior to that, she worked as a staff medical officer at the Shenandoah Valley Medical Center, another community health center, in Martinsburg, WV.

Dr Linde-Feucht is board certified in Family Practice and is a graduate
of the Uniformed Service University of the Health Sciences Medical
School in Bethesda, MD. She was commissioned to the Public Health
Service in 1988 and has been very active in many Public Health Service
activities, such as the Physicians Professional Advisory Committee, the
Disaster Medical Assistance Team, and the Commissioned Appointment
Readiness Force. She has also served on the Medical Professional
Category Appointment Board and the Medical Review Board. She is a member
of the COA and the recipient of the Clinical Physician of the Year Award
presented at the 1998 COA meeting.

## Steven Strauss: Dr. Steven Strauss is a Professor of Forest Sciences at Oregon State University. Dr. Strauss's research is on the application of molecular genetic methods to the genetic improvement and analysis of forest trees. He has a major research effort in association with several paper and energy industries on genetic engineering of poplar trees, population genetics of conifers using organelle and nuclear genome markers, and constructing genome maps of Douglas-fir to identify genes that control growth and adaptation.

Current tree projects include development of more efficient means for
gene transfer; testing of genes for resistance to the herbicide Roundup
in transgenic poplars; testing genes for insect resistance and means for
their safe deployment; and genetic engineering of trees for complete
reproductive sterility. The latter project is motivated by desire for
genetic containment of inserted genes from wild populations. Included in
the sterility work are sub-projects on early flower induction, isolation
and study of floral homeotic gene expression from poplars, and testing
of transgenic trees for sterility. Six floral homeotic genes have been
cloned and are now being intensively characterized; they are
evolutionary homologs to the floral homeotic genes *agamous, leafy,
apetala1* and *apetala3* from Arabidopsis.

# 

# **Jeff Wolt:** Dr. Jeff Wolt is Professor of Agronomy at Iowa State university. Dr. Wolt's areas of expertise are as follows: biotechnology safety analysis applied to risk management and science policy decision-making, environmental and ecotoxicological risk assessment, soil and environmental chemistry applied to exposure assessment, efficacy, environmental monitoring, environmental toxicology, and environmental fate of xenobiotics.

Dr. Wolt conducts research in biotechnology risk assessment with
emphasis on uncertainty analysis using probability and possibility
theory, ecological consequences of pollen and gene flow, and risk
management and communication. Earlier research centered on method
development and application of soil solution compositional analysis to
problems of environmental monitoring and ecological exposure assessment.
Dr. Wolt directed a discovery support effort to evaluate
efficacy/environmental sorption/degradation processes, elucidation of
solute flow paths through the soil profile, methods of enhancement of
retardation/degradation within the soil profile, modeling evaluation of
environmental fate and ecotoxicity in ground and surface water.

**Neal Gutterson:** Dr. Neal Gutterson currently serves as the Chief
Operating Officer and Senior Vice President, Research and Development,
for Mendel Biotechnology, Inc. Mendel is a leading plant genomics
company, dedicated to creating new plant and chemical products based on
knowledge of plant pathways. Prior to joining Mendel, Dr. Gutterson
spent 18 years at DNA Plant Technology, a leading plant biotechnology
company, beginning with 5 years at Advanced Genetic Sciences, later
acquired by DNAP. Dr. Gutterson\'s roles included: project leader for
the development of transgenic biological control products based on
fluorescent pseudomonads; project leader for an ornamentals program
focused on modification of flower color and shelf life; Director of
Research in new crops and technologies, focused on specialty crops, and
transgenic methodologies; and later Vice President of Research.

Dr. Gutterson\'s research areas have included: the regulation of plant
gene expression; development of plant transformation vectors and
transformation methods; methods of gene silencing, with a focus on sense
suppression; plant disease resistance; plant pathways and transcription
factors. He has published more than two dozen research articles; he is a
named inventor on 10 U.S. patents, and more than a dozen pending U.S.
patent applications. He holds a Ph.D. in Biochemistry from the
University of California, Berkeley, and a B.S. in Chemistry from Yale
University.

**Alan McHughen:** Alan McHughen is a public sector educator, scientist
and consumer advocate. After earning his doctorate at Oxford University
and lecturing at Yale University, Dr McHughen worked at the University
of Saskatchewan before joining the University of California, Riverside.
A molecular geneticist with an interest in applying biotechnology for
sustainable agriculture and safe food production, he served on recent
National Academy of Science, Institute of Medicine and OECD panels
investigating the environmental and health effects of genetically novel
plants and foods. Having developed internationally approved commercial
crop varieties using both conventional breeding and genetic engineering
techniques, he has first hand experience with issues from both sides of
the regulatory process, covering both recombinant DNA and conventional
breeding technologies. McHughen also served for six years as President
of the International Society for Biosafety Research.

***Appendix B: Workshop Participants***

  ------------- -------------- ---------------------- ----------------------- ------------
  **First       **Last name**  **Title**              **Affiliation**         **Work
  name**                                                                      Location**

                                                                              

  Herbert       Aldwinkle      Professor - Plant      Cornell University      NY
                               Pathology                                      

  Victor        Amoah          Research Consultant    Citrus Research Board   CA

  George        Acquaah        Researcher             Langston University     OK

  Ted           Batkin         President              Citrus Research Board   CA

  Alan          Bennett        Professor              PIPRA at University of  CA
                                                      Calfornia Davis         

  Kent          Bradford       Professor              University of           CA
                                                      California - Davis      

  Samuel        Besong         Coordinator - Center   Alcorn State University MS
                               for Biotechnology                              

  Dan           Cantliffe      Chair - Department of  University of Florida   FL
                               Horticulture                                   

  Janet         Carpenter      Biotechnolgy Advisor   USAID                   DC

  Elicia        Chaverest      Research Associate -   Alabama A & M           AL
                               Department of          University              
                               Agribusiness                                   

  Duncan        Chembezi       Co-Director - Small    Alabama A & M           AL
                               Farms Research Center  University              

  David         Clark          Professor              University of Florida   FL

  Joel          Cohen          Director - Biosafety   IFPRI                   DC
                               Systems                                        

  Greg          Conko          Director - Food Safety Competitive Enterprise  DC
                               Policy                 Institute               

  Jim           Cook           Professor              Washington State        WA
                                                      University              

  John          Cordts         Biotechnologist        USDA-APHIS              MD

  Katrina       Cornish        Senior Financial       Yulex Corporation       CA
                               Executive                                      

  Carole        Cramer         Director - Arkansas    Arkansas State          AR
                               Biotechnology          University              
                               Institute                                      

  Deborah       Delmer         Associate Director of  Rockafeller Foundation  NY
                               Food Safety                                    

  Mary          Ditto          Consumer Safety        FDA                     DC
                               Officer                                        

  Michael       Dobres         President and CEO      NovaFlora Inc.          PA

  Hortense      Dodo           Researcher             Alabama A & M           AL
                                                      University              

  Steve         Duke           Supervisor             USDA-ARS                MS

  Mary          Duryea         Assistant Dean for     FAES, IFAS/University   FL
                               Research               of Florida              

  Jose          Falck-Zepeda   Research Fellow        IFPRI                   DC

  Mike          Fernandez      Director of Science    Pew Initiative on Food  DC
                                                      and Biotechnology       

  Sharie        Fitzpatrick    Director of Regulatory Forage Genetics         WI
                               Affairs                International           

  Vicki         Forster        Principal              Forster & Associates    DE
                                                      Consulting, LLC         

  Bob           Frederick      Senior Scientist       EPA                     DC

  Tom           Fretz          Executive Director     NERA                    MD

  Sarah         Linde-Feucht   Medical Officer        FDA                     MD

  Dale          Gallenberg     Director - Plant       South Dakota State      SD
                               Sciences               University              

  Jeanette      Glew           Enivronmental          FDA                     DC
                               Scientist                                      

  Dennis        Gonsalves      Center Director        Pacific Basin           HI
                                                      Agricultural Center     

  Elizabeth     Grabau         Professor              Fralin Biotechnology    VA
                                                      Center and Department   
                                                      of Plant Pathology      

  Neal          Gutterson      Chief Operating        Mendel Biotechnologies  CA
                               Officer                                        

  Deb           Hamernik       Program Leader - Plant USDA-CSREES             DC
                               and Animal Systems                             

  Freddi        Hammerschlag   Supervisor             USDA-ARS                MD

  John          Hammond        Research Leader        USDA-ARS                MD

  Levis         Handley        Biotechnologist        USDA-APHIS              MD

  Michael       Harrington     Executive Director     WAAESD                  CO

  Zane          Helsel         Extension Specialist   Rutgers University      NJ

  Maud          Hinchee        Chief Technology       Arborgen                SC
                               Officer                                        

  Neil          Hoffman        Regulatory Agency      APHIS                   MD

  Bob           Holm           National Dir of IR-4   IR-4 at Rutgers         NJ
                               Project                University              

  Elizabeth     Hood           Associate Vice         Arkansas State          AR
                               Chancellor - Research  University              
                               and Technology                                 
                               Transfer                                       

  Greg          Jaffe          Director of            Center for Science in   DC
                               Biotechnology          the Public Interest     

  Margaret      Jahn           Professor              Cornell University      NY

  Alberto       Jerardo        Economist              ERS                     DC

  Eluned        Jones          Director               Texas A&M               TX

  Eileen        Kabelka        Associate Professor    Univ of Florida         FL

  Frederick     Keter          Student                University of Maryland  MD
                                                      Eastern Shore           

  Lawrence      Kent           Director -             Danforth Center         MO
                               International Programs                         

  Harry         Klee           Professor              University of Florida   FL

  John          Kough          Senior Scientist       EPA                     DC

  Gary          Lemme          Associate Director     Michigan Agricultural   MI
                                                      Experiment Station      

  Richard       Levine         Consultant             Better Earth            MD
                                                      Communications, Inc.    

  Josette       Lewis          Chief Biotechnology    USAID                   DC
                               Officer                                        

  Nicholas      Linacre        Post Doctoral Fellow   IFPRI                   DC

  Jiang         Lu             Researcher             Florida A & M           FL
                                                      University              

  Bob           Martin         Researcher             USDA-ARS                OR

  Marshall      Martin         Associate Director -   Purdue University       IN
                               Agricultural Research                          
                               Programs                                       

  Adrianne      Massey         Principal              Massey and Associates   NC

  Kanyand       Matand         Researcher - Forage    Langston University     OK
                               grass                                          

  John          Matheson       Senior Regulatory      FDA/CVM                 MD
                               Review Scientist                               

  Sally         McCammon       Science Advisor        USDA-APHIS              MD

  Mark          McCaslin       President              Forage Genetics         MO
                                                      International           

  Alan          McHughen       Biotechnologist        University of           CA
                                                      California - Riverside  

  Sreenivasa    Mentreddy      Associate Professor -  Alabama A & M           AL
  Rao                          Crop Sciences          University              

  Hodeba        Mignouna       Associate Professor    Virginia State          VA
                                                      University              

  Craig         Nessler        Head of Dept of Plant  Virgnia Tech            VA
                               Pathology                                      

  Jay           Norelli        Plant Pathologist      USDA-ARS                WV

  Okeleke       Nzeogwu        Associate Professor -  University of           MD
                               Department of          Maryland - Eastern      
                               Agriculture            Shore                   

  Paul          Olson          Research Scientist     Pioneer                 IA

  Eldon         Ortman         IPA/NPL                CSREES-USDA             DC

  Peggy         Ozias-Akins    Professor of           University of Georgia   GA
                               Horticulture                                   

  Bhavani       Pathak         Biotechnology Advisor  USAID                   DC

  Les           Pearson        Director - Regulatory  Arborgen                SC
                               Affairs                                        

  Jane          Polston        Professor - Plant      University of Florida   FL
                               Pathology                                      

  Steven        Pueppke        Professor - Plant      University of Illinois  Ill
                               Genetics                                       

  Hector        Quemada        BBI Program Manager -  Western Michigan        MI
                               Biosafety Systems      University              

  Umesh         Reddy          Researcher             Alcorn State Univ       MS

  Keith         Redenbaugh     Associate Director -   Seminis Vegetable Seeds CA
                               Regulatory Affairs                             

  Carlos        Reyes          US Markets Specialty   Monsanto                CA
                               Crops                                          

  Sandra        Ristow         Associate Director     Washington State        WA
                                                      University              

  Ray           Rodriguez      Professor              University of           CA
                                                      California - Davis      

  Rick          Roush          Professor-Entomology   University of           CA
                                                      California - Davis      

  Larisa        Rudenko        Senior Advisor on      FDA                     MD
                               Biotechnology                                  

  Eric          Sachs          Director - Scientific  Monsanto                MO
                               Affairs                                        

  Michael       Schechtman     Biotech Coordinator    USDA-ARS                DC

  Ralph         Scorza         Researcher             USDA-ARS                WV

  Roger         Sedgo          Senior Fellow          RFF                     DC

  Ken           Sink           Director - Plant       Michigan State          MI
                               Transformation Center  University              

  Ann           Smigocki       Research Geneticist    USDA-ARS                MD

  John          Stiles         Chief Scientific       Integrated Coffee       HI
                               Officer                Technologies            

  Mark          Stowers        President and CEO      MBI International       MI

  Terry         Stone          Director of            Scott\'s                OH
                               Biotechnology and                              
                               Regulatory Affairs                             

  Steven        Strauss        Professor - Department Oregon State University OR
                               of Forest Sciences                             

  Hollee        Stubblebine    Director - Industry    National Potato Council DC
                               Communications                                 

  Christian     Studlein       Chairman               Integrated Coffee       HI
                                                      Technologies            

  Kathy         Swords         Manager - Business     Simplot Plant Sciences  ID
                               Development                                    

  Scott         Thenell        Biotechnology          Consultant              CA
                               Regulatory Affairs                             

  Cheryl        Toner          Director - Health      International Food      DC
                               Communications         Information Council     

  David         Tricoli        SRA Supervisor         University of           CA
                                                      California - Davis      

  George        Ude            Plant Breeder          Bowie State University  MD

  Michael       Wach           Biotechnlogist         USDA-APHIS              MD

  David         Williams       Senior Vice            Cholorgen               MO
                               President - Operations                         

  Janet         Whitley        Researcher             Orphan Drugs Program -  DC
                                                      FDA                     

  Jeffrey       Wolt           Professor - Soil       Iowa State              IA
                               Chemistry              University/BIGMAP       
                                                      Program                 

  Ning          Wu             Professor              Langston University     OK

  Paul          Zankowski      Commissioner           USA-PVP                 MD

  David         Zilberman      Professor -            University of           CA
                               Agricultural Economics California - Berkeley   

                                                                              

  **Steering                                                                  
  Committee**                                                                 

  June          Blalock        Coordinator            USDA-ARS                MD
                               -Technology Licensing                          
                               Program                                        

  Marvin        Burns          Dean - School of       Langston University     OK
                               Agriculture and                                
                               Applied Sciences                               

  William       Goldner\*      National Program       USDA-CSREES             DC
                               Leader - SBIR                                  

  Daniel        Jones          National Program       USDA-CSREES             DC
                               Leader - Biotechnology                         

  Ed            Kaleikau       National Program       USDA-CSREES             DC
                               Leader - Competive                             
                               Programs                                       

  Jill          Long Thompson  CEO and Senior Fellow  NCFAP                   DC

  John          Radin          Crop Production -      USDA-ARS                MD
                               Product Value and                              
                               Safety                                         

  Sujatha       Sankula        Director of            NCFAP                   DC
                               Biotechnology Research                         

  Ann Marie     Thro\*         National Program       USDA-CSREES             DC
                               Leader - Plant and                             
                               Animal Systems and                             
                               Steering Committee                             
                               Chair                                          
  ------------- -------------- ---------------------- ----------------------- ------------

\*Steering Committee Co-Chair

***Appendix C: Workshop Agenda***

### Monday, 8 November 2004

# 8:00-8:30 Continental breakfast and registration

8:30-8:35 Call to order, Adrianne Massey, Principal, A. Massey and
Associates

8:35-8:40 Welcome message, Jill Long Thompson, CEO and Senior Fellow,
NCFAP

8:40-8:45 Welcome message, Colien Hefferen, Administrator, USDA-CSREES

8:45-8:50 Welcome message, Marvin Burns, Dean, School of Agriculture and
Applied Sciences, Langston University

8:50-8:55 Welcome message, Edward Knippling, Associate Administrator,
ARS

8:55-9:00 Workshop purpose/challenge at hand, Ann Marie Thro, CSREES

9:00-9:15 Overview of a Workshop (June 2004) co-organized by Pew
Initiative on Food and Biotechnology and USDA-APHIS on "Impacts of
biotechnology regulation on small business and university research --
possible barriers and solutions", Michael Fernandez, Pew Initiative on
Food and Biotechnology

9:15-10:15 Overview session - Economic Research Service, USDA, and
regulatory agencies

> Moderator: Dan Jones, CSREES

-   Alberto Jerardo, Economic Research Service

-   Sally McCammon, Animal and Plant Health Inspection Service

-   John Kough, Environmental Protection Agency

-   Mary Ditto, Food and Drug Administration

10:15-10:35 Panel and audience discussions (A. Massey, Facilitator)

10:35-11:00 Break

11:00-12:00 Regulatory challenges - Experiences from the perspective of
public researchers

> Moderator: John Radin, ARS

-   Dennis Gonsalves, ARS (virus-resistant papaya)

-   Ralph Scorza, ARS (virus-resistant stonefruit)

-   Alan McHughen, University of California-Riverside
    (herbicide-tolerant flax)

-   David Clark, University of Florida (Petunias with delayed flower
    senescence)

12:00-12:20 Panel and audience discussions (A. Massey, Facilitator)

12:20-1:20 Lunch

1:20-2:20 Regulatory challenges **-** Viewpoints from the perspective of
private business enterprises

> Moderator: Bill Goldner, CSREES

-   Keith Redenbaugh, Seminis

-   Neal Gutterson, Mendel Biotechnology

-   Terry Stone, Scotts

-   Les Pearson, ArborGen

2:20-2:45 Panel and audience discussions (A. Massey, Facilitator)

2:45-3:15 Break

## 3:15-4:00 Approaches to regulatory realities -- a look into existing models 

> Moderator: June Blalock, ARS

## Bob Holm, IR-4 Program

## Sarah Linde-Feucht, Orphan Drug Program, FDA

##  

## 4:00-4:45 Approaches to regulatory realities -- exploration of possible new models

-   Steven Strauss, Oregon State University

-   Jeff Wolt, Iowa State University

4:45-5:15 Panel and audience discussions (A. Massey, Facilitator)

5:15 Adjourn

## 

## 

## Tuesday, 9 November 2004

8:00-8:25 Reconvene and continental breakfast

8:25-8:30 Review of goals for the day (A. Massey, Facilitator)

## 8:30:10:30 Brainstorming for solutions to surmount challenges and identify alternative scenarios 

-   Breakout Session Question 1: Critical crops and traits that need to
    move through regulatory process

-   Breakout Session Question 2: Areas of research that could enhance
    and accelerate the deregulation of small market crops

-   Breakout Session Question 3: The appropriateness of existing models
    to overcome the barriers and identify new models or propose changes
    to existing models

-   Breakout Session Question 4: Identification of next steps including
    how we can address the issues raised

10:30-10:45 Break

> 10.45:12:15 Report from Breakout Groups and Discussion - (A. Massey,
> Facilitator)

## 12:15-1:15 Lunch 

## Working lunch for breakout group leaders and steering committee to prepare first draft of recommendations based on breakout group reports

## 1:30-2:15 Discussion and development of second draft of workshop recommendations (A. Thro, CSREES)

2:15-2:40 Finalization of workshop recommendations (A. Massey,
Facilitator)

## 2:40-2:45 Closing remarks: Ann Marie Thro, CSREES

## Adjourn 

[^1]: The text below is based upon transcription of the actual
    presentations, questions, and comments.