Policy Perspectives - University of Calgary

sweatertableBiotechnology

Dec 3, 2012 (4 years and 6 months ago)

432 views












Plant Molecular Farming: Policy Perspectives from Canada
and the United States


Ashley Susan Groenewegen

University of Calgary

April 27, 2006.































2


TABLE OF CONTENTS


INTRODUCTION
…………
.
………………………………………………………
...
.....3


REGULA
TORY
RESPONSIBILITY
…………………………………………………..5

United States
……………………………………………………………………………...5

Canada
…………………
.
……………………………………………………
...
…………6


REGULATORY
FRAMEWORK
……
.
………………………
...
…………....................8

United States
……………………………………………………………………………...8

Qualification f
or Regulation
................................................................................................
8

Permit Application Requirements
…………………………………………………………
9

Conditions of Permit Grants
…………………………..………………………………...
1
1

United States’ Path Forward
………………
…………………………………………….
12

Summar
y
…………………………………………………………………..……………..
13

Canada
……………………………………
.
…………………………………………
...
..13

Qualification for Regulation
…………………………………………………..…………
14

Permit Application Requirements
………………………………………………………..
14

Conditions of Permit Grants
………………
…………………………………………..…
15

Canada’s Path Forward
……………………………………………………………...….
16

Summary
…………………………………………………………………………………
16


RISK ASSESSMENT
….……………………………………...………………………..17

United States
…………………………………………………………………………….17

Canada
…………………………………………………………………………………..18


CON
CLUSION
………….…………………………………………………...…………19


GLOSSARY OF TERMS
………………………………………………………………21


BIBLIOGRAPHY
………………………………………………………………………24


APPENDIX A: Table 2: PMF Products at Various Stages of Development
………..27
















3


INTRODUCTION


M
odern
scientific

and tec
hnological capabilities

are
being
developed at suc
h a pace that

the implications for
human and animal health, environmental security, economic
feasibility, and e
thical acceptability

are threatening to exceed the capacity of the
current
policy framework.
Th
e emerging technology of Pla
nt Molecular Farming is widening

the
policy
-
technology gap as it moves from
research and
d
evelopment to
commercialization.
The Canadian Food Inspection Agency defines plant molecular farming as, “The use of
plants in agriculture

for the production of pharmaceuticals or industrially useful
biomolecules, rather than for the production of food, feed, or textile fibres.”
1

One
example is the development of
transgenic tobacco that produces proteins useful in the
treatment of certain hu
man ailments. Some applications include patient
-
specific cancer
treatments
-
non
-
Hodgkins lymphoma, various cancer drugs
-
Mullerian Inhibiting
Substance for treating ovarian, fallopian, and uterine cancers, and human serum albumin
-
multiple blood replacement t
herapies.
2

M
uch of the controversy and regulatory
uncertainty surrounding the development of PMF stems from the use of food crops, for
non
-
food purposes.
For instance
, corn is a much more popular plant for producing human
proteins than tobacco, because the

infrastructure for milling and grinding corn for
extraction of proteins is already well u
nderstood, and corn seed is more easily and
efficiently stored
.
3

The policy

implications for PMF are not as

much the
result

of a new technology
as they are the result

of a

new application of technology. PMF crops
, the “third
generation” of transgenic crops,

are produced

using t
he same technology as the first two
generations of Genetically Modified Foods, the first generation being crops that are
genetically engineered
to resist pesticides and herbicides, and the second generation
being crops that are genetically engineered to enhance some desirable quality of the plant.
What distinguishes PMF from the first two generations of transgenic crops is that PMF
crops are genet
ically engineered
to produce products for which the plants have not
traditionally been used.

This new application necessitates th
e development of a

policy
framework that is comprehensive in its s
co
pe, as well as in the process through

which it
is developed
.


The current regulatory framework regarding plant molecular farming in both
Canada and the United States is
quite clearly established in regards to the regulation of
field testing of PMF cr
ops under the more general regulation of
PNTs (plants with novel
traits). However, the

practical operation of who does what in terms of regulating,
monitoring, data collection and remedial action
for GMOs in general
has
,

in some cases,
been

compromised by jurisdictional overlap, jurisdictional ambiguity, and lack of
com
municati
on among the mutually responsible regulatory agencies.
In an Audit Report
released in December 2005 by the Office of Inspector General, United States Department



1

CFIA. (Canadian Food Inspection Agency). 2001.

CFIA Multi
-
Stakeholder Consultation of Plant
Molecular Farming.


Report of Proceedings
. 20.

2
Nevitt, Jonathan, George Norton, Bradford Mills, Mary Ellen Jones, Mike Ellerbrock, Dixie Reaves, Kelly
Tiller and Gary Bullen. 2003. “Participatory Assessment of Social and Economic Effects of Using
Transgenic Tobacco to Produce Pharmaceuticals.”

Working

Paper. Department of Agricultural and Applied
Economics Virginia Tech.

5
.

3

Ibid.,
12



4


of Agriculture, the need for the American Plant Health Inspection Service to strengthen

accountability for field tests of Genetically Engineered Crops, along with a lack of
communication between APHIS’ branches BRS and PPQ were identi
fied
.
4

Even as the
regulation of field testing PMF crops

in Canada and the United States is still becoming
co
nsolidated, the need for commercial regulation is pressing, and is, at present, not
sufficient to manage the commercialization of PMF
.


The process by which Plant Made Pharmacueticals (PMPs), and Plant Made
Industrial Products (PMIPs) are tested in field t
rials is regulated on a case
-
by
-
case
permitting process in both Canada and the United States. The process generally includes
a permit application, in which the applicant must include certain pertinent information
regarding the crop used, the product it is
intended to produce, the method of gene
transfer, and pr
oposed methods of containment or

confinement. The permit is reviewed,
and granted, granted under certain conditions, or denied.
There are procedures for
monitoring during the field test, as well as po
st
-
harvest monitoring, and post
-
harvest land
use restrictions in many cases. However, the permit application process is comparatively
more strictly regulated
and enforced
than the post
-
harvest land use, and excess biomass
disposition procedures.


Decisions

regarding permit grants are based on the risk assessment processes in
place. Very generally, both Canada and the United States operate on a cost
-
benefit
analysis model of risk assessment, although the weighting of contributing factors is
somewhat ambiguou
s due to the many aspects of society that may potentially be affected
by the development of PMF technology, including agriculture, industry, health care,
environmental security, and consume
r benefit
. Recently the perceived dominance of
science in analyzing

costs and benef
its of a
technology
and new scientific applications
has been challenged, not only by the general public, but from other sources such as the
academic community, and
the
United States’
Nat
ional Research Council. In 2002, the
NRC’s Committee o
n Environmental Impacts Staff(CB) released its book,
Environmental
Effects of Transgenic Plant
s
: The Scope and Adequacy of Regulation,
in which it states

that “Risk assessment literature and history demonstrate that environmental regulation of
agricultural

practices and technologies involves an interplay between ecological and
social factors.”
5

From its study, the committee concluded that risk analysis of transgenic
plants has t
w
o distinct roles to fulfill
;

one
of technical support for regulatory d
ecis
ion
m
aking, and the other of

establishing and maintaining
regulatory legitimacy.
6

In Canada,
the Genome Prairie GE3LS group has been carrying out studies on different aspects of
commercialization of biotechnology and genomics, recognizing that new innovations i
n
these areas raise social, environmental, and regulatory challenges which need to be
addressed when considering how these products might be commercializaed successfully
and responsibly.
7




4

Office of the Inspector General South Region. U.S. Department of Agriculture. 2005. “Animal and Plant
Health Inspection Service Controls Over Issuance of Genetically E
ngineered Organism Release Permits.”
Audit Report
. December. i, ii.

5

National Research Council Committee on Environmental Impacts Staff (CB). 2002.
Environmental
Effects of Transgenic Plants: The Scope and Adequacy of Regulation.
Washington, DC, National
Academies Press. 2

6

Ibid.,
6
.

7

Einsiedel, Edna F. and Jennifer Medlock. 2005. “A Public Consultation on Plant Molecular Farming.”
AgBioforum

8(1): 4.



5



As new biotechnology applications and public awareness about them h
ave
developed in Canada and the United States, the role of multiple stakeholders in
contributing to the policy making process has been increasingly considered. Access to
information has increased in both countries via the internet, where information
concer
ning the regulation of certain applications is made available through the Plant
Biosafety Office in Canada, and the Federal Register in the United States. In 2001, the
Canadian Food Inspection Agency held a Multi
-
Stakeholder Consultation on Plant
Molecular

Farming, including presentations by representatives from the CFIA,
B
IOTECanada, the PBO, and USDA
-
APHIS. Workshops were conducted by Health
Canada, the CFIA, and a representative from the Department of Nutrition, University of
North Carolina at Greensboro
.
A project by the Genome Prairie GE3LS group began in
2003 to examine the perceptions and reactions to PMF among lay Canadians
through
public consultations in the form of focus groups,
with the goal of incorporating public
input to on
-
going policy develop
ment.
8

In the United States, public input is solicited
during the application process, and is incorporated more at the review stage on a case
-
by
-
case basis which allows for public feedback
on
certain permits

through the internet
-
accessible Federal Register
.


To explore the policy landscape in which the PMF application of transgenic crop
technology is
emerging, it is necessary to identify the responsible regulatory agencies,
and their respective jurisdictions
, as well s the mechanics of the

current regulator
y
framework
, which appears to be

underdeveloped in that it does not address the terms and
conditions of commercialization.
This state of uncertainty is a reflection of the lack of
policy decisions to direct the path of PMF development. The current model of

risk
assessment used in the case
-
by
-
case regulatory decisions for granting
permits for
field
trials of PMF crops
must be examined in order to understand whether it is

sufficient to
manage the wider implications of commercialization
.


REGULATORY RESPONSIB
ILITY


United States

In the United States, regulatory responsibility for PMF crops is shared by a number of
agencies, which receive their delegation of res
ponsibility from Federal
Acts.
In the case
of PMF applications, much of the terminology used in Feder
al Acts include
s PMPs and
PMIPs under broad

categories, such as “Genetically Engineered Organisms”, thereby
granting regulatory oversight to a number of Federal Agencies.

The first line of regulatory oversight for field release
of Genetically Engineered
(GE) O
rganisms is
granted to

the American

Plant Health Inspection Agency
(APHIS)
by
the Plant Quarantine Act, and the Federal Plant Pest Act.
APHIS has the authority to
grant permits for growth of bioengineered pharmaceutical plants.
In June of 2002, APHIS

consolidated all plant biotechnology activities into the current unit responsible for overall
management of the inspection program, the Biotechnology Regulatory Services Division
(BRS) of the United States Department of Agriculture.
9

Specifically, BRS is
responsible
for the release into the environment, and oversees importation and interstate movement of
bioengineered pharmaceutical plants, as well as addressing environmental safety issues



8

Einsiedel, Edna F. and Jennifer Medlock. 2005. “A Public Consultation on Plant Molecular Farming.” 4.

9

Office of the Inspector General, USDA. “Audit Report.” 5.



6


associated with these activities.
The Plant Protection Quarantine (
PPQ) is the first agency
to deal directly with a PMP

or PMIP
, as it issues permits for importation, interstate
movement and field

testing of PMPs.
10

The USDA also

has

regulatory authority through
the Federal Meat Inspection Act (FMA), the Poultry Products I
nspection Act (PPIA), the
Virus, Serum, Toxin, and Analogous Products Act (VISTA), and the Federal Seed Act
(FSA). The Food and Drug Administration (FDA)
regulates the pharmaceutical products
of PMF
under the Federal F
ood, Drug and Cosmetic Act (FD&C
), and

the Food Quality
Protection

Act (FQPA). T
he FDA regulates human biologics and human and animal
drugs derived from bioengineered pharmaceutical plants, intended for therapeutic,
preventative, or diagnostic purposes, as well as animal drugs derived from bio
engineered
pharmaceutical plants, intended for use in the diagnosis, cure, mitigation, treatment, or
prevention of disease in animals, or to alter the structure or function of the animal.
Under
the Public Health Service Act (PHS
A
), and the Federal Food, Dr
ug, and Cosmetic Act
(FD&C), the Center for Biologics Evaluation and Research has the authority to regulate
geological products and drugs for use in humans. The Environmental Protection Agency
has regulatory oversight through the Federal Insecticide, Fungi
cide, and Rodenticide Act
(FIFRA), and the Toxic Substances Control Act (TSCA) at the commercial stage of
development.

In order to deal with jurisdictional overlap for the regulation of GE plants, the
Coordinated Framework for the Regulation of Biotechnol
ogy was established in 1986,
coordinating the USDA, EPA,
FDA, NIH (National Institutes of Health), and the NSF
(National Science Foundation).
11

The Coordination between these regulatory jurisdictions
resulted in a regulatory proces
s that takes

a case by cas
e approach to regulating

genetically engineered products based on regulation that was already in place.
12

This
mandate allows for decisions to be made considering one case at
a time, but does not
appear to
have the capacity to
distinguish between differen
t applications of GE plants,
such as PMF and GM foods.


Canada

The situation in Canada

is similar to that in

the United States in that there is mutual
regulatory responsibility shared among a number of agencies for the regulation of PMF
applications. The C
anadian Food Inspection Agency (CFIA), has the a
uthority to regulate
and enforce the conditions of

confined and unconfined
environmental release of PNTs

under the
“Seeds Act and Seeds Regulations (Part V)”, the use of by
-
products as feed
under the “Feeds A
ct and Regulations”, and the purity, potency, safety and efficacy of the
product under the “Health of
Animals Act and regulations.”
13

A
2005 Draft Directive
entitled “Assessment Criteria for the Evaluation of Environmental Safety of Plants with
Novel Traits

Intended for Commercial Plant Molecular Farming” (Directive 200X
-
Y),
published by the Plant Biosafety Office, places the regulation of PNTs in confined



10

Stewart, Patrick A. and Andrew J. Knight. 2004. “Trends affecting the next generation of U.S.
agricultural biotechnology: Politics, policy, and plant
-
made pharmaceuticals.”
Technological Foreca
sting
and Social Change
,
4
.

11

Ibid.

12

Ibid.

13
CFIA. (Canadian Food Inspection Agency). 2004. Assessment Criteria for Determining Environmental
Safety of Plants With Novel Traits
. DIR94
-
08.

10.





7


research field trials and unconfined release under the jurisdiction of The S
eeds Act, and
Seeds Regulat
ions
. The Seeds Act is administered by the Plant Products Directorate,
which is
granted authority by the CFIA to regulate the quality, testing, inspection and sale
of seeds in Canada.
14

Importation of plant materials falls under the Plant Protection Act,
an
d Plant Protection Regulation.
The “Food and Drugs Act and Regulations” delegates
responsibility for the regulation of pharmaceutical production, biologics and veterinary
drugs, as well as well as the use of plant byproducts as human food to Health Canada.

The agency is responsible for food safety standards, including the approval of medicinal,
therapeutic or diagnostic products. A branch of Health Canada, the Biologics and
Radiopharmaceuticals Evaluation Centre (BREC), would be responsible for regulating
P
MP products of PMF
, should the application become fully developed and
commercialized.

Environment Canada has regulatory oversight of the release into the
environment of PMF crops
as n
ew substances to Canada
under the “Canadian

Environmental Protection Act.

15

The Plant Biosafety Office (PBO) assesses the
environmental safety of PNTs.
Under the current regulatory framework, Provincial and
Municipal Regulation is

responsible for the disposal of

by products and processing waste
materials. PMF crops are also sub
jected to regulation under the “Pest Control Products
Act”, as they may classify as plant pests.
The parameters of regulatory jurisdiction of
PMF ar
e summarized in the table below for Canada and the United States.


Table 1:

PMF Regulation in Canada and the

United States


Regulation

United States

Canada

Permit Grants

APHIS

(growth of
bioengineered pharmaceutical
plants) under the Plant
Quarantine Act, and the Federal
Plant Pest Act.

PPQ

(importation, interstate
movement and field testing)

PBO

(confined rese
arch field
trials)

Site Inspection

BRS

manages,

PPQ

executes

Plant Products Directorate

(quality, testing, inspection and
sale of seeds.)

Release into the
Environment

BRS

CFIA

under the Seeds Act and
Seeds Regulation Part V.

PBO

(environmental safety)

En
vironment Canada under the
Canadian Environmental
Protection Act.

Health Canada

(for unconfined
release)

Importation
and Interstate
BRS

Plant Products Directorate

under the Plant Protection Act



14

CFIA. 2003. Plant Products Directorate, Plant Biosafety Of
fice
. Interim Amendment to DIR2000
-
07 for
Confined Research Field Trials of PNTs for Plant Molecular Farming.

15

CFIA.

DIR94
-
08.

10.



8


Regulation

United States

Canada

Movement

and Regulations.

Pharmaceutical
Products

FDA

under
the Federal Food,
Drug and Cosmetic Act.

Health Canada

Human
Biologics,
Human and
Animal Drugs

FDA

CBER

(human drugs)

Health Canada

CFIA
under the Health of
Animals Act and Regulations.

Commercial
Development

EPA

under the Federal
Insecticide, Fungicide
, and
Rodenticide Act, and the Toxic
Substances Control Act.

Biologic and
Radiopharmaceuticals
Evaluation Centre
, branch of
Health Canada

PBO

CFIA’s
cee搠dec瑩潮

Use of
byproducts

APHIS, BRS, PPQ

CFIA

under the Feed Acts and
Regulations.

Health Canada

(
use of
byproducts as human food).

Disposal of
byproducts
and
Waste

APHIS, BRS, PPQ

PBO

Provincial and Municipal
Regulation.


REGULATORY FRAMEWORK


United States

Qualification for Regulation

In order to conduct

a field test of a PMF crop, a
permit applica
tion must be submitted to
APHIS

120 days before the proposed release into the environment
. The permitting
process applies to
regulated articles, which are, by definition,
“Any organism that has
been altered or produced through genetic engineering, if the d
onor organisms, recipient
organisms, or vector or vector agent belongs to any genera or tax designated in 7 CFR
340.2, dated January 1, 2003, and meets the definition of plant pest, or is an unclassified
organism and/or an organism whose classification is
unknown.”
16

Regulation as a plant
pest depends on the method of insertion of recombinant DNA.
17

(It is the process, rather
than the
produ
ct, that determines the status of a plant pest
).
For example, an organism

which had been modified using DNA inserted thro
ugh Agrobacterium would fall under
this regulation

(as a plant pest)
, while an organism that had been modified using a gene
gun would not, even if neither transferred gene were from a plant pest.
18







16

Government Printing Office, 2005. Code of Federal Regulations. Title 7 Agriculture. Part 340.

Introduction of Organisms A
nd Products Altered or Produced Through Genetic Engineering which are
Plant Pests or which there is reason to believe are Plant Pests,
” 430.

17

Ibid., 5

18

. Stewart, A.J. Knight,

“Trends affecting the next generation of U.S. agricultural biotechnology: Poli
tics,
policy, and plant
-
made pharmaceuticals.”

5.



9


Permit Application Requirements

Under Title 7 Part 340 o
f
the Code of Federal Regulations;

“Introduction of Organisms
and Products Altered or Produced Through Genetic Engineering Which are Plant Pests
Or Which There is Reason To Believe are Plant Pests”, t
he
permit
applicant is to include
certain information in

the application for a field trial permit, and/or release into the
environment of a regulated article, including an

assessment of other organisms affected
by the recipient plant (PMF plant)
. Such organisms are those that
may consume,
pollinate, be pollinat
ed by, or be sexually compatible with the GE plant. An analysis of
whether the engineered protein will have direct or indirect damaging or toxic effects on
non
-
target organisms is required.

Additionally,

the applicant is required by the FDA to prepare an

Environmental
Assessment. The EA is an informative public document that is to “focus on relevant
environmental issues relating to the use and disposal from use of FDA
-
regulated articles
and shall be a concise, objective, and well
-
balanced document that al
lows the public to
understand the agency’s decision.”
19



Applicants must submit

certain
information about the
host plant, including

the
reproductive biology of the unmodified plant, its growth habitat, timing of sexual
maturity and duration of flowering, s
eed production and harvesting, transportation,
storage and sorting of harvest materials. A
s well
,

a description of the
gene
product
being
harvested, and its current and potential use

must be

included
. The levels of the gene
product

being produced
, and

the
plant

tissue in which it is grown must also be described.
An applicant is required to submit data in the application that demonstrate that the source
plan
t produces a consistent product, as well as information about the supplier of the
product.

The propert
ies of the engineered proteins and enzymes are to be compared with
the native molecule of the recipient

organism in order for APHIS to carry

out a risk
assessment of the regulated article.
20


Applications for release into the environment of a regulated arti
cle are required to
detail the processes to be used by the applicant to prevent contamination. An applicant
must establish Standard Operating Procedures (SOPs), and is required to implement an
approved training program to ensure that personnel are capable
of carrying out the
necessary actions in compliance with permit conditions. SOPs include detailed
descriptions of procedures such as who performs operations, and their qualifications, the
restricted access or use of the equipment, and where and when equipm
ent is to be
cleaned.

P
ost
-
harvest
information concerning the final destination of the product must a
lso
be included

in the permit application. The means of transportation and intended
destination, as well as the measures taken to prevent escape of the pro
duct must be
detailed. Any other biological material that accompanies, or contacts the PMF material
during movement should be identified. Finally, the applicant must include a proposal for
the final method of disposition of the regulated article, and exces
s biomass included in
production.
21




19

Code of Federal Regulations. Title 21 Food and Drugs. Part 25. “Environmental Impact Considerations.”
25.40.

20

Government Printing Office, 2005. 7 CFR Part 340. 438.

21

Ibid.




10



Once the FDA has reviewed the EA, and made any necessary additional
investigation, the EA will be published in the publicly accessible Federal Register for a
60 day period to allow for public input and feedback. The FDA
evaluates the
Environmental Assessment, as well as any public input, and

alternative

courses of action
that may mitigate environmental risk.
The EA
is the preliminary document used by the
FDA to determine whether to issue an Environmental Impact Statement
(EIS), or a
Finding of No Significant Impact (FONSI).

An EIS explains the relationships between
local short term uses of the environment and the maintenance and enhancement of long
term productivity, as well as any irreversible and irretrievable commitment
s of resources
that would be involved in the proposed action should it be implemented.
22

If the FDA
prepares an EIS, it will make a public record of its decision, including
what the decision
is regarding the conduction of the field test, the alternatives th
at have been considered,
and the means that have been adopted to minimize environmental harm.
A

summary of
the program for monitoring and enforcing measures to minimize environmental harm

is
prepared by the FDA
.
The FDA will inform the public of National E
nvironmental
Protectio
n

Agency procedures, and provide public notice of NEPA hearings, public
meetings, and availability of environmental documents.
The issuance of an EIS generally
implies a greater risk factor, or a greater novelty related to the

article

that is to be
released, than the issuance of
a

FONSI.


If the FDA proposes a rulemaking in the Federal Register
, the notice will state
that an Environmental Impact Statement is not nec
essary, and that the Finding O
f No
Significant Impact, and Environmenta
l Assessment are available for public review at the
FDA’s Dockets Management Branch.
When a proposed action is unprecedented (as with
most PMF applications),
and no EIS is issued,
a FONSI and EA are made available for
public review for 30 days before the f
in
al decision

whether to prepare an EIS

is made.


Prior to
2003,
some
PMPs and PMIPs could be released into the environment via
the notification track, a simplified, fast
-
track version of the permit process. If the PMF
crop was a corn, cott
on, potato, soy
bean, tobacco or

tomato crop, and provided that the
method of ge
ne transfer, and that the

genetic material used did not qualify it as a plant
pest, or toxic or viral threat to human or animal health, the notification track could be
used

for release of PMF
crops. However,
t
here were a few incidents in particular that
stirred up public concern, and resulted in APHIS removing the notification track option
for PMF applications

in 2003
. In 1999, concern grew for the safety of the monarch
butterfly because of the

environmental release of Bt corn, which was engineered to
express a protein that kills targeted insects that attack economically important crops.
23

The Bt protein caused even more public alarm when it was found that Starlink corn, in
which a variant of Bt

is produced, was found to have entered the human food supply,
although it had been deemed unfit for human consumption.
In 2002, APHIS found
volunteer Prodigene corn plants, which had been genetically engineered to produce a
pharmaceutical to prevent trave
ler’s diarrhea, growing in soybean fields in violation of
permit conditions in Iowa and Nebraska.
24


Not only did APHIS remove the notification
track option for PMF crops following these events, but the permit conditions for field



22

Ibid., 25.42.

23

P. Stewart,

A.J. Knight,

“Trends affecting the next generation of U.S. agricultural biotechnology:
Politics, policy, and plant
-
made pharmaceuticals.”

7.

24

Ibid., 8.



11


tests of PMP and PMIP appl
ications were overhauled to reflect the perceived greater risk
of the escape of PMF plants and products into the environment and the human food
chain
.

Following the Starlink and Prodigene corn incidents, in 2003 APHIS published a number
of new regulations
specifically regarding PMPs and PMIPs in the Federal Register (Vol.
687, No. 46.) The size of the perimeter fallow zone surrounding PMF crops was
increased from 25 to 50 feet, and the production of food an feed crops at the field test
site, and within the
perimeter fallow zone was restricted for the season following the field
test. Planters and harvesters were required to be dedicated for the duration of the field
test; tractors and tillage equipment were required to be cleaned in accordance with
establishe
d APHIS protocols, and facilities for storage of equipment and regulated
articles were required to be dedicated for the duration of the field test. APHIS changed
permit conditions so that an isolation distance of one mile for open
-
pollinated corn, and
one
half
-
mile for controlled pollinated corn was implemented. The num
ber of fieldsite
inspections
corresponding with critical times relevant to the confinement measures
(flowering, pollination, etc.), were increased, as was the auditing of permit records.


Co
nditions of

Permit Grants

All GMOs

considered as regulated articles under 7 CFR part 340 that are granted permits
for introduction into the environment are subject to c
ertain conditions. PMF crops can be

recognized under this category, if they qualify as r
eg
ulated articles
.

Because each GMO
is granted
a
permit individually, on a case
-
specific basis, p
ermit conditions vary from
case

to case: 7 CFR 340 states
,

“If
a

permit is granted, the permit will specify the
applicable conditions for introduction of the r
egulated article.”
25

In general, the regulated
article is to be kept separate from other organisms, and maintained and disposed of in a
manner so as to prevent the dissemination and establishment of pests. It is to be kept only
in specific a
reas, which are
designated by the permit.

APHIS
-
conducted
field inspections
,

as well as access

to records are to be allowed
without prior notice throughout the field
test. Within six months after termination of the field test, the permittee is to submit a
report to APHIS
including methods of observation, resulting data, and analysis regarding
all deleterious effects on

plants, nontarget organisms, and

the environment.
26



In a 2004 letter from USDA to permit applicants,
the agency stipulated

that
applicants must submit a 7

day pre
-
plant notice, as well as a 21
-
day pre
-
harvest notice.
Four weeks into the field test, a post
-
planting report is to be submitted including a map of
GPS coordinates, the total acreage of the test plot, the actual distance from test plants to
the nea
rest plants of the same crop, and the specific confinement option employed.
27

The
letter also recommends that, “Viable plant material should be destroyed, stored in or
returned to locations authorized in the permit. Non
-
viable material may be disposed of
th
rough appropriate waste disposal methods. No recovered plant material may be directed
toward food or feed use.”
28

However, a USDA Audit report published in December 2005
recognized that APHIS does not set a timefra
me for disposing of harvests of

high
-
risk G
E



25

Government Printing Office,7 CFR 340. 439.

26

Ibid.

27

USDA. (United States Department of Agriculture)
. 2004.
Letter to Permit Applicants
,
6
.

28

Ibid., 4.



12


crops, nor does it promptly destroy GE crops at the conclusion of the field test so that
their seeds do not spread outside the field test site.
29



United States’ Path Forward

Pertaining to the commercial development of PMF, in September 2002, APHIS, joi
ntly
with the USDA, FDA, CBER, CDER, CFSAN, CDRH, CVM, CVB, and BRS,
released a
Draft document entitled


Guidance for Industry on Drugs, Biologics, and Medical
Devices Derived from Bioengineered Plants for Use in Humans and Animals

. The
document outlines
extensively the responsibilities of the manufacturer of PMF
applications. The producer is required to consider the potential environmental impact of
all aspects of the manufacturing process. This means that the producer must ensure there
are confinement me
asures, as well as measures to prevent mixing of bioengineered
pharmaceutical plants with plant material intended for food or feed. Tests are to be
available to detect the presence of the target gene, and the protein product in the raw
agricultural commodi
ty, and traceable documentation of the growth and expression phase
of the manufacturing process is to be maintained.
30

The document recommends that the
producer consider p
otential soil contaminants that may affect the source material, and a
list of expecte
d pests that will require control during growth of th
e test crop
. The
producer is to document the manufacturing process, as well as lot specific data, including
the size and location of all sites where the bioengineered pharmaceutical plants are being
grow
n, the control of pollen spread, subsequent use of the field, and destruction of
volunteer plants in subsequent growing seasons.
31


The document states that, prior to marketing the product, a complete
characterization should be completed to ensure the prod
uct’s identity, strength, quality,
and purity. The producer should also have a stability protocol containing testing for
potency. In the case of edible biologics, the plant source must be clearly identified in the
label. Pre
-
clinical testing for bioenginee
red pharmaceuticals for use in humans must
include evaluation for impurities, including toxicants, pesticide, herbicide and fungicide
levels, evaluation of metal toxicants, and the potential for allergenicity, and
immunogenicity.

Although the
guidance
doc
ument is comprehensive in scope, it is somewhat
lacking in authority, as a final draft has not yet been published, and the stipulations it
proposes have not been published as rules in the Federal Register. It does not address the
PMF applications of Plant
Made Industrial Products.
Clear
and established

policy
directives still require

the implementation of a broad, yet well defined regulatory and
policy framework for the commercialization of PMF applications. This need is pressing,
as some PMF applications h
ave already reached the market in the U.S., including corn
-
produced Avidin, a diagnostic reagent, and corn
-
produced Trypsin, a protease used in the
processing of some biopharmaceuticals.
32

A more compreh
ensive list of PMF products at
v
arious stages of devel
opment in the U.S. and Canada

can be found in Appendix A
.




29
Office of the Inspector General, USDA. “Audit Report.” 7.

30
U.S. Department of Health and Human Services, FDA, CBER, CDER, CFSAN, CDRH, CVM, APHIS,
CVB, and BRS. “Guidance for Industry.” 2002. Drugs, Biol
ogics, and Medical Devices Derived from
Bioengineered Plants for Use in Humans and Animals.
Draft Guidance,

4.

31

Ibid., 10.

32
Horn, M.E., S.L. Woodard and J.A. Howard. 2004.

Plant molecular farming: systems and products.


Plant Cell Rep.

22:711
-
720, 714.



13



Summary

Although

the
re are procedures and permit conditions in place for the

field testing of
PMPs
and PMIPs

to minimize environmental risk, the efficacy of regulation is contingent
upon the enforc
eability of the rules
, and the overall maintenance of the program
. The
USDA Audit R
eport released in December 2005

identified
the need for APHIS to
maintain vigilant monitoring practices, and
t
ake remedial actions in cases

of non
-
compliance.
The Inspector
General found that APHIS has not finished updating its
regulations to comply with the Plant Protection Act of 2000. The agency has not made
efforts towards clearly delineating the mutual responsibilities of BRS and PPQ, in regards
to field test sites. The
need for delegation was
made apparent by

the finding that PPQ was
not performing the majority of inspections requested by BRS.
33

With regards to the
monitoring of field tests, the Inspector General found that APHIS
could not produce 55%
of the field test da
ta reports from pharmaceutical and industrial permits.
34

Furthermore,
the agency had not been withdrawing permits from applicants who were in violation of
regulations or permit conditions by not submitting required reports on or before the dates
they are du
e,
35

an infraction that, by law, can result in a fine of up to $250 000,
imprisonment for up to five years, or both.
36

The commercialization of PMF applications requires a far more comprehensive
regulatory and policy framework than the fie
ld testing of a par
ticular crop.

At

present, no
adequate policy and regulatory framework for commercialization has been established.

Curren
tly, a PMF product can theoretically

begin to move towards commercialization by
petition for the removal of a particular PMF crop from t
he list of regulated articles under
7 CFR 340. The petition will include a statement of why the subject is not a plant pest,
including scientific data to support this statement. Such data should demonstrate this by
comparing known and potential differences

from the unmodified recipient organism that
would substantiate that the regulated article is unlikely to pose a greater plant pest risk
than the unmodified organism from which it was derived.
37



Canada

There is currently no Government of Canada policy on
PMF. The Canadian Food
Inspection Agency (CFIA), has identified this as a probl
em for the agency in the
development of
a regulatory framework for the technology
38
. However, as there is no
regulation

surrounding the research of recombinant DNA in enclosed la
bs, greenhouses,
building
s

or mines,

PMF applications are being developed, and producers are

seeking to
test the applications in field sites, with an eye to the future and
to
commercialization. So
in 2003, the CFIA

began to develop a science
-
based regulato
ry framework around
the
environmental release of
PMF

applications
.





33

Ibid., 9.

34

Office of the Inspector General, USDA. “Audit Report
. 36.

35

Ibid., 39.

36

Ibid., 4.

37

G
overnment Printing Office. 7 CFR 340. 442.

38
CFIA. (Canadian Food Inspection Agency). 2005. Plant Biosafety Office.


Developing a Regulatory
Framework for the

Environmental Release of Plants with Novel Traits Intended for Commercial Plant
Molecular Farming in Canada
,”

2.



14


Qualification for Regulation


In Canada,
the presence of a novel trait in a plant, irrespective of the method used to
introduce it, will trigger notification and authorization requi
rement
s, under Directive
94
-
08. Under Directive 2000
-
07, a new variety of a species is novel if it possesses
characteristic(s) or trait(s) novel to that species in Canada.
39

By this definition, all PMF
applications are qualified as PNTs, and therefore all regulat
ion of PNTs applies to PMF
applications.


Permit Application Requirements

To be granted a permit for the confined research field trial of a PNT, an application must
be submitted to the Plant Biosafety Offic
e

(PBO)
.
(
In this context, the term

confinement


indicates reproductive isolation, site monitoring, and post
-
harvest land use
restrictions

of the field test site
40
).
Applicants must include information regarding the
PNT, as specified in Directive 2000
-
07.
The information required in Canada

is very
simila
r to that in

the United States. A
description of the taxonomy of the PNT, details
regarding its intended use, a description of the novel gene products, and the methods use
d
to introduce the novel traits are to be submitted.

The modification of the PNT thro
ugh
recombinant DNA must be explained. Other pertinent information includes the
description of the inheritance and stability of introduced traits which are functional in the
plant, a description of the parental genome, and a description of the novel trait’
s products,
by
-
products and their metabolic pathways, as well as their known or potential toxicity to
other organisms, and adverse human health effects.
41



In order to be granted a permit for the confined field test of a PNT, an ap
plicant
must provide data

regarding

the identity and origin of the PNT, properties of the novel
gene and gene product, relative phenotypic expression of the PNT compared to its similar
counterpart (unmodified organism), and anticipated or known relative effects on the
environment
resulting from release.
42

The applicant is responsible to submit appropriate
test methodologies for detection and identification of PNTs, as well as written agreement
to provide the CFIA with reference material suitable to support these methods.
43

Applicants

must fulfill a number of obligations in order to be considered for an
unconfined field test permit. All plant material that will be in proximity to each field trial
must be determined, and the applicant

must have a contingency plan in case

of accidental
r
elease of material or inadvertent breakdown of reproductive isolation measures. The
applicant is responsible to notify all necessary regulatory agencies besides the PBO
.
44

These may include the Pest Regulatory Agency, Health Canada, and Feed Section of the
CFIA, depending on the characteristics of the specific PNT, and according to the
regulatory jurisdiction of each agency.






39
CFIA.
Interim Amendment to DIR2000
-
07 for Confined Research Field Trials of PNTs for Plant
Molecular Farming.

40

Ibid.

41

Ibid., Appendix 3.

42

Ibid., 12.

43

Ibid., 13.

44

44
CFIA. Interim
Amendment to DIR2000
-
07 for Confined Research Field Trials of PNTs for Plant
Molecular Farming.



15


Conditions of Permit Grants

The CFIA evaluates the request for authorization to conduct confined field trials under
regulatory Direc
tive 2000
-
07.
45

The applications are considered on a case
-
by
-
case basis,
and if permission is granted, the terms and conditions of the field trial are established.
Some general rules apply to all test sites. No more than 1 hectare per trial location site
ma
y be devoted to the PNT crop. There is a limit of ten trial site locations per submission
per province, and no more than 5 cumulative hectares per submission per province is
allowed.
All PNTs must be
reproductively isolated by spatial isolation distance, s
uch as
by bags, nets, or cages placed over flowering plants to prevent pollen exchange, the
harvest of plants before flowering, removal of floral parts before pollen maturity, or the
use of guard rows or pollen traps. Any progeny from the guard rows are to

be han
dled in
the same manner as PNTs

(destroyed).
46


The permittee is required to supply GPS coordinates and maps to the PBO. These
documents
must
include the city/town, and province nearest to the f
ield trial, along with
compass d
irections and the legal
land location. Exact trial dimensions and indication of
surrounding crops, as well as measurements from permanent surrounding landmarks and
the trial number designated by the PBO are to be included, along with the planting date,
and the name and phone numb
er of the field contact.


The permittee

must maintain records of all confined research field trials, to be
made available to the CFIA upon request. These should include the crop type,
reproductive isolation method used, isolation distance, and the area un
der post harvest
land use restriction. Any transportation of the material, as well as storage of the surplus
seed, and disposition or storage of all material are to be recorded. Under Directive 2000
-
07, “Seed must be disposed of by an approved method that
will render the seed or
propogable plant material non
-
viable” (by autoclaving, burning, or deep burial to a depth
of greater than 1 metre).
47

No harvested material or byproduct from a confined research
field trial may be used as human food or livestock feed

without the approval of Health
Canada
, or

the Feed Section, CFIA. It is the applicant’s responsibility to comply with all
terms and conditions under which the field test is authorized.


CFIA regional inspectors have the right to inspect trial sites durin
g and after
harvest for compliance with terms and conditions under which the trials were
authorized.
48

Inspections will be conducted on a random basis, without prior notification.
Records must be maintained, and available for inspection both during and afte
r the field
trial.

The trial site is subject to post
-
harvest restrictions in subsequent growing seasons
to identify and destruct PNT volunteer plants and sexually compatible related species.
Restrictions on the post
-
harvest land use include the disallowan
ce of planting any species
related to the PNT on the field site, or surrounding 10m perimeter.
49

If the reproductive
isolation measures failed, monitoring of the isolation distance zone may be required. If



45

Arcand, Francois, and Paul Arnison. 2004.

Development of Novel Protein Production Systems and
Economic Opportunitie
s & Regulatory Challenges for Canada.


Discussion Paper
, 201.

46

CFIA.

Interim Amendment to DIR2000
-
07 for Confined Research Field Trials of PNTs for Plant
Molecular Farming.

47

Ibid.

48

Ibid.

49

Ibid.



16


the field test was harvested by combine, an additio
nal 50
-
metre buffer zone around the
site must be monitored.


Canada’s Path Forward

In the absence of a Government of Canada policy on Plant Molecular Farming, the
current path for commercialization of PMF appli
cations would theoretically follow the
genera
l guidelines under the more general cagetory of PNTs.

Under directive 94
-
08, an
applicant can file a petition with the PBO for the unconfined release of a PNT.
50

The
PBO coordinates with Health Canada, and Feeds Section of the CFIA on its decision. The
PBO,

Health Canada, and CFIA Section Section may organize a meeting with the
proponent to analyze the status of the product, and provide guidance on applicable
requirements.
51
It is the proponent’s responsibility to determine whether they have
produced a PNT.

I
n it’s discussion document, “Developing a Regulatory Framework for the
Environmental Release of Plants with Novel Traits Intended for Commercial Plant
Molecular Farming in Canada”, the PBO suggests specific conditions for the regulation
of PNTs intended fo
r
commercial
PMF.
Standard Operating Procedures (SOPs), are
described specifically for PMF crops. These include SOPs for seeding, transplanting,
harvesting, and site maintenance, cleaning of machinery, disposition, storage, and off
-
site
transportaion of pl
ant materials from fields, and SOPs for d
ealing with non
-
compliance.
SOPs

for site monitoring and post
-
harvest land use restrictions, as well as for the
maintenance of records pertaining to all site
-
specific operations, and for staff training are
proposed.

In the case of food crops, the PBO has developed risk mitigation strategies
such as limiting the expression of the novel biomolecule to a specific part of the plant,
triggering the expression of the novel biomolecule in response to a specific event, or
li
miting the potential gene flow by using chloroplast transgenic systems, or male sterility
traits.
52



Summary


As
the United States, Canada is still lacking a thorough policy and regulatory framework
for the commercial development of PMF applications. Witho
ut a Government of Canada
policy on Plant Molecular Farming, the CFIA and other regulatory agencies cannot
implement
a
definite regulatory structure for the testing and commercialization of PMPs
and PMIPs. It is likely that in this situation, PMF applicati
ons will continue to be
regulated as PNTs in general, and not considered by regulation as a separate application
of transgenic technology.



RISK ASSESSMENT





50

CFIA.

DIR94
-
08.

12.

51

CFIA.

DIR94
-
08,

8.

52

52
CFIA. (Canad
ian Food Inspection Agency). “Developing a Regulatory Framework for the
Environmental Release of Plants with Novel Traits Intended for Commercial Plant Molecular Farming in
Canada.” 11.



17


The universal standard of risk management for biotechnology is often referred to as the
“Precauti
onary Principle”, commonly defined as “Where there are threats of serious or
irreversible damage, lack of full scientific certainty shall not be used as a reason for
postponing cost
-
effective measures to prevent environmental degradation.”
53

However, as
dis
cussed earlier, the risks of developing PMF reach beyond the environmental spectre.
Economic,
trade relationship
, human health,
agricultural,
and
ethical risks of developing
PMF must all
be
factored in to government policy on PMF that
clearly maps

the path

for
development. In the absence of such policies, the respective agencies in Canada and the
U.S. must carry out
their own risk analysis within

the narrowly defined parameters of
their jurisdictions, considering only one aspect of risk at a time.
Environme
ntal and
Health risks are the primary focus of risk analysis models. This is reflected in
the
current
risk assessment models. Evaluation of risk proceeds on a case
-
by
-
case basis, focusing on
scientific evidence, and comparative analysis.

The National Rese
arch Council
addressed APHIS


risk assessment of PMF in its
recent publication,

Environmental Effects of Transgenic Plants: The Scope and
Adequacy of Regulation.”

The NRC

claims that environmental regulation of agricultural
practices and technologies invo
lve an interplay of ecological and social factors.
54

The
Committee

recommended that the potential impacts of transgenic crops should be placed
within the context of environmental effects caused by other agricultural practices and
technologies.
55

R
egulating
transgenic plants differently from conventiona
lly improved
plants involves an assumption
that the risks associated with the introduction of genetic
novelty are related to the number of genetic changes and the origin of the novel genes.
56

The committee ident
ified this assumption,
but did not acknowledge its validity. Based on
empirical evidence of comparison, the NRC found that the transgenic process itself does
not present any new categories of risk
, but that specific traits introduced either
transgenically,

or conventionally, can pose unique risks.
57

This finding points to the
inadequacy of the current regulatory framework for PNTs, which defines plant pests
based on the method by which a plant is altered.


United States

In August 2002, the United States Offi
ce of Science and Technology Policy published
“Proposed Federal Actions To Update Field Test Requirements for Biotechology Derived
Plants and To Establish Early Food Safety Assessments for New Proteins Produced by
Such Plants.”
58

The OSTP outlined

four

prin
ciples for the risk assessment of such plants:

1)

The level of confinement should be consistent with the level of environmental,
human and animal health risk.




53

CFIA

CFIA Multi
-
Stakeholder Consultation of Plant Molecular Farming
.
”19.


54

National Research Council Committee on Environmental Impacts Staff (CB
).

Environmental Effects of
Transgenic Plants: The Scope and Adequacy of Regulation,


2.

55

Ibid.

56

Ibid., 4.

57

Ibid.

58

P. Stewart, A.J. Knight,

“Trends affecting the next gener
ation of U.S. agricultural biotechnology:
Politics, policy, and plant
-
made pharmaceuticals.”

9.



18


2)

If a trait or protein presents an unacceptable or undetermined risk, field test
confinement requirem
ents would be rigorous to restrict outcrossing or
commingling of seed.

3)

Genes of gene products from these field tests would be prohibited in commercial
seed, commodities, and processed food and feed.

4)

Even if these traits or proteins do not present a health
or environmental risk, field
test requirements should still

minimize the occurrence of out
crossing and
commingling of seed.


Canada

In Canada, the precautionary principle is implemented in such a way that authorities

are obliged to act even if there is on
ly a theoretical risk of harm
, although this standard
has been identified as a regulatory challenge.
59

The risk management model for
molecular farming is such that the level of regulation reflects the level of risk: A high
level of risk is met by a high lev
el of control. The process of risk assessment involves the
comparison of a PNT to its unaltered counterpart, with consideration for changes in
weediness, gene flow to wild relatives, plant pest properties, impact on non
-
target
organisms, and impact on biod
iversity.
60

The CFIA is currently looking to revise the
context of acceptable risk in order to de
termine whether regulation

of PMF will fall under
the banner of PNTs.
This will be determined by risk assessments of the potential health
impacts of the novel b
iomolecule resulting from its adventitious presence in food and
feed commodities.
61

The PBO
has noted

that the potential for commercial scale PMF to
be developed in Canada may be impacted by the resources required to carry out adequate
inspections.
62



At th
e 2001 CFIA Multi

S
takeholder consultation on Plant Molecular Farming, a
numb
er of issues were identified in association with PMF, including human health,
animal health, environment, growth of the industry and international trade, and public
trust.
63

Howeve
r, there does not seem to be an established procedure for consolidating all
issues into the risk analysis, and policy making system. Established risk assessment
models operate on a science
-
based, case
-
by
-
case basis.


In a CFIA Draft Directive
for the “Ass
essment Criteria for the Evaluation of
Environmental Safety of Plants with Novel Traits Intended for Commercial Plant
Molecular Farming”, the
evaluation of the
environmental safety of PMF applications is
delegated to the Plant Biosafety Office
, which consi
ders

the following
criteria to
determine an acceptable level of risk:

1)

Potential of the PNT to become a weed

2)

Potential for gene flow to wild relatives

3)

Potential for the PNT to become a plant pest

4)

Potential impact on non
-
target species




59

CFIA. “CFIA Multi
-
Stakeholder Consultati
on of Plant Molecular Farming.”

9.

60

CFIA.
Plant Biosafety Office.


Developing a Regulatory Framework for the Environm
ental Release of
Plants with Novel Traits Intended for Commercial Plant Molecular Farming in Canada
.” 4.

61

Ibid.

62

Ibid,

63

CFIA. “CFIA Multi
-
Stakeholder Consultati
on of Plant Molecular Farming.” 20.



19


5)

Potential impact on bi
odiversity.
64


In order to determine this potential, the PBO considers the toxicity and allergenicity,
transformation method, characteristic of the novel trait, and altered plant char
acteristics
of the PNT. T
he indigenous species present at the trial site,
and the habitat where the
PNT is released are also considered.
65



The Health Canada Office of Food Biotechnology uses a team of scientific
evaluators to assess levels of health risk. The team compares a modified food to another
non
-
modified or conventional

food, looking for intended and unintended effects as a
result of modification. These safety assessments apply to any food crop, whether intended
for pharmaceutical or indust
rial products
. The only criteria for evaluation is that the crop
has the potential

to enter the food supply.
66

Evaluation of how the crop was developed,
the composition of the novel food compared to its conventional counterpart, the
nutritional composition, and the toxicity and allergenicity of the product determine
approval. For applica
tions

of PMF, the regulatory triggers would
be the toxicity and
allergenicity of the product in a crop traditionally used for food purposes, since the crops
are not intended for human consumption.


CONCLUSION


As can be seen in Table 2 in Appendix 1, the f
inished products of PMF applications are
ready for market in Canada, and many are already on the market in the United States.
Neither country, however, can be said to have a comprehensive and specific policy for
the development, or marketing of these produ
cts that adequately addresses the unique
implications of this technology. In Canada, an indefinite moratorium on the use of food
crops for PMF purposes awaits policy decisions, while in the United States, applications
of the technology proceed to market un
der regulatory oversight as would any other
genetically modified organism, or drug product. The situation in each country
demonstrates the inability of the current regulatory agencies to address broader
implications of PMF such as market viability, consume
r benefit, and public trade issues
into a consolidated risk assessment model. While it is apparent from the current

models
of risk assessment that the environmental and health a
spects of risk management

are well
established within their respective areas of

jurisdiction,
the broader social, econom
ic, and
ethical issues arising from

PMF are outside of this scope.

Both Canada and the United States have comprehensive procedures and guidelines
for the step by step regulation of PNTs, GMOs, and drug testing, inc
luding Standard
Operating Procedures that are designed to minimize environmental and health risks.
However, the specific regulation of PMF applications should be built on the foundation
of a directive government policy, in order to ensure the highest level

of public trust. With
increased access to information through the internet, and by the efforts of government
and non
-
governmental agencies, such as the academic community and NGOs, the policy



64

CFIA.

2005.

Assessment Criteria for the Evaluation of
Environmental Safety of Plants with Novel
Traits Intended for Commercial Plant Molecular Farming
.”

Draft Directive,
3.

65
CFIA.

Interim Amendment to DIR2000
-
07 for Confined Research Field Trials of PNTs for Plant
Molecular Farming.



66
CFIA. “CFIA Multi
-
Stake
holder Consultation of Plant Molecular Farming.”
Report

of Proceedings
, 14.



20


making process is being transformed, and challenged to broaden
it’s parameters past the
traditional science
-
based model.

Government policy
concerning
the specific application of

PMF would help to address
gaps between policy and technology.
In order to map out a clear path forward for the
commercial development of PMF
, a more collaborative approach could be implemented
to incorporate the public input that is gained through projects such as those undertaken by
Genome Prairie, as well as input from stakeholders gained from projects such as the
CFIA’s Multi Stakeholder Co
nference.
Government policy formed in such a way would
provide a greater potential for the legitimate authority of regulatory agencies, and a high
level of public trust. As the National Research Council notes, regulatory agencies must
not only use science,

but maintain authoritative legitimacy.
67
































67

National Research Council Committee on Environmental Impacts Staff (CB). “Environmental Effects of
Transgenic Plants: The Scope and Adequacy of Regulation,” 6.



21



Glossary Of Terms


APHIS


American Plant Health Inspection Service


BREC


Biologics Radiopharmaceuticals Evaluation Centre (Canada)


BRS



Biotechnology Regulatory Sercvices (U.S.A.)



CBER


Center for Biologics Evaluation and Research (U.S.A.)


CDER


Center for Drug Evaluation and Research (U.S.A.)


CDRH


Center for Devices and Radiological Health (U.S.A)


CFIA



Canadian Food Inspection Agency



CFR



Code of Federal Regulations (U.S.A
.)


CFSAN


Center for Food Safety and Applied Nutrition (U.S.A.)


Confinement

In this paper, confinement refers to biological and genetic mechanisms
that isolate a PNT from its environment, including other sexually
compatible plants.


Containment

In this
paper, containment refers to physical isolation of a PNT from its
environment. Containment is provided by physical structures such as
secure greenhouses, indoor growth facilities or laboratories, and ensures
that there is no release from the facility to th
e environment of the
organism, the genetic material of the organism, or material from the
organism involved in toxicity.


CVB



Center for Veterinary Biologics (U.S.A.)


CVM



Center for Veterinary Medicine (U.S.A.)



DNA


Deoxyribonucleic acid; the mater
ial of which genes are made. DNA
consists of a linear sequence of subunits called bases. DNA is the carrier
of genetic information, which is encoded in the sequence of bases. It is
present in chromosomes in the cell nuclus, and also in chromosomal
material

of subcellular units such as mitochondria and chloroplasts.


EA



Environmental Assessment (U.S.A.)


EIS



Environmental Impact Statement (U.S.A.)




22


EPA



Environmental Protection Agency (Canada)


FDA



Food and Drug Association (U.S.A.)


FONSI


Finding o
f No Significant Impact (U.S.A.)


Genetic

The process of modifying the genetic makeup of an organism, usually by

Engineering

insertion or one of more genes. The genes may come from the same or



another organism, even from an unrelated organism such as
from another



phylum.


GMO



Genetically Modified Organisms


NEPA



National Environmental Protection Agency (U.S.A.)


NIH



National Institutes of Health (U.S.A)


NRC



National Research Council (U.S.A.)


NSF



National Science Foundation (U.S.A.)


PBO



Plant Biosafety Office (Canada)


Plant

Pest


Any plant that is injurious or potentially injurious, whether directly or
indirectly, to plants or to products or by
-
products of plants.



PMF:


Plant Molecular Farming; The use of plants in agriculture for th
e
production of pharmaceuticals or industrially useful biomolecules, rather
than for the production of food, feed, or textile fibres.


PMIP
:

Plant Made Industrial Product; Non
-
pharmaceutical enzymes, biopolymers


or other recombinant compound with indust
rial properties made from



Plants through the technique of plant molecular farming.


PMP
:

Plant Made Pharmaceutical; The production of pharmaceuticals from
agricultural plants through the technique of plant molecular farming.


PNT
:

Plants with Novel T
raits; Plant varieties that are not considered
substantially equivalent, in terms of their specific use and safety both for
environment and for human health, to plants of the same species, having
regard to weediness potential, gene flow, plant pest potenti
al, impact on
non
-
target organisms and impact on biodiversity. PNTs may be produced
by conventional breeding, mutagenesis, or more commonly, by
recombinant DNA techniques.




23


PPQ


Plant Protection Quarantine (U.S.A.)


Recombinant

DNA that has been cut and r
espliced.

DNA


SOP


Standard operations procedures


Transgenic

Refers to introduction of a gene into an organism by genetic engineering.
A transgenic plant is one in which a gene has been inserted.


USDA


United States Department of Agriculture


Viral ve
ctor

A virus that has been modified to contain foreign genes.


Virus

Infectious agents containing only nucleic acid and a protein coat that can
enter and replicate in a cell.





























24



Bibliography


Arcand, Francois, and Paul Arnison. 2004
. “Development of Novel Protein Production
Systems and Economic Opportunities & Regulatory Challenges for Canada.”
Discussion Paper
.


Biotechnology Industry Organization. 2002.
Reference Document for Confinement and
Development of Plant
-
Made Pharmaceutical
s in the United States.


Breithaupt, Holger. 2004. “GM Plants for your health: The acceptance of GM crops in
Europe might grow as soon as the first products to offer direct benefits for consumer
health become available
.


Science and Society

11
(5): 1031
-
10
34.


Canadian Agri
-
Food Research Council. Genome Prairie. “Biobased Molecular
Production Systems Workshop. Towards the development of a policy framework
leading to an action plan for responsible commercialization.” Crowne Plaza Hotel.
101 Lyon Street Ottaw
a, Ontario. April 26
-
28.


CFIA (Canadian Food Inspection Agency). 2005. “Assessment Criteria for the Evaluation
of Environmental Safety of Plants with Novel Traits Intended for Commercial Plant
Molecular Farming
.


Draft Directive.


CFIA. (Canadian Food Ins
pection Agency). 2001. CFIA M
ulti
-
Stakeholder Consultation
on

Plant Molecular Farming.
Report of Proceedings
.


CFIA. (Canadian Food Inspection Agency). 2003. Plant Products Directorate, Plant
Biosafety Office. Interim Amendment to DIR2000
-
07 for Confined
Research Field
Trials of PNTs for Plant Molecular Farming.


CFIA. (Canadian Food Inspection Agency). 2005. Plant Biosafety Office. “Developing a
Regulatory Framework for the Environmental Release of Plants with Novel Traits
Intended for Commercial Plant Mo
lecular Farming in Canada.”


CFIA. (Canadian Food Inspection Agency). 2004. “Assessment Criteria for Determining
Environmental Safety of Plants With Novel Traits
.


DIR94
-
08.



Chromatin Inc. <
http://www.chromatininc.com
>


Controlled Pharming Ventures LLC.
<http://www.controlledpharming.com>


Einsiedel, Edna F. and Jennifer Medlock. 2005. “A Public Consultation on Plant
Molecular Farming.”
AgBioforum

8(1): 26
-
32.


Horn, M.E., S.L. Woodard and J.A. Howard. 2004. “Plant molecular farming: systems
and products.

Plant Cell Rep.

22:711
-
720.



25



Julian K
-
C. Ma, Pascal M.W. Drake and Paul Christou.2003. “The Production of
Recombinant Pharmaceutical Proteins in Plants.”
Nature

(4): 794
-
805.


Large Scale Biotechnology Corporation. <
http://www.lsbc.com/cgi
-
bin/index.cgi
>


Medicago Inc. <http://www2.medicago.com/en/>


National Research Council Committee on Environmental Impacts Staff (CB). 2002.
Environmental Effects of Transgenic Plants: The Scope and Adequacy of Regulation.
Washington, DC, National Academies Press.


Nev
itt, Jonathan, George Norton, Bradford Mills, Mary Ellen Jones, Mike Ellerbrock,
Dixie Reaves, Kelly Tiller and Gary Bullen. 2003. “Participatory Assessment of
Social and Economic Effects of Using Transgenic Tobacco to Produce
Pharmaceuticals.”

Working Pap
er.

Department of Agricultural and Applied
Economics Virginia Tech.


North American Millers’ Association. October 2002. “Statement on the Use of Food and
Feed Crops for the Production of Plant
-
made Pharmaceuticals and Industrial
Products.”
Issue Brief.



O
ffice of the Inspector General South Region. U.S. Department of Agriculture. 2005.
“Animal and Plant Health Inspection Service Controls Over Issuance of Genetically
Engineered Organism Release Permits.”
Audit Report
.


Planet Biotechnology. <
http://www.pla
netbiotechnology.com
>


Plantigen. <
http://www.lhsc.on.ca/plantigen/whats_new.html
>


SemBiosys. <http://www.sembiosys.ca>


Stewart, Patrick A. and Andrew J. Knight. 2005. “Trends affecting the next generation of
U.S. agricultural biotechnology: Politics, po
licy, and plant
-
made pharmaceuticals.”
Technological Forecasting and Social Change

72
(5): 521
-
534.


The Dow Chemical Company. <http://pharma.dow.com/>


USDA. (United States Department of Agriculture). 2004.
Letter to Permit Applicants.

January 14.


U.S. De
partment of Health and Human Services, FDA, CBER, CDER, CFSAN, CDRH,
CVM, APHIS, CVB, and BRS. “Guidance for Industry.” 2002. “Drugs, Biologics,
and Medical Devices Derived from Bioengineered Plants for Use in Humans and
Animals.”
Draft Guidance.
September
.




26


Veeman, Michele. “The Emerging Technology of Plant Molecular Farming.” In
Emerging Technologies: From Hindsight to Foresight
, ed. Edna Einsiedel.
Vancouver: University of British Columbia, 2006. (in press).


Washington, DC: U.S. Government Printing Offi
ce, 2005. Code of Federal Regulations.
Title 21 Food and Drugs, Part 25: “Environmental Impact Considerations.”


Washington, DC: U.S. Government Printing Office, 2005. Code of Federal Regulations.
Title 7 Agriculture. Part 372. “National Environmental Pol
icy Act Implementing
Procedures.”


Washington, DC: U.S. Government Printing Office, 2005. Code of Federal Regulations.
Title 7 Agriculture. Part 340. “Introduction of Organisms And Products Altered or
Produced Through Genetic Engineering which are Plant Pe
sts or which there is
reason to believe are Plant Pests.”


Washington, DC: U.S. Government Printing Office, 2003. United States Department of
Agriculture. The Federal Register. “Field Testing of Plants Engineered To Produce
Pharmaceutical and Industrial C
ompounds. Proposed Rules.” (68
)
46.



APPENDIX A







27


Table 2
:

PMF Products at Various stages of Development

Commercialized products are marked with an asterisk.

Company

Technology Platform

Products

Function

Status

Dow BioPharma
(U.S.A.)

Pfenex
Expression
Technology™
:
increases
the cellular expression of
recombinant proteins and
peptides

*
Producing a heat labile
enterotoxin, used in
immunization platform
technology for the
deliver of vaccines to the
skin.

Treatment of
Excherichia coli, the
most c
ommon cause ot
traveler’s diarrhea for
people visitng third
world countries.

Entered into a
commercial license
agreement with Iomai
Corp June 23, 2005.

Large Scale Biology
Corporation (U.S.A.)

GENEWARE®
: a viral
vector used with tobacco
plants. Does not c
ause
permanent genetic
modification of the host
plant.

Alpha Galactosidase A:


Enzyme replacement
therapy for Fabry disease

Granted Orphan

Drug Status by the FDA
in 2003.

Large Scale Biology
Corporation (U.S.A.)

GENEWARE®

*
Lysosomal Acid Lipase

Prevents
fatty acid
deposits in the
cardiovasculature of
patients with
artherosclerotic
cardiovascular disease

In early development.

LSBC has a worldwide
license to
commercialize.

Large Scale Biology
Corporation (U.S.A.)

Info not available

*
Aprotinin

Used to lower

inflammatory response
during cardiopulmonary
bypass surgery.

Used as a manufacturing
aid to prevent
degradation of protein
products.

Introduced in 2004 to
R&D and manufacturing
markets through Sigma
-
Aldrich Fine Chemicals.

Pharmaceutical grade is
still in

field trial.

Large Scale Biology

Corporation (U.S.A.)

GENEWARE®

Non
-
Hodgkin’s
lymphoma personalized
Patient specific
therapeutic vaccines

Currently in clinical
development.

APPENDIX A







28


Company

Technology Platform

Products

Function

Status

cancer vaccines

Large Scale Biology
Corporation (U.S.A.)

CP Fusion/Virus
-
Like
P
article Virus Vectors:

converts plant viruses
into carrier and display
vehicles for peptides,
promotes high
production of peptides.

Papillomavirus vaccines
for Humans and Animals

Preventative and
therapeutic vaccines that
are stable during
manufacture, sto
rage and
shipment, designed to
serve multiple
populations.

In pre
-
clinical stage
research.

Large Scale Biology
Corporation (U.S.A.)

CP Fusion/Virus
-
Like
Particle Virus Vectors

Parvovirus Vaccines

To prevent infection in
kittens, puppies, piglets
and other

young animals

In advanced efficiency
trials.

Large Scale Biology
Corporation (U.S.A.)

Hybrid TMV Vectors for
Transient RNA
Vaccination:

Possible multivalent, bi
-
functional (gene/protein)
vaccines against cancers
and infectious diseases.

Would encode pro
tein
only after injection as a
vaccine. Vectors cannot
integrate into the
chromosome and do not
persist in the body.

In early development.

Planet Biotechnololgy
(U.S.A.)

Protected SlgA

:

a渠
a湴n扯by⁴y灥a瑵牡汬y
灲潤pce搠dy⁴桥⁢潤y⁴漠
灲潴pc琠t畣潳o氠
獵牦ace猠
a条楮獴⁩湦 c瑩潵猠
潲条湩獭猠s湤⁴潸楮献i
Ca渠灲n摵de潮
-
獰sc楦楣⁓汧䄠l潲o
瑨敲a灥畴uc a湤n
灲p癥湴慴楶攠age湴献n
F牯洠瑯扡rc漠汥o映
ex瑲tc琮

CaroRX™

m污湴楢潤y⸠呯灩ca氠
a灰汩ca瑩潮⁴桡琠灲e癥湴猠
扡c瑥t楡ia摨d物湧⁴漠 ee瑨t
景f⁴桥⁴ ea瑭e湴映
䑥湴n
氠la物r献

f渠n桡se 䥉 c汮lca氠l物r汳l
a猠s渠n䑁
J
a灰牯癥搠
f湶e獴s条瑩潮o氠乥眠
䑲ugK

m污湥琠t楯iec桮潬潬gy
Protected SlgA™

RhinoRx™

c畳楯u⁰牯瑥楮⸠i汯l歳k
m牥
J
c汩湩捡氠獡晥ty
APPENDIX A







29


Company

Technology Platform

Products

Function

Status

(U.S.A.)

infection by rhinovirus, a
major cause of the
common cold

testing.


Plane
t Biotechnololgy
(U.S.A.)

Protected SlgA™

DoxoRx™

䅮瑩扯Ay⁴漠灲 ve湴n
c桥浯m桥牡py
J
楮摵捥搠
ga獴牯楮se獴s湡氠l潸楣楴yⰠ
a湤⁰ne癥湴⁨a楲潳iK

f渠c汩湩捡氠l物r汳l

C桲潭h瑩渠f湣o牰潲ate搠
⡕⹓⹁⸩

m牯灲楥瑡ry⁴散桮潬hgy
a汬潷猠楤敮瑩晩oa瑩潮o
a湴n潭敲e⁄ 䄠
晲潭o
any⁰ a湴⁳灥n楥猬i
a獳敭扬y映
浩湯n桲潭潳潭敳h
c潮瑡楮楮o⁤e獩牡扬攠
瑲t楴猬⁡湤⁵獥映浩湩
J
c桲潭潳潭敳⁴漠摥汩癥爠
gene猠瑨慴sge湥牡瑥潶el
灬慮瑳⁡湤⁣潭oe牣ia氠
灲潤pc瑳⸠

fn景f琠慶t楬a扬b

fn景f琠慶t楬a扬b

fn景f琠慶t楬a扬b

C潮瑲潬oe搠d桡牭楮r

噥湴畲n猠䱌C
 ⹓⹁KF

m桡牭rce畴uca氠慮搠
楮摵i瑲楡氠灲潴敩渠
灲潤pc瑩潮⁩渠⁴潢occ漬o
c潲測⁡湤⁴潭a瑯攠灬t湴猠
楮⁡‱〰⁡cre
畮摥rg牯畮r⁦ac楬楴y⸠K

fn景f琠慶t楬a扬b

fn景f琠慶t楬a扬b

fn景f琠慶t楬a扬b

m污湴楧e渠⡃nna摡F

PLANTimmune™:

System

to synthesize
edible target proteins
within leaf tissue of
plants.

GAD (glutamic acid
decarboxylase) and
cytokines.

For treatment of Type 1
Diabetes

Info not available

APPENDIX A







30


Company

Technology Platform

Products

Function

Status

Plantigen (Canada

PLANTimmune™

䵈䌠⡭j橯爠
桩獴潣潭灡瑩扬e
c潭灬ex
⤠F湤⁣y瑯歩湥s

c潲⁴oea瑭e湴映nr条渠
呲a湳灬a湴⁒e橥j瑩潮o

fn景f琠慶t楬a扬b

m污湴楧e渠⡃nna摡

佒䅭l畮u
™:

Sy獴敭s
瑯⁰ta湴
-
灲潤pce
獥汥l瑩癥⁡畴漠慮瑩ge湳n

I湴n牬r畫楮‱u

F潲⁴桥⁴ ea瑭e湴映
楮晬i浭a瑯ty⁢ 睥氠
摩獥d獥

In景f琠慶t楬a扬b

P污湴楧e渠⡃nn
a摡

佒䅭O畮u


Interleukin 4

Use as an adjuvant to
enhance immune
response.

Info not available

Medicago Inc. (Canada)

Proficia:

protein
technology for
producing therapeutic
proteins in alfalfa plants
grown in greenhouses

Four products under
early stage dev
elopment.

Info not available

One monoclonal
antibody product and
one plasmatic protein
product were in
preclinical trials in 2005.

SemBiosys

Genetic engineering of
oleosins to develop
recombinant proteins.

Insulin, produced in
safflower seeds

Info not ava
ilable

To initiate clinical trials
late 2006.

Has achieved
commercial production.

SemBiosys

Info not available

Apolipoprotein AI

HDL therapy for use in
cardiovascular therapies
to reduce plaque
associated with heart
attacks and angina.

To initiate clinica
l trials
by early 2007

SemBiosys

Info not available

ImmunoSphere Feed
Additive:
Immunostimulatory
protein
-
based feed
additive

that Enhances disease
resistance in shrimp

Plan to launch product in
late 2007 or 2008.

SemBiosys

Info not available

StratoCaptu
re Protein A
For the purification of
Currently conducting
APPENDIX A







31


Company

Technology Platform

Products

Function

Status

Reagent

pharmaceutical
antibodies

feasibility tests