1. Navigating the Regulatory System:
Lessons Learned from Golden Rice
Gerard Barry
IRRI Program 4 Leader - Rice and Human Health
International Rice Research Institute (IRRI)
Delivering Vitamin A Crops:
a Visible Nutrient
Tuesday, 4:00-6:00PM

2. Outline
• Update on Golden Rice
• Progress for the regulatory phase
• Howdy‟s 3 questions
• Farmer and consumer acceptance

3. Golden Rice in 1999/2000
The „Golden Rice‟ technology was developed by Potrykus (ETH) and
Beyer (ALUF) and was funded by the Rockefeller Foundation, the
Swiss Federal Institute of Technology, the European Union, and the
Swiss Federal Office for Education and Science.
Polished rice now contained meaningful
levels of -carotene, the plant-produced
precursor of vitamin A.
Golden Rice (GR) could be used in
food-based approaches, and complement
others, in reducing the persistent
problem of Vitamin A Deficiency in
rice-dependent populations

4. Golden Rice – New Materials
2000 2004-2005
SGR1 SGR2
New GR1 and GR2 were developed by Syngenta as part of their
then-commercial pipe-line and were donated for use by the
Golden Rice Network when Syngenta decided not to pursue this
trait as a commercial product.
GR1 – 2004 GR2 - 2005

5. IPP DMAPP
GGPP (C20)
Phytoene (C40)
desaturation
Lycopene (C40)
- carotene - carotene
cyclization
Carotenes
zeaxanthin
-cryptoxanthin
astaxanthin
canthaxanthin
Xanthophylls
Phytoene synthase
Maize
Phytoene desaturase
Bacterial source
-cryptoxanthin
lutein
Carotenoid Biosynthetic Pathway in GR2
Genes
added
into
Golden
Rice
and
their
source
-carotene/other provitamin A carotenoids are converted to Vitamin A as needed in the body.
The sugar-based
PMI gene was
used as the
selectable marker

6. Progress on Golden Rice
• Six GR2 events in Kaybonnet, a US variety (Paine et al. 2005)
– All single-locus, and single insert
– Carotenoid levels up to 25 ug/g (screen-house samples)
– Event-specific markers to assist back-crossing into varieties for the
Philippines, India, Bangladesh and elsewhere.
• Only one event will be released/go through regulatory approval
• The final event and lines will be chosen on the bases of:
– retained level of -carotene (product performance).
– agronomic performance (farmer needs)
T-DNA insert

7. A record 14 million farmers, in 25 countries, planted 134 million hectares (330 million acres) in 2009, a
sustained increase of 7% or 9 million hectares (22 million acres) over 2008.
Source: Clive James, 2010.
GLOBALAREA OF BIOTECH CROPS
Million Hectares (1996 to 2009)
25 Biotech Crop CountriesTotal Hectares
Industrial
Developing
“Trait Hectares”
0
20
40
60
80
100
120
140
160
180
200
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

8. Biotech Crop Countries and Mega-Countries, 2009
2010

9. Some of the contexts in which Golden
Rice will undergo further development
• Vitamin A Deficiency remains a very large problem in many countries
• The leading countries have policies conducive to the use of modern
biotechnology for national development.
• A number of the leading countries have approved GM crops for commercial
production:
• India (cotton) -5 events (~ 300 varieties/hybrids)
• Philippines (maize) – 5 events (52 crop/traits for food/feed/processing; LY038)
• Indonesia – 1 (temporary approval)
• China – 7 (diverse crops)
• Local GM food crop products are in advanced development in India,
Bangladesh, Indonesia, and the Philippines
• There is a lot GM rice activity, worldwide
– China has issued a biosafety certificate for Bt (insect resistant) rice; final variety
trials underway (also for improved processing maize)
– Bt rice in India is entering large scale biosafety, pre-commercial trials

10. • Interaction with national
regulatory system
• Development and submission of
data for regulatory review
Philippines

11. “A fully integrated approach to the hazard
assessment and characterization of all elements
involved in producing a new GM variety”
Adapted from: König et al., 2004. Food and Chemical Toxicology 42: 1047-1088
Parent Crop
Donor, Transgene(s)
and Delivery Process
Characterization of
Gene Product(s)
Safety Assessment of
New GM Crop/Food
Identity, Phenotypic &
Agronomic Performance
Geographical
Distribution
History of Safe Use
Compositional
Analysis
Description of
Donor
Description of
Vector DNA
Transgene Delivery
Process
Characterization of
Introduced DNA
Characterization of
Insertion Site
Structure, Identity
and Characterization
Mode of Action/
Specificity
Toxicity
Allergenicity
Identity, Phenotypic &
Agronomic Performance
Compositional
Analysis
Nutritional
Analysis
Safety Analysis
(Animal Studies)

12. “A fully integrated approach to the hazard
assessment and characterization of all elements
involved in producing a new GM variety”
Adapted from: König et al., 2004. Food and Chemical Toxicology 42: 1047-1088
Parent Crop
Donor, Transgene(s)
and Delivery Process
Characterization of
Gene Product(s)
Safety Assessment of
New GM Crop/Food
Identity, Phenotypic &
Agronomic Performance
Geographical
Distribution
History of Safe Use
Compositional
Analysis
Description of
Donor
Description of
Vector DNA
Transgene Delivery
Process
Characterization of
Introduced DNA
Characterization of
Insertion Site
Structure, Identity
and Characterization
Mode of Action/
Specificity
Toxicity
Allergenicity
Identity, Phenotypic &
Agronomic Performance
Compositional
Analysis
Nutritional
Analysis
Safety Analysis
(Animal Studies)
Not event-specific; documents
can be produced early
OECD Consensus documents

13. Consultations on science-based risk
assessment of Golden Rice in the
Philippines
• Initial consultations organized by the Department
of Agriculture in 2004/2005
• Three meetings held
• Minutes of these meetings and edits of the
Application Form recorded decisions on what was
in/out (i.e., no non-target insect studies)
• Process completed in 2010

14. Bringing the process to a close
• Two reviews/briefings held in June/July 2010
– Bureau of Plant Industry Biotech Core Team, Department
of Agriculture
– Bureau of Animal Industry Biotech Core Team,
Department of Agriculture
– Biotechnology Coalition of the Philippines
– Biotech Policy Group, Undersecretariat for Policy,
Department of Agriculture
– Science and Technology Review Panel members
– Biosafety Resource Network
– PhilRice
– IRRI

15. Comparative Safety Assessment
Approach for GMOs
Underlying assumption:
• Traditionally cultivated crops have gained a history of generally
accepted use (environment/consumer/animals)
• These crops can therefore serve as a baseline for the
environmental and food/feed safety assessment of GM crops
European Food Safety Authority Stakeholder Consultation
“Conventional Counterpart” - means a related plant variety, its
components and/or products for which there is experience of
establishing safety based on common use as food.
Codex Alimentarius Guideline for the Conduct of Food Safety
Assessment from Recombinant-DNA Plants (CAC/GL 45-2003)

16. “A fully integrated approach to the hazard
assessment and characterization of all elements
involved in producing a new GM variety”
Adapted from: König et al., 2004. Food and Chemical Toxicology 42: 1047-1088
Parent Crop
Donor, Transgene(s)
and Delivery Process
Characterization of
Gene Product(s)
Safety Assessment of
New GM Crop/Food
Identity, Phenotypic &
Agronomic Performance
Geographical
Distribution
History of Safe Use
Compositional
Analysis
Description of
Donor
Description of
Vector DNA
Transgene Delivery
Process
Characterization of
Introduced DNA
Characterization of
Insertion Site
Structure, Identity
and Characterization
Mode of Action/
Specificity
Toxicity
Allergenicity
Identity, Phenotypic &
Agronomic Performance
Compositional
Analysis
Nutritional
Analysis
Safety Analysis
(Animal Studies)
Substantially equivalent, except
for the intended changes…

17. “A fully integrated approach to the hazard
assessment and characterization of all elements
involved in producing a new GM variety”
Adapted from: König et al., 2004. Food and Chemical Toxicology 42: 1047-1088
Parent Crop
Donor, Transgene(s)
and Delivery Process
Characterization of
Gene Product(s)
Safety Assessment of
New GM Crop/Food
Identity, Phenotypic &
Agronomic Performance
Geographical
Distribution
History of Safe Use
Compositional
Analysis
Description of
Donor
Description of
Vector DNA
Transgene Delivery
Process
Characterization of
Introduced DNA
Characterization of
Insertion Site
Structure, Identity
and Characterization
Mode of Action/
Specificity
Toxicity
Allergenicity
Identity, Phenotypic &
Agronomic Performance
Compositional
Analysis
Nutritional
Analysis
Safety Analysis
(Animal Studies)
OECD Consensus documents

18. Suggested Nutritional and Compositional
Parameters to be Analysed in Rice
Matrices for Food Use
Parameter Bran oil Rice flour Paddy Rice
Proximate Analysisa X X
Minerals X
Vitamins X
Amino Acids X X
Fatty Acids X X X
Phytic Phosphorus X
Amylose Content X X
a Proximate includes protein, fat, total dietary fibre, ash and carbohydrates.
OECD Consensus Document on Compositional Considerations for New Varieties of Rice (Oryza Sativa): Key Food and
Feed Nutrients and Anti-Nutrients. August 2004 http://appli1.oecd.org/olis/2004doc.nsf/linkto/env-jm-mono(2004)15

19. Suggested Nutritional and Compositional
Parameters to be Analysed in Rice
Matrices for Feed.
Parameter Paddy Rice/Bran Straw Whole Plant
Proximate Analysis1 X X X
Amino Acids X
Calcium X X X
Phosphorus X X X
Phytic Phosphorus X
1 NDF (neutral detergent fibre) and ADF (acid detergent fibre) should be substituted for
crude fibre.
OECD Consensus Document on Compositional Considerations for New Varieties of Rice (Oryza Sativa): Key Food and
Feed Nutrients and Anti-Nutrients. August 2004 http://appli1.oecd.org/olis/2004doc.nsf/linkto/env-jm-mono(2004)15

20. Administrative Order
No. 8, Series of 2002
Importation and Release into the
Environment of Plants and Plant
Products Derived from the Use of
Modern Biotechnology
Department of Agriculture

21. “No regulated article shall be released for propagation
unless:
(i) a Permit for Propagation has been secured from BPI;
(ii) it can be shown that based on field testing conducted in
the Philippines, the regulated article will not pose any
significant risks to the environment;
(iii) food and/or feed safety studies show that the regulated
article will not pose any significant risks to human and
animal health; and,
(iv) [If the regulated article is a pest-protected plant, it has
been duly registered with the Fertilizer and Pesticide
Authority.]”
POLICY ON RELEASE FOR
PROPAGATION

22. APPLICATION TO
RELEASE FOR
PROPAGATION
Applicant
BPI
Sufficient in
Form &
Substance?
STRP
For evaluation on
risk assessment
For conduct of
public consultation
Process & evaluate
within 5 days of
receipt
YESNO
APPROVED
DENIED
Within 90 days
from acceptance
Applicant shall publish Public Info Sheet in 2
newspapers, and invite comments w/in 30-day period.
Grace period
of 60 days to
correct
defects
Shall submit report w/n 30 days
BAFPS
FPA
BAI
If pest-protected
plant
In all instances
If intended as
feed
Shall submit report w/n 30 days
Shall submit report w/n 30 days
Shall submit report w/n 30 days
Applicant
Bureau of
Agricultural
and Fisheries
Product
Standards

23. International Acceptance of Food
Safety Data/Assessments
1. The food safety assessment of the GM product must be carried out
according to the Codex Alimentarius Guideline for the Conduct of
Food Safety Assessment from Recombinant-DNA Plants (CAC/GL
45-2003).
2. Because of the nutritional enhancement in the Golden Rice trait,
adherence to the Annex 2: Food Safety Assessment from
Recombinant-DNA Plants Modified for Nutritional or Health
Benefits is also critical

24. Outline Timeline for GR2 Approval

25. Golden Rice and Howdy’s 3 Questions
• Target level?
– +50% of EAR
– +50% of RDA (IRRI unpublished)
• Bioavailable?
– Bioconversion = 3.8:1 (Tang et al., 2009)
– Bioefficacy studies planned for 2011 - 2013
• Acceptance?
– Qualitative and environmental scanning completed
– Quantitative studies underway (IRRI unpublished)
– Bioefficacy studies planned for 2011 - 2013

26. GR nutritional data
- completed and planned
Funds Where Trial Complete Published
NIH USA Adult β-c bioconversion (10g butter) √ √
NIH/SF USA Adult β-c bioconversion (5g, 0g butter) √
NIH/SF China Adult β-c bioconversion (10g, 5g, 0g oil) √
NIH China Child β-c bioconversion (10g oil) √
Future
Grant
China Child β-c bioconversion/bioefficacy (10g oil) 2011
USDA USA Adult β-c bioconversion/bioefficacy 2011
Future
Grant
Philippines Clinical Adult β-c bioefficacy 2013
Future
Grant
Philippines Community Adult β-c bioefficacy 2013
Future
Grant
Philippines Study of long term population benefit Post 2014
Source: Rob Russell and IRRI

27. Consumer acceptance activities
• Rice taste panel (2011; 2012)
• Consumer taste panel (2011; 2013)
• Consumer research
– Focus Group Discussion (2009)
– Consumer Survey (2010)

28. PhilRice Golden Rice Team
MILLING AND SENSORY: Marissa Romero, Ph.D.
PILOT SEED PRODUCTION: Marlon Labuguen, MSc.
COMMUNICATION AND PROMOTION: Andrei Lanuza, MSc.
PROJECT LEADER
Antonio A. Alfonso, Ph.D.
BREEDING
Gerald B. Ravelo, Ph.D.
Nelson S. Garcia, MSc.
Jean J. Somera, MSc.
Emilie O. Espejo
Eleanor S. Avellanoza

30. Thank
you
www.harvestplus.org
www.irri.org
g.barry@cgiar.org