Barry delivery vit a

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

Outline

• Update on Golden Rice

• Progress for the regulatory phase

• Howdy‟s 3 questions

• Farmer and consumer acceptance

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

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

IPP DMAPP

GGPP (C20)

Phytoene (C40)

desaturation

Lycopene (C40)

- carotene - carotene

cyclization

Carotenes

zeaxanthin

-cryptoxanthin

astaxanthin

canthaxanthin

Xanthophylls

Phytoene synthaseMaize

Phytoene desaturaseBacterial 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

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

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.

GLOBAL AREA 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

Biotech Crop Countries and Mega-Countries, 2009

2010

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

• Interaction with national

regulatory system

• Development and submission of

data for regulatory review

Philippines

“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 CropDonor, 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



Compositional

Analysis

Nutritional

Analysis

Safety Analysis

(Animal Studies)





Characterization of

Gene Product(s)


New GM Crop/Food



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


Mode of Action/

Specificity

Toxicity

Allergenicity



Compositional

Analysis

Nutritional

Analysis

Safety Analysis

(Animal Studies)

Not event-specific; documents

can be produced earlyOECD Consensus documents

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

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

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)

“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



Characterization of

Gene Product(s)


New GM Crop/Food



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


Mode of Action/

Specificity

Toxicity

Allergenicity



Compositional

Analysis

Nutritional

Analysis

Safety Analysis

(Animal Studies)

Substantially equivalent, except

for the intended changes…





Characterization of

Gene Product(s)


New GM Crop/Food



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


Mode of Action/

Specificity

Toxicity

Allergenicity



Compositional

Analysis

Nutritional

Analysis

Safety Analysis

(Animal Studies)

OECD Consensus documents

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

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

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

“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

APPLICATION TO

RELEASE FOR

PROPAGATION

Applicant

BPI

Sufficient in

Form &

Substance?

STRPFor 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




Applicant

Bureau of

Agricultural

and Fisheries

Product

Standards

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

Outline Timeline for GR2 Approval

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

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

GrantChina Child β-c bioconversion/bioefficacy (10g oil) 2011

USDA USA Adult β-c bioconversion/bioefficacy 2011

Future

GrantPhilippines Clinical Adult β-c bioefficacy 2013

Future

GrantPhilippines Community Adult β-c bioefficacy 2013

Future

GrantPhilippines Study of long term population benefit Post 2014

Source: Rob Russell and IRRI

Consumer acceptance activities

• Rice taste panel (2011; 2012)

• Consumer taste panel (2011; 2013)

• Consumer research

– Focus Group Discussion (2009)

– Consumer Survey (2010)

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

Thank

you

www.harvestplus.org

www.irri.org

[email protected]