DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service 

Food and Drug Administration 

College Park, MD 20740 

November 15, 2007 

Delia R. Bethell, Ph.D. 

Vice President for Clinical Development 

Ventria Bioscience 

4110 N. Freeway Blvd. 

Sacramento, CA 95834 

Re: GRAS Notice No. GRN 000235 

Dear Dr. Bethell: 

The Food and Drug Administration (FDA) has received the notice, dated September 27, 2007, 

that you submitted in accordance with the agency’s proposed regulation, proposed 21 CFR 

170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS)). FDA 

received this notice on October 2, 2007, filed it on October 19, 2007, and designated it as GRN 

No. 000235. 

The subject of the notice is lactoferrin (human) purified from rice. The notice informs FDA of 

the view of Ventria Bioscience that lactoferrin (human) purified from rice is GRAS, through 

scientific procedures, for use as an ingredient in oral rehydration solutions at levels not to exceed 

1 milligram of lactoferrin per milliliter of solution. 

In accordance with proposed 21 CFR 170.36(f), a copy of the information in the notice that 

conforms to the information described in proposed 21 CFR 170.36(c)(1) is available for public 

review and copying on the homepage of the Office of Food Additive Safety (on the Internet at 

http://www.cfsan.fda.gov/~lrd/foodadd.html). If you have any questions about the notice, contact 

me at 301-436-1173 or jeremiah.fasano@fda.hhs.gov. 

 Sincerely yours,

 Jeremiah Fasano

 Division of Biotechnology and 

 GRAS Notice Review

 Center for Food Safety

 and Applied Nutrition 

Revision History 

Hard copy cc: GRN 000235 (1 copy) 

Filename: GRN 235 Acknowledgement Letter 

R/D:HFS-255:JMFasano:11/20/07 

F/T:HFS-255:JMFasano:11/20/07 
 

 

 

 

 

 

 

 

 

 

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service 

Food and Drug Administration 

College Park, MD 20740 

November 15, 2007 

Delia R. Bethell, Ph.D. 

Vice President for Clinical Development 

Ventria Bioscience 

4110 N. Freeway Blvd. 

Sacramento, CA 95834 

Re: GRAS Notice No. GRN 000235 

Dear Dr. Bethell: 

The Food and Drug Administration (FDA) has received the notice, dated September 27, 2007, 

that you submitted in accordance with the agency’s proposed regulation, proposed 21 CFR 

170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS)). FDA 

received this notice on October 2, 2007, filed it on October 19, 2007, and designated it as GRN 

No. 000235. 

The subject of the notice is lactoferrin (human) purified from rice. The notice informs FDA of 

the view of Ventria Bioscience that lactoferrin (human) purified from rice is GRAS, through 

scientific procedures, for use as an ingredient in oral rehydration solutions at levels not to exceed 

1 milligram of lactoferrin per milliliter of solution. 

In accordance with proposed 21 CFR 170.36(f), a copy of the information in the notice that 

conforms to the information described in proposed 21 CFR 170.36(c)(1) is available for public 

review and copying on the homepage of the Office of Food Additive Safety (on the Internet at 

http://www.cfsan.fda.gov/~lrd/foodadd.html). If you have any questions about the notice, contact 

me at 301-436-1173 or jeremiah.fasano@fda.hhs.gov. 

 Sincerely yours,

 Jeremiah Fasano

 Division of Biotechnology and 

 GRAS Notice Review

 Center for Food Safety

 and Applied Nutrition 

Revision History 

Hard copy cc: GRN 000235 (1 copy) 

Filename: GRN 235 Acknowledgement Letter 

R/D:HFS-255:JMFasano:11/20/07 

F/T:HFS-255:JMFasano:11/20/07 
October 7, 2004 

Dr. Joanne Rhoads 

Division of Scientific Investigation 

7520 Standish Place 

Rockville, MD 20855 

Dear Dr. Rhoads, 

Below please find the requested information about the human studies sponsored by Ventria 

Bioscience using recombinant human lactoferrin derived from rice and recombinant human 

lysozyme derived from rice, two food ingredients that we are investigating for possible use as a 

dietary supplement and/or a medical food. 

There are two studies, one is complete and one is on going. I have provided descriptions of the 

studies and information on the investigators, IRB and ethics committees for each study. The first 

study was designed to investigate the use of recombinant human holo-lactoferrin derived from 

rice for the dietary supplementation of iron levels in women through addition to foods or drinks. 

The second study, which is ongoing, is designed to investigate the use of these food ingredients 

for the dietary management of diarrhea in children. If the study is successful, the product would 

be marketed as a medical food for use under physician supervision. 

Ventria has submitted a Premarket Biotech Notification, BNF No. 082 to the Center for Food 

Safety and Nutrition Division of the FDA on the rice grain that produces the recombinant human 

lactoferrin. 

If there are any additional questions or information required, please do not hesitate to contact me. 

Ventria is committed to an open dialog in this matter. 

Sincerely, 

Delia Bethell, Ph.D. 

Vice President for Clinical Development 
 

 

 

 

 

Study 1 

The purpose of this study was to determine whether holo-recombinant human lactoferrin derived 

from rice could be used for the supplementation of iron levels. The study is completed. Eight 

women enrolled in the study. The exposure level was 4.8 grams of lactoferrin per day for 6 

weeks. Four subjects completed the study. There were no major adverse events; one complaint 

of headache immediately after taking the capsules at some times. Full clinical chemistry panels 

were run at the beginning and end of the study and there were no significant changes in any 

parameters. The four individuals did not complete the study for the following reasons: 

1. Screen failure 

2. Non compliance 

3. Screen failure 

4. Decided capsules were too big and withdrew 

Principle Investigator: Kathryn Rigonan, M.D. 

 11100 Warner Ave., Suite 154 

 Fountain Valley, CA 92708 

 (714) 754-0100 

 (714) 754-6806 (fax) 

Study Coordinators: Southland Clinical Research Center 

 11100 Warner Ave., Suite 352 

 Fountain Valley, CA 92708 

 (714) 430-1455 

 (714) 430-1456 (fax) 

 Saniata L. Batac, M.D., Clinical Research Coordinator 

scrcenter@yahoo.com 

IRB: Independent Review Consulting, Inc. 

100 Tamal Plaza, Suite 158 

 Corte Madera, CA 94925 

 (415) 485-0717 

 (415) 485-0328 (fax) 

ejheath@irb-irc.com 

Approval number: 04013-01 
 

 

 

 

 

 

 

 

 

Study 2 

The purpose of this study is to determine whether the use of the human breast milk proteins 

recombinant human apo-lactoferrin derived from rice and recombinant human lysozyme derived 

from rice will support the dietary management of diarrhea in children with acute watery diarrhea 

and is being conducted at the Oral Rehydration Unit of the Instituto de Salud del Niño, 

(Children’s Hospital) in Lima, Peru and Trujillo, Peru. Exposure level is 1 gram of recombinant 

human lactoferrin derived from rice and 200 mg of recombinant human lysozyme derived from 

rice per liter of ORS. These are the levels of native human lactoferrin and native human 

lysozyme in mature breast milk. 

Principle Investigator: Nelly M. Zavaleta 

 Instituto de Investigación Nutricional 

Av. La Molina 685 – La Molina – Lima 12 

 Peru 

51 1 3496146 ex 223 

 51 1 3496025 (fax) 

nzavalet@iin.sld.pe 

Co-Investigators: Dr. Dante Figueroa 

 Director General 

 Instituto de Salud del Niño 

 Av. Brasil 600 

 Breña – Lima 5 

 Peru

 Dr. Bo Lonnerdal 

 Department of Nutrition

 University of California Davis 

 One Shields Avenue 

 Davis, CA 95616 

 (530) 752-8347 

 (530) 752-3564 

bllonerdal@ucdavis.edu 

IRB/Ethics: Instituto Nacional de Salud 

Dr. Luis Fernando Lianos Zavalaga 

 No. 148-2003-J-OPD/INS 

 Instituto de Salud 

Dr. Carlos del Augila Villar 

 Ministerio de Salud 

 Instituto de Salud del Niño 

 No. 0066-DIDT-ISN-2003 
 

 

Instituto de Investigacion Nutricional 

 Hilary Creed-Kanashiro

 President, Committee Ethics 

 No. 189-2003/CEI-IIN 

 University of California, Davis 

 Office of Human Research Protectoin 

 Ambulatory Care Center, Suite 3870 

 UCDMC 

 (916) 734-6864 

 Frank Hirtz, Acting Chair 

 No. 200311050-2 
 

 

 

 

 

 

 

 

 

Page 1 of 1 

Fasano, Jeremiah 

From: Scott Deeter [sdeeter@ventria.com] 

Sent: Monday, March 03, 2008 4:33 PM 

To: Fasano, Jeremiah 

Subject: Previous FDA Correspondence 

Attachments: Final DSI letter 10-7.pdf 

Dear Jeremiah: 

In response to your inquiry about who we have communicated with at FDA regarding the studies Ventria has sponsored and the FDA 

review of these studies, I have the following information: 

1) We were contacted on October 6th, 2004 by Lloyd Johnson (301) 827-5459 of the Division of Scientific Investigations. He 

said he would like information on the human studies we were conducting or intended to conduct. At the time, he mentioned 

that another Company had filed an IND application for a different recombinant human lactoferrin for therapeutic use. He asked 

that we inform the FDA of our studies. He suggested that we send a letter to Dr. Joanne Rhoads at FDA/Division of Scientific 

Investigations describing our studies. He said he would keep Ruthanne Giusti informed as well. He communicated that they 

wanted to make sure our studies were appropriate for our designation as foods. 

2) On October 7th, 2004 we sent the attached letter to Dr. Rhoads. 

3) On October 22nd, 2004 Lloyd Johnson called to say that he had circulated our letter and wanted to confirm that the letter 

included all studies. We informed him that this was the case. He said Ruthanne Giusti reviewed the situation and mentioned 

that the studies we had completed and intended were appropriate for foods and the Ventria product was not considered a 

drug as long as there are not drug claims in the marketing of the product. Ventria was asked to keep FDA/CDER informed of 

studies completed in the future. 

Following October 22nd, 2004 Dr. Delia Bethell (Ventria’s VP) informed Ruthanne Giusti and Lloyd Johnson of human studies 

sponsored by Ventria for use of recombinant human lactoferrin derived from rice. 

If you have further questions regarding this matter, please let me know. 

Sincerely, 

Scott Deeter 

President & CEO 

Ventria Bioscience 

(970) 420-9598 

www.Ventria.com 

Your Life. Our Passion. 

This message (including any attachments) may contain confidential information intended for a specific individual and purpose, and is 

protected by law. If you are not the intended recipient, you should delete this message. Any disclosure, copying, or distribution of this 

message, or the taking of any action based on it, is strictly prohibited. 

9/18/2008 
 

 

 

 

 

 

 

 

 

 

 

MEMORANDUM OF MEETING 

March 7, 2008 

11:00 a.m. – 12:00 p.m. 

Parklawn Building 

Attendees: FDA: Andrew von Eschenbach, Stephen Mason, Dotty Foellmer, Bill McConagha, 

Michael Landa, Laura Tarantino, Kristy Moran, Shawnee Jacobs 

Ventria Bioscience: 

Scott Deeter, President and CEO of Ventria Bioscience 

William Rutter, Ph.D., Chairman of Synergenics, Member, National Academy of

 Sciences, Founder of Chiron and previous Board Member of Novartis 

Thomas Urban, Jr, Chairman of Ventria Bioscience and former Chairman and 

CEO of Pioneer Hi-Bred International; Board Member Carnegie Institute 

Stephen Taylor, Ph.D. Professor of Food Science and Technology, University of

 Nebraska, Lincoln and Chairman of Ventria’s “generally recognized as safe” GRAS

 panels for GRN 235 and GRN 191 

Subject: Meeting with Ventria Bioscience to discuss their GRAS applications for recombinant 

human lactoferrin and lysozyme (GRN 235 and GRN 191). 

Highlights: 

• Ventria introduced themselves and presented information regarding their recombinant human 

lactoferrin and lysozyme products, Lactiva and Lysomin. 

• Ventria gave a chronology of events and interactions with FDA/CFSAN relevant to the FDA 

regulatory process and their GRAS Notices. 

• Ventria presented their perspective that section 912 of the Food and Drug Administration 

Amendment Act of 2007 does not apply to their intended uses of their products. 

• The visitors and FDA discussed the agency’s proposed plans to engage the wider scientific 

community for further consideration of complex scientific issues. 

Action Items: 

• FDA will follow-up with Ventria to facilitate reaching a decision regarding their applications. 

Shawnee Jacobs 

Jr. Policy Analyst 

FDA Executive Secretariat 
 
Fasano, Jeremiah 

From: Slater, Jay 

Sent: Wednesday, May 14, 2008 1:48 PM 

To: Fasano, Jeremiah; Tarantino, Laura M 

Cc: Rosenberg, Amy; Rabin, Ronald 

Subject: rhLF and rhLZ allergy summary 

[From Rabin, edited by Slater:] 

The sponsor proposes use of recombinant human lactoferrin (rhLF) and/or lysozyme (rhLZ), expressed in transgenic rice, 

in an oral rehydration formula for infants with diarrhea. These two recombinant proteins s are not perfectly identical to 

their endogenous counterparts, as there may be differences in glycosylation or other post-translational modification that in 

turn may generate novel epitopes for T cell recognition and activation. While infectious diarrhea may be due to active 

secretion of solutes (and the water that follows) or an impairment in absorption of solutes (and water), the mucosal injury 

associated with infection and inflammation is frequently if not always accompanied by increased permeability of large 

molecules from the intestinal tract into the blood stream. Since infants may experience 3-6 diarrheal episodes per year 

for the first two years of life, inclusion of rhLF and rhLZ in oral rehydration fluids has the potential for repeated intermittent 

systemic exposure to neoantigens. This is precisely the scenario that is known to induce allergic responses to exogenous 

proteins. Furthermore, after T cell responses to neoantigens, there is potential for the process of "antigenic spread" to 

other parts of the recombinants that are identical to their endogenous counterparts. If an allergic response is precipitated 

by the neoantigens, it is possible that the infants may become allergic to endogenous LF and LZ. Antigenic spread is also 

associated with induction of autoimmunity that when directed, for example, against pancreatic islet beta cells, can cause 

type I diabetes mellitus. Therefore, it is our opinion that these two recombinants should not be considered GRAS, as they 

have the potential of inducing in infants allergic responses to the recombinants themselves and their endogenous 

counterparts, and may also induce autoimmunity. 

Jay E. Slater, MD 

Deputy Director, DBPAP 

Chief (Acting), Laboratory of Immunobiochemistry 

301.496.4575 

301.480.4103 (fax) 

1



 

 

Supplemental Scientific Assessment 

GRN 235: Rice-Based Recombinant Human Lactoferrin 

We, the undersigned scientific experts, have reviewed GRN 235 submitted by Ventria 

BioSciences for use of its rice-based recombinant human lactoferrin (rhLF) in oral 

rehydration solutions and pediatric “medical” foods. This review supplements an earlier 

assessment of Ventria’s original GRAS notice. We continue to believe that Ventria has not 

established a reasonable certainty of no harm from ingestion of its rhLF, that there are many 

unanswered safety issues, and that, if anything, targeting use of the product in infants and 

young children increases our safety concerns. We are, therefore, in strong and unanimous 

agreement that Ventria’s rhLF is not Generally Recognized as Safe (GRAS) for use in food 

products. The basis for this conclusion follows. 

Ventria’s Safety Data Remains Inadequate and Raises More Questions than it Answers 

Ventria’s GRAS re-submission contains the same animal safety data that was presented in 

GRN No. 000162. To the best of our knowledge, this data has not been published or peer 

reviewed. Expert commentary on the inadequacy of Ventria’s animal safety data was 

presented in the earlier Scientific Assessment, which was submitted to CFSAN on November 

9, 2005.1 Concerns expressed in that initial Scientific Assessment are hereby incorporated in 

this Supplemental Scientific Assessment by reference. 

The only new data presented in Ventria’s re-submission comes from a Peruvian clinical trial 

involving 140 children suffering from diarrhea (Zavaleta 2007), about a third of whom 

received Ventria’s rhLF for a few days. Ventria claims that no related material adverse 

events were observed in this trial.2 However, contrary to Ventria’s claim, this trial received 

substantial public criticism for a lack of proper clinical methodologies and controls after it 

was reported that two children suffered serious allergic reactions following administration of 

the study drug.3

 We agree with this criticism. The conduct of this clinical trial is also 

reported to be the subject of a government ethics investigation.4

 In addition, the trial 

administered both rhLF and recombinant human lysozyme (rhLZ) concurrently in an oral 

rehydration solution (Zavaleta 2007), precluding a proper safety and efficacy analysis of the 

individual drugs by themselves. As stated by the authors themselves “It is not certain that the 

effects observed were caused by the combination of lactoferrin and lysozyme, even though in 

vitro data support this notion. Lysozyme alone could have exerted an antibacterial effect 

because of its enzyme activity ...”. Further, rather than establishing the safety of Ventria’s 

rhLF, this clinical data increases our concerns about its safety, including concern regarding 

the risk of acute allergic reactions to its foreign glycosylation. 

1

 Scientific Assessment Submitted to CFSAN, November 9, 2005, pages 2-3. 

2 Ventria GRAS Re-submission, September 2007, page 19. 

3

 “A Grain of Caution: A Critical Assessment of Pharmaceutical Rice” Center for Food Safety, April 2007, page 

20. 4

 Leighton, P. Study on infants in Peru sparks ethics inquiry. Science and Development Network, July 18, 

2006. http://www.scidev.net/content/news/eng/study-on-infants-in-peru-sparks-ethics-inquiry.cfm. 

June 3, 2008 1 
 

The conduct of this trial has been widely criticized by the media in both Peru (Diaz 2006) 

and the United States.5 Some of the concerning issues reported include the lack of proper 

informed consent, the occurrence of allergic reactions and selective and potentially 

misleading presentation of the data.6 A published analysis of Ventria’s trial touches on both 

safety and consent issues, as follows: 

“According to an account in Peru’s La Republica (Diaz 2006), at least one 

mother whose infant was enrolled in the experiment was not informed that 

the treatment (“suero de arroz” or “rice serum”) was experimental and 

involved compounds from transgenic rice. Diana Canessa Garay, who 

enrolled her son Fabrizio in the experiment on February 15, 2005, states 

that she was “deceived”. According to Garay: “After they gave him the 

serum, my baby became sickly, delicate. Now he is allergic to 

everything...” A second mother, Johana Sanchez Turreate, says that her 

3-year-old son Jordano also developed allergies after receiving the 

“serum”. Peruvian Member of Parliament Mercedes Cabanillas has 

initiated an investigation of the experiment by the Public Defender’s 

office.”6 

Although it has not been conclusively established that Ventria’s rhLF is responsible for the 

allergic reactions reported by these mothers, it is clear that substantial additional clinical 

research is needed before a reasonable researcher could conclude that it is safe for this 

indication. In addition, other potential safety concerns have been identified in the publication 

describing this trial (Zavaleta 2007). For example, the authors state that there was a higher 

frequency of bacterial pathogen isolation in the stool of children receiving the Lf/Lz-R-ORS. 

The administration of lactoferrin to patients suffering from high loads of bacterial pathogens 

is a great concern, as Ventria’s rhLF is reported to induce transitory antibiotic tolerance in 

certain pathogenic bacteria (Andres 2005). That is, simultaneous treatment with antibiotics 

may be less effective in patients receiving lactoferrin-containing ORS. 

There also appears to be a lack of proper follow-up on the trial subjects. The researchers 

reportedly followed up on the infants for only 14 days (Bethell 2006) which, as noted in the 

initial Scientific Assessment of November 9, 2005, is far too short a period to detect many 

potential immunological consequences of rhLF administration.7

 It is also concerning that in 

its GRAS submission Ventria failed to disclose these reported allergic reactions as well as the 

follow-on concerns by the patients’ families and the Peruvian authorities regarding this trial. 

In addition to these safety issues, the validity of Ventria’s analysis of the trial results has 

been questioned. According to published papers (Zavaleta 2007, Zavaleta 2006), 140 

Peruvian boys aged 3 – 36 months with acute diarrhea and dehydration were enrolled in the 

study and treated in one of three cohorts: 

5

 USA Today, “Uproar in Peru over genetically-engineered diarrhea treatment” July 14, 2006. 

6 “A Grain of Caution: A Critical Assessment of Pharmaceutical Rice” Center for Food Safety, April 2007, 

page 20. 

7 Scientific Assessment Submitted to CFSAN, November 9, 2005, page 16. 

June 3, 2008 2 
1) Cohort 1: Low osmolarity WHO oral rehydration solution (G-ORS); 

2) Cohort 2: ORS based on conventional rice (R-ORS); or 

3) Cohort 3: ORS based on conventional rice to which recombinant lactoferrin and 

lysozyme extracted from Ventria’s rice had been added (Lf/Lz-ORS). 

An analysis of the data in these two reports shows several flaws: 

1. As mentioned previously, co-addition of recombinant human lysozyme and 

recombinant human lactoferrin precludes the ability to assess the safety and efficacy of either 

of the two compounds. Perhaps any activity comes from lysozyme, and it is even possible 

that lysozyme reduces some of the potential side-effects of lactoferrin. The current study 

thus does not prove nor disprove anything about the safety or efficacy of lactoferrin. 

2. The three study groups are clearly not similar, despite claims to the contrary. The 

authors report in Table 3 that the group receiving the Lf/Lz-ORS contains a much larger 

proportion of children with identified bacteria in their stool upon study entry (almost 80% 

versus below 55%). In particular, E.coli infections are more prominent in the Lf/Lz-ORS 

group (50% of all children, vs. 30% in the other groups). In contrast, the other two groups 

have a larger proportion of children with no identified pathogens in their stool. The children 

with bacterial load as a cause of diarrhea may be more susceptible to ORS treatment 

compared to those with another unidentified cause, thus creating a bias towards the group 

receiving Lf/Lz-ORS. 

3. The authors combine the two control groups receiving R-ORS and G-ORS, claiming 

there are no significant differences between these two groups. This finding is surprising, 

since several previous studies have shown a clear benefit of adding nutritional support (such 

as rice) to the ORS formulation (Wall 1997; Sarker 2001; Dutta 2000; Maulen-Raduvan 

2004, see also discussion in CDC 1992). A meta-analysis of 13 clinical trials (Gore 2002) 

shows that rice-based ORS reduced the rate of stool output in children with cholera by 32% 

and for those with acute non-cholera diarrhea by 18% versus children treated with standard 

glucose-based (WHO) ORS. 

4. The Kaplan-Meyer curves for the study (Zavaleta 2007, Figure 2) show that the RORS group mostly follows the Lf/Lz-ORS group, except for day 1+2, and after day 6. 

Furthermore, combining the R-ORS and G-ORS groups, as was done to evaluate clinical 

outcomes (Table 4), creates a bias in the data. Since the G-ORS group is expected to do 

worse than the R-ORS group, combining these two groups for use as the control group 

artificially creates a favorable apparent comparison for Lf/Lz-ORS. 

In conclusion, the data does not seem to suggest that there is a meaningful, or statistically 

significant, benefit from adding LF/LZ to a rice-based ORS solution, although the primary 

concern from the GRAS perspective is still the absence of established safety. 

June 3, 2008 3 
 

At a minimum, the reported issues with this Peruvian trial raise serious questions about 

whether either the safety or efficacy data from this trial have been adequately disclosed, and 

whether even the selective disclosures of the data can be relied upon without a full 

investigation and audit by the FDA. The reported occurrence of allergic reactions, and the 

fact that these reports do not appear to have been disclosed by Ventria to CFSAN when they 

would clearly be relevant to Ventria’s GRAS notice, casts doubt about the accuracy, 

completeness and reliability of the GRAS notice. 

Even if there had not been serious safety concerns raised by the Peruvian trial, it would not 

have resolved the safety concerns regarding Ventria’s rhLF described by numerous leading 

experts. The number of patients was far too small and the treatment duration was far too 

short. As discussed in the initial Scientific Assessment of November 9, 2005, long term 

human studies are necessary to assess the risks of immunogenicity,8

 a concern that is even 

more relevant in this particularly vulnerable population. The fact that the treatment duration 

hypothesized in Ventria’s amended GRAS notice is relatively short, does not rule out longer 

term exposure from other uses that Ventria has publicly described, nor even from multiple 

uses over several years by the children that Ventria now claims (for purposes of its amended 

GRAS notice) to be targeting. 

The Possibility of Acute Allergic Reactions Was Raised Previously 

RhLF produced in rice is a biologically active immunostimulatory molecule that has potential 

risks which have not been thoroughly evaluated by credible human studies. These risks were 

outlined in the initial Scientific Assessment submitted to CFSAN dated November 9, 2005. 

In that assessment, the potential acute and long-term health risks posed by the foreign 

glycosylation of Ventria’s rhLF were detailed. The assessment stated 

“that α(1,3) fucose and β(1,2) xylose glycans appear on virtually 100% of 

rice-produced rhLF, and that these are cross-reactive carbohydrate 

determinants (CDDs) known to produce IgE antibodies. These same epitopes 

have been shown to induce immunogenicity in other therapeutic proteins 

produced in plants (Bardor 2002). It has been demonstrated that a 

considerable number of healthy individuals have antibodies circulating against 

α(1,3)-fucose and β(1,2)-xylose residues. Furthermore, these α(1,3)-linked 

fucose and β(1,2)-linked xylose glycans occur on many parasites and 

microorganisms that cause disease in people, and immune responses to these 

unusual carbohydrates, and even the carbohydrates themselves, may be 

profoundly important in disease pathogenesis (Die 2006, Foetisch 2003, 

Malandain 2005, Nyame 2004).”9 

The potential adverse events that could be triggered by these glycans include acute allergic 

reactions as well as a host of longer-term immunological consequences. In view of this 

8 Scientific Assessment Submitted to CFSAN, November 9, 2005, page 7. 

9

 Scientific Assessment Submitted to CFSAN, November 9, 2005, page 4. 

June 3, 2008 4 
 

 

assessment, it is of particular concern that some of the children in Ventria’s clinical study are 

reported to have experienced acute allergic reactions. It is also of concern that insufficient 

follow-up monitoring was conducted to determine whether other delayed reactions or allergic 

sensitization may have occurred. 

Pediatric Populations May be at Increased Risk 

Ventria’s revised intended use targeting pediatric populations is also cause for increased 

concern. Exposure to recombinant, non-natural proteins, especially in infants where the 

immune system is under development, may pose an increased risk for development of allergy 

or autoimmune diseases later in life. The risk would even be higher if ORS containing the 

recombinant protein is administered during gastrointestinal infections. Children are 

especially prone to a variety of gastrointestinal infections, including diarrheal diseases that 

increase gut permeability (leaky gut syndrome) and result in stimulation of the gut-associated 

lymphoid tissue. Published data suggests that such infections can result in abnormal antigen 

delivery across the mucosal barrier of the gut that triggers multi-organ processes leading to 

autoimmunity (Fassano 2005, Turley 2005, Wildner 2003). Enteric viral infections in 

children have also been associated with type 1 diabetes and an enhanced antibody response to 

other dietary ingredients such as bovine insulin in infant formula (Makela 2006). In view of 

the data associating autoimmune responses in children to increased intestinal permeability 

resulting from gastrointestinal infections, it is troubling that Ventria’s rhLF is specifically 

targeted for children and infants suffering from gastrointestinal infections and diarrhea and 

that the FDA may not have been properly informed of the apparent immune reactions. The 

initial Scientific Assessment of November 9, 2005 specifically cautioned that the novel 

mechanism of action of rhLF might actually exacerbate these risks: 

“RhLF is a biologically active immunostimulatory drug that interacts 

directly with receptors in the gut responsible for regulating immune 

response. Through receptor binding, lactoferrin might actually serve as 

a vector to deliver cross-reactive plant glycans directly to activated 

immune cells. It would seem likely that the presence of these glycans on 

lactoferrin might actually increase the risk of an IgE response.”10 

Given the reported occurrence of allergic reactions in Ventria’s trial, this caution should not 

be overlooked. Also of concern is the occurrence of food protein-induced enterocolitis 

syndrome caused by rice-derived proteins (Hjsak 2006; Nowak-Wegrzyn 2003). In this 

syndrome, children with rice allergy can present with vomiting, diarrhea and dehydration 

without a diagnosis of allergy. Although the appropriate treatment in these patients is the 

withdrawal of rice-derived proteins from their diet, a GRAS approval for the use of ricederived rhLF in these patients could potentially result in an additional exposure to ricederived proteins, worsening of the allergy and potentially death. 

In summary, children, especially neonates and infants with GI disorders, are a uniquely 

vulnerable patient population whose physiological state may make them especially 

10 Scientific Assessment Submitted to CFSAN, November 9, 2005, page 6. 

June 3, 2008 5 
susceptible to many of the potential risks from unsupervised administration of rice-derived 

rhLF. In the absence of large, long term, credible studies proving otherwise, children 

suffering from intestinal conditions should not be considered safe targets for the 

unsupervised administration of compounds containing Ventria’s rhLF. 

Longer-Term Safety Risks Remain 

In addition to these acute risks, the initial Scientific Assessment of November 9, 2005 also 

pointed out that there may be longer term risks with the administration of rhLF including 

among others: 

• Long-term immunogenicity risks. As discussed previously, long-term 

immunogenicity risks can take time to manifest and can only be evaluated with 

appropriately sized long-term human trials. Although these risks are significant 

even with the general population, they may be substantially enhanced in the 

population targeted by Ventria’s current GRAS notice. The factors that may 

enhance the long-term immunogenicity risks in this patient population include: (i) 

potentially increased gut permeability and breakdown of normal gut-protective 

mechanisms in these patients; (ii) a heightened immune responsiveness in 

response to gut-derived infection; and (iii) a dosing schedule consisting of a bolus 

of the antigen administered for short periods of time followed potentially by 

additional exposures during future diarrheal episodes, reminiscent of an 

immunization schedule. Some of the immunogenicity risks include: 

- The risk of immunogenicity and the breaking of B-cell tolerance, which may 

take over a year to manifest; 

- The risk of inducing anti-lactoferrin antibodies, which could both crossneutralize endogenous lactoferrin with negative biological effects and 

neutralize the efficacy of exogenous lactoferrin, which could compromise 

future treatments; 

- The risk of exacerbating autoimmune diseases that are associated with antilactoferrin antibodies; 

• The risk of toxicity in individuals with iron overload; 

• The risk of iron delivery to iron constrained pathogens; 

• The risk of iron delivery to tumors, which need iron for growth; 

• The risk of systemic amyloidosis caused by lactoferrin variants; and 

• The risk of viral activation by lactoferrin. 

These risks have not been evaluated in human populations. Ventria notes in its resubmission that children up to 5 years of age are targeted for receiving treatment with rhLF 

June 3, 2008 6 
 

and that the average number of episodes of diarrhea may be as high as 2.3 per year.11 This 

could potentially expose children to as many as 11 multi-dose administrations of Ventria’s 

rhLF in their first 5 years of life. It is our continued opinion, as experts in the fields relevant 

to the safety of rhLF, that the longer-term risks described above (and more fully described in 

previous submissions12) remain real and substantial concerns under Ventria’s revised 

conditions of use. 

Conclusion 

Ventria’s current resubmission of September 2007 provides insufficient evidence to warrant 

a GRAS determination for rice-produced rhLF to be marketed as a treatment for diarrhea in 

pediatric populations. Serious safety issues remain. 

• Ventria’s trial in Peruvian children was not designed to address the serious safety 

concerns. The children received only a single cycle of only a few days of 

treatment, the number of children receiving treatment with Ventria’s rhLF was 

small, and they did not receive adequate follow-up. Moreover, published reports 

of allergic reactions in the trial – even though the trial involved administration of 

Ventria’s rhLF to only a small number of children and for only a few days of 

treatment – only adds to the safety concerns. The other reported issues, including 

those involving selective and inadequate disclosure, further undermine the 

credibility of the trial and of the GRAS notice. 

• Children with intestinal conditions may be particularly vulnerable to adverse 

reactions following administration of Ventria’s rhLF. 

• The potential longer-term risks described in the initial Scientific Assessment of 

November 9, 2005 remain serious safety concerns. 

It is our scientific judgment, in view of the continuing risks described above and in the initial 

Scientific Assessment of November 9, 2005, that Ventria’s rice-based rhLF is not GRAS for 

its proposed uses, and that Ventria’s GRAS notice should be denied. 

11 See Ventria’s September 2007 re-submission, page 15. 

12 Scientific Assessment Submitted to CFSAN, November 9, 2005, pages 9-15. 

June 3, 2008 7 
 

 

 

Richard D. Cummings, Ph.D. 

William Patterson Timmie Professor & Chair 

Department of Biochemestry 

Emory University School of Medicine 

Dr. Arno Kromminga, M.D. 

Director, Immunology 

Institute for Immunology, Clinical Pathology, 

Molecular Medicine (IPM) 

Hamburg, Germany 

Marco van de Weert, PhD 

Associate Professor Biomacromolecules Group, 

Dept. of Pharmaceutics and Analytical 

Chemistry, The Danish University of 

Pharmaceutical Sciences 

Michael P. Sherman, M.D. 

Southern Illinois University School of Medicine, 

Department of Pediatrics 

Simon David Roger, M.D. , FRACP 

Director of Renal Medicine, 

Chairman, Medical Staff Council, 

Gosford Hospital, NSW Australia 

Nicole Casadevall, M.D. 

Professor of Hematology 

Hôpital Saint Antoine 

Paris, France 

E.D. Weinberg, Ph.D. 

Professor Emeritus 

Biology & Medical Sciences 

Indiana University 

James Michael Pierce, Ph.D. 

George E. and Sarah F. Peters Mudter Professor in 

Cancer Research, Director - University of Georgia 

Cancer Center, Member - Complex Carbohydrate 

Research Center, University of Georgia 

Sidney E. Grossberg, M.D. 

Walter Schroeder Professor of Microbiology and 

Molecular Genetics, Professor of Medicine, Medical 

College of Wisconsin 

Huub Schellekens, M.D. 

Professor - Faculty Pharmaceutical Sciences, 

Utrecht University Central Laboratory, 

Animal Institute and Department of Innovation 

Studies, Utrecht University 

Netherlands 

Irma van Die, PhD 

Associate Professor – Glycoimmunology 

Department of Molecular Cell Biology & 

Immunology, VUMC Glyco-immunology Group VU 

University Medical Center , Netherlands 

Martin K. Kuhlmann, M.D. 

Associate Professor of Medicine and Nephrology, 

Director, Department of Internal Medicine, 

Vivantes Clinical Center - Friedrichshain, Berlin 

Dr. Ashraf Mikhail, MB B Ch, MSc, FRCP 

Consultant Nephrologist 

Morriston Hospital 

Swansea, Wales 

Professor Wolfgang Jelkmann, M.D. 

Professor of Physiology, 

Director - Institute of Physiology 

University of Luebeck, Germany 

June 3, 2008 8 
References 

Andres MT, Viejo-Diaz M, Perez F, Fierro JF, “Antibiotic tolerance induced by lactoferrin 

in clinical Pseudomonas aeruginosa isolates from cystic fibrosis patients.” 

Antimicrob Agents Chemother. 2005 Apr;49(4):1613-6. 

Bethell, D. “Lactiva and Lysomin: Helping to Save Lives By Improving Oral Rehydration 

Solution.” http://www.ventria.com/news/ORS%20Article%2005-06.asp 

CDC “The management of acute diarrhea in children: oral rehydration, maintenance, and 

nutritional therapy,” U.S. Centers for Disease Control, 1992. 

www.cdc.gov/mmwr/preview/mmwrhtml/00018677.htm. 

Diaz, D. “Transgénicos: Niños ya sufren sus efectos,” La Republica (Peru), July 14. 

http://archivo.larepublica.com.pe/index.php?option=com_content&task=view&id=116503&I 

temid=38&fecha_edicion=2006-07-14 

Die I, “Glycans modulate immune responses in helminth infections and allergy.” Chem 

Immunol Allergy. 2006 90:91-112. 

Dutta, D. “Evaluation of oral hypo-osmolar glucose-based and rice-based oral rehydration 

solutions in the treatment of cholera in children,” Acta Paediatr 89(7): 787-790. 

Fasano A, Shea-Donohue T., Mechanisms of disease: the role of intestinal barrier function in 

the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol 

Hepatol. 2005 Sep;2(9):416-22. 

Foetisch K, “Biological activity of IgE specific for cross-reactive carbohydrate 

determinants.” J Allergy Clin Immunol. 2003 111:889-96. 

Gore, S.M., “Impact of rice based oral rehydration solution on stool output and duration of 

diarrhoea: metaanalysis of 13 clinical trials,” British Medical Journal 304(6822): 287-91. 

Hojsak I, Kljaić-Turkalj M, Misak Z, Kolacek S. ”Rice protein-induced enterocolitis 

syndrome”. Clin Nutr. 2006 Jun;25(3):533-6. Epub 2006 May 12. 

Makela M, ”Enteral virus infections in early childhood and an enhanced type 1 

diabetes-associated antibody response to dietary insulin”. J. Autoimmun. 2006 Aug;27(1):54-

61. Epub 2006 Jun 6. 

Malandain H, “IgE-reactive carbohydrate epitopes--classification, cross-reactivity, and 

clinical impact.” Allerg Immunol (Paris). 2005 37:122-8. 

Nowak-Wegrzyn A, Sampson HA, Wood RA, Sicherer SH. “Food protein-induced 

enterocolitis syndrome caused by solid food proteins”. Pediatrics. 2003 Apr;111(4 Pt 1):829-

35. 

June 3, 2008 9 
Nyame AK, Kawar ZS, Cummings RD, “Antigenic glycans in parasitic infections: 

implications for vaccines and diagnostics.” Arch. Biochem. Biophys. 2004 426:182-200. 

Sarker, S.A. “Reduced osmolarity oral rehydration solution for persistent diarrhea in infants: 

a randomized controlled clinical trial,” J. Pediatr 138(4): 532-538. 

Turley SJ, Lee JW, Dutton-Swain N, Mathis D, Benoist C. “Endocrine self and gut non-self 

intersect in the pancreatic lymph nodes”. Proc. Natl. Acad. Sci. U.S.A. 2005 Dec 

6;102(49):17729-33. 

Ventria PR. Ventria press release on Peruvian trial, May 1, 2006. 

http://www.ventria.com/news/Press%20Release%2005-01-06.asp 

Wall, C.R., C.E. Swanson and G.J. Cleghorn. “A controlled trial comparing the efficacy of 

rice-based and hypotonic glucose oral rehydration solutions in infants and young children 

with gastroenterities,” J. Gastroenterol Hepatol 12(1): 24-28. 

Wildner G, Diedrichs-Maehring M. “Autoimmune uveitis induced by molecular mimicry of 

peptides from rotavirus, bovine casein and retinal S-antigen”. Eur. J. Immunol. 2003 

Sep;33(9):2577-87. 

Zavaleta, N. (2006). “Efficacy of a rice-based oral rehydration solution (ORS) containing 

recombinant human lactoferrin and lysozyme in Peruvian children with acute diarrhea,” 

abstract of a presentation at the Pediatric Academic Societies conference in San Francisco, 

CA, on April 30, 2006. 

Zavaleta, N. “Efficacy of rice-based oral rehydration solution containing recombinant 

human lactoferrin and lysozyme in Peruvian children with acute diarrhea,” Journal of 

Pediatric Gastroenterology and Nutrition 44(2), January 2007, pp. 258-264. 

June 3, 2008 10 
 

Addendum to Scientific Assessment of November 9, 2005: 

Supplemental References 

The following supplemental references further support arguments made in the scientific 

assessment previously submitted on November 9, 2005. We are submitting these additional 

references for inclusion in the record. 

Topic: Glycosylation Risks 

A recent publication showed that even expression of a plant protein (bean α-amylase 

inhibitor) in a different plant species (peas) produced novel post-translational protein 

modifications (including variations in glycosylation). This resulted in altered 

immunogenicity, including CD4+ TH2-type inflammation in mice (Prescott 2005). 

* * * * 

Besides being antigenic and allergenic, carbohydrate moieties of glycolipids and 

glycoproteins in plants, animals and humans have very high biological activity and are 

involved in a tremendous range of biological processes including cell-cell adhesion, cell-cell 

signaling, immune regulation, innate immunity, and cell biological phenomena including 

organelle biosynthesis (Bertozzi 2001, Engering 2002, Feizi 2000, Freeze 2005, Gu 2004, 

Helenius 2004, Rudd 2004, van Kooyk 2004). 

* * * * 

Carbohydrate moieties have increasingly been implicated in the immunogenicity and 

allergenicity of recombinant proteins (Betenbaugh 2004, Fotisch 2001, Jin 2008) 

Topic: Immunostimulation by Lactoferrin 

Lactoferrin has a broad range of immunostimulatory properties that have been extensively 

documented and discussed in the literature. Orally administered lactoferrin can result in 

substantial systemic immunomodulation, which must be evaluated thoroughly before 

permitting unsupervised availability of rhLF, especially in pediatric populations. (Artym 

2005, Curran 2006, Fischer 2006, Hwang [a] 2007, Hwang [b] 2007, Kuhara 2006, 

Legrand 2006, Legrand [a] 2005, Prgomet 2007, Rosa 2008, Spadaro 2008, Spadaro 

2007, Takakura 2006, Varadhachary 2006, Varadhachary 2005, Wakabayashi 2006, 

Wilk 2007, Wolf 2007, Zimecki 2007, Zimecki 2005, Zuccotti 2007) 

* * * * 

In vitro, lactoferrin has been shown to activate macrophages (Edde 2001) and has been 

shown to induce immune maturation and proliferation of a range of immune cells (Legrand 

[b] 2005, Shau 1992, Dhennin-Duthille 2000). 

June 3, 2008 11 
Topic: Immunotoxicity Risks 

Immunomodulatory agents (like rhLF) present a distinct risk of immunotoxic effects that 

require careful preclinical and clinical evaluation. A recent review by a noted 

immunotoxicologist summarized these concerns (Descotes 2004). 

Utility to Pathogens 

Iron availability is critical to the growth of intestinal pathogens such as Helicobacter pylori 

and Entamoeba histolytica – organisms that have evolved a mechanism to acquire iron from 

lactoferrin. Infection with the later organism can often lead to Amoebic dysentery. Before 

children are exposed to lactoferrin, special care should be taken to screen for any amoebic 

parasites. ( Dhaenens 1997, Husson 1993, Johansson 2008, Leon-Sicairos 2005, 

Olakanmi 2007) 

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humoral and cellular immune response during chemotherapy-induced immunosuppression 

and bone marrow transplant in mice”. Stem Cells Dev. 2005 Oct;14(5):548-55. 

Bertozzi, C.R., Kiessling L.L. Chemical glycobiology. Science. 2001 291:2357-64. 

Betenbaugh MJ, Tomiya N, Narang S, Hsu JT, Lee YC, “Biosynthesis of human-type Nglycans in heterologous systems.” Curr Opin Struct Biol. 2004 Oct;14(5):601-6. Review. 

Curran CS, Demick KP, Mansfield JM. “Lactoferrin activates macrophages via TLR4-

dependent and -independent signaling pathways”. Cell Immunol. 2006 Jul;242(1):23-30. 

Epub 2006 Oct 10. 

Descotes J, “Importance of immunotoxicity in safety assessment: a medical toxicologist's 

perspective.” Toxicol Lett. 2004 Apr 1;149(1-3):103-8. Review. 

Dhaenens L, Szczebara F, Husson M-O. “Identification, characterization and 

immunogenicity of the lactoferrin-binding protein from Helicobacter pylori”. Infec Immun 

(1997) 65:514-518. 

Dhennin-Duthille I, Masson M, Damiens E, et al: Lactoferrin upregulates the expression of 

CD4 antigen through the stimulation of the mitogen-activated protein kinase in the human 

lymphoblastic T Jurkat cell line. J. Cell. Biochem. 79: 583–593, 2000. 

June 3, 2008 12 
Edde L, Hipolito RB, Hwang FF, Headon DR, Shalwitz RA, Sherman MP. Lactoferrin 

protects neonatal rats from gut-related systemic infection. Am J Physiol Gastrointest Liver 

Physiol. 2001 Nov;281(5):G1140-50. 

Engering, A., T.B. Geijtenbeek, and Y. van Kooyk. “Immune escape through C-type lectins 

on dendritic cells.” Trends Immunol. 2002 23:480-5. 

Feizi T. “Carbohydrate-mediated recognition systems in innate immunity.” Immunol Rev. 

2000 173:79-88. 

Fischer R, Debbabi H, Dubarry M, Boyaka P, Tomé D. “Regulation of physiological and 

pathological Th1 and Th2 responses by lactoferrin”. Biochem Cell Biol. 2006 

Jun;84(3):303-11. 

Fotisch K, Vieths S, “N- and O-linked oligosaccharides of allergenic glycoproteins.” 

Glycoconj J. 2001 May;18(5):373-90. Review. 

Freeze H.H., and M. Aebi.. “Altered glycan structures: the molecular basis of congenital 

disorders of glycosylation.” Curr Opin Struct Biol. 2005 15:490-8. 

Gu J., and N. Taniguchi. “Regulation of integrin functions by N-glycans.” Glycoconj J. 2004 

21:9-15. 

Helenius A., Aebi M. “Roles of N-linked glycans in the endoplasmic reticulum.” Annu Rev 

Biochem. 2004 73:1019-49. 

Husson M-O, Legrand D, Spik G, Leclerc H. “Iron acquisition by Helicobacter pylori: 

importance of human lactoferrin”. Infec Immun (1993) 61:2694-2697. 

Hwang [a] SA, Wilk KM, Budnicka M, Olsen M, Bangale YA, Hunter RL, Kruzel ML, 

Actor JK. ”Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective 

responses against challenge with virulent Mycobacterium tuberculosis”. Vaccine. 2007 Sep 

17;25(37-38):6730-43. Epub 2007 Jul 27. 

Hwang [b] SA, Wilk KM, Bangale YA, Kruzel ML, Actor JK. “ Lactoferrin modulation of 

IL-12 and IL-10 response from activated murine leukocytes”. Med Microbiol Immunol. 

2007 Sep;196(3):171-80. Epub 2007 Mar 22. 

Jin C, Altmann F, Strasser R, Mach L, Schähs M, Kunert R, Rademacher T, Glössl J, 

Steinkellner H. “A plant-derived human monoclonal antibody induces an anti-carbohydrate 

immune response in rabbitsGlycobiology”. 2008 Mar;18(3):235-41. Epub 2008 Jan 18. 

Johansson C, Jonsson M, Marttila M, Persson D, Fan XL, Skog J, Frängsmyr L, Wadell G, 

Arnberg N. ”Adenoviruses use lactoferrin as a bridge for CAR-independent binding to and 

infection of epithelial cells”. J Virol. 2007 Jan;81(2):954-63. Epub 2006 Nov 1. 

June 3, 2008 13 
Kuhara T, Yamauchi K, Tamura Y, Okamura H. “Oral administration of lactoferrin 

increases NK cell activity in mice via increased production of IL-18 and type I IFN in the 

small intestine”. J Interferon Cytokine Res. 2006 Jul;26(7):489-99. 

Legrand D, Elass E, Carpentier M, Mazurier J. “Interactions of lactoferrin with cells 

involved in immune function”. Biochem Cell Biol. 2006 Jun;84(3):282-90. Review. 

Legrand [a] D, Elass E, Carpentier M, Mazurier J. “Lactoferrin: a modulator of immune and 

inflammatory responses”. Cell Mol Life Sci. 2005 Nov;62(22):2549-59. Review. 

Legrand [b] D, Elass E, Carpentier M, Mazurier J. Lactoferrin: a modulator of immune and 

inflammatory responses. Cell Mol Life Sci. 2005 Nov;62(22):2549-59. 

Leon-Sicairos N, Reyes-Lopez M, Carizalis-Roman A, Bermudez-Cruz R M, Serrano-Luna 

J, Aroyo R, de la Garza M. “Human hololactoferrin: endocytosis and use as an iron source by 

the parasite Entamoeba histolytica”. Microbiology (2005) 151:3859-3871. 

Olakanmi O, Schlesinger LS, Britigan BE. “Hereditary hemochromatosis results in 

decreased iron acquisition and growth by Mycobacterium tuberculosis within human 

macrophages”. J Leuk Biol (2007) 81:195-204. 

Prescott VE, Campbell PM, Moore A, Mattes J, Rothenberg ME, Foster PS, Higgins TJ, 

Hogan SP, “Transgenic expression of bean alpha-amylase inhibitor in peas results in altered 

structure and immunogenicity.” J Agric Food Chem. 2005 Nov 16;53(23):9023-30. 

Prgomet C, Prenner ML, Schwarz FJ, Pfaffl MW. “Effect of lactoferrin on selected immune 

system parameters and the gastrointestinal morphology in growing calves”. J Anim Physiol 

Anim Nutr (Berl). 2007 Apr;91(3-4):109-19. 

Rosa G, Yang D, Tewary P, Varadhachary A, and Oppenheim JJ. “Lactoferrin acts as an 

alarmin to promote the recruitment and activation of antigen presenting cells and antigenspecific immune response.” Journal of Immunology, 2008 (In Press). 

Rudd P.M., M.R. Wormald, and R.A. Dwek. “Sugar-mediated ligand-receptor interactions in 

the immune system.” Trends Biotechnol. 2004 22:524-30. 

Shau H, Kim A, Golub SH: Modulation of natural killer and lymphokine-activated killer cell 

cytotoxicity by lactoferrin. J. Leukoc. Biol. 51: 343–349, 1992. 

Spadaro M, Caorsi C, Ceruti P, Varadhachary A, Forni G, Pericle F, Giovarelli M. 

“Lactoferrin, a major defense protein of innate immunity, is a novel maturation factor for 

human dendritic cells”. FASEB J. 2008 Mar 25; [Epub ahead of print] 

Spadaro M, Curcio C, Varadhachary A, Cavallo F, Engelmayer J, Blezinger P, Pericle F, 

Forni G. “Requirement for IFN-gamma, CD8+ T lymphocytes, and NKT cells in 

talactoferrin-induced inhibition of neu+ tumors”. Cancer Res. 2007 Jul 1;67(13):6425-32. 

June 3, 2008 14 
Takakura N, Wakabayashi H, Yamauchi K, Takase M. “Influences of orally administered 

lactoferrin on IFN-gamma and IL-10 production by intestinal intraepithelial lymphocytes and 

mesenteric lymph-node cells”. Biochem Cell Biol. 2006 Jun;84(3):363-8. 

van Kooyk Y., A. Engering, A.N. Lekkerkerker, I.S. Ludwig, and T.B. Geijtenbeek.. 

“Pathogens use carbohydrates to escape immunity induced by dendritic cells.” Curr Opin 

Immunol. 2004 16:488-93. 

Varadhachary A, Spadaro M, Engelmayer J, Blezinger P, Valli VE, Petrak K, Pericle F, 

Mokyr MB, Forni G, and Hayes TG. Talactoferrin alfa is an anti-cancer agent with activity 

in Renal Cell Cancer (RCC) patients and a novel immunomodulatory mechanism of action. 

Proceedings of the American Society of Clinical Oncology, 2006. 

Varadhachary A, Spadaro M, Curcio C, Yankee E, Pericle F, Forni G, and Wang Y. 

Talactoferrin alfa, a novel immunomodulatory agent. Conference on Translational 

Immunology Related to Cancer, National Cancer Institute, 2005. 

Wakabayashi H, Takakura N, Yamauchi K, Tamura Y. “Modulation of immunity-related 

gene expression in small intestines of mice by oral administration of lactoferrin”. Clin 

Vaccine Immunol. 2006 Feb;13(2):239-45. 

Wilk KM, Hwang SA, Actor JK. “Lactoferrin modulation of antigen-presenting-cell 

response to BCG infection”. Postepy Hig Med Dosw (Online). 2007;61:277-82. 

Wolf JS, Li G, Varadhachary A, Petrak K, Schneyer M, Li D, Ongkasuwan J, Zhang X, 

Taylor RJ, Strome SE, O'Malley BW Jr. “Oral lactoferrin results in T cell-dependent tumor 

inhibition of head and neck squamous cell carcinoma in vivo” Clin Cancer Res. 2007 Mar 

1;13(5):1601-10. 

Zimecki M, Artym J, Chodaczek G, Kocieba M, Kuryszko J, Houszka M, Kruzel ML. 

“Immunoregulatory function of lactoferrin in immunosuppressed and autoimmune animals”. 

Postepy Hig Med Dosw (Online). 2007;61:283-7. Review. 

Zimecki M, Artym J, Chodaczek G, Kocieba M, Kruzel M. “Effects of lactoferrin on the 

immune response modified by the immobilization stress”. Pharmacol Rep. 2005 NovDec;57(6):811-7. 

Zuccotti GV, Vigano A, Borelli M, Saresella M, Giacomet V, Clerici M. “Modulation of 

innate and adaptive immunity by lactoferrin in human immunodeficiency virus (HIV)-

infected, antiretroviral therapy-naïve children”. Int J Antimicrob Agents. 2007 

Mar;29(3):353-5. Epub 2007 Feb 2. 

June 3, 2008 15 
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DEPARTMENT OF HEALTH & HUMAN SERVICES 

Food and Drug Administration 

Center for Drug Evaluation & Research 

Date: 6-17-08 

To: Dr. Steven Sundlof, Director, Center for Food Science and Nutrition 

From: Amy S. Rosenberg, M.D. and Daniela Verthelyi, Ph.D., M.D. 

Through: Dr. Steven Kozlowski, Director, OBP/OPS/CDER and Dr. Janet 

Woodcock, Director, Center for Drug Evaluation and 

Research 

Re: GRN 000235 and GRN 000191 GRAS Notices 

Introduction 

This document communicates our concerns regarding the decision not to contest the 

GRAS designation for recombinant human lysozyme (hLZ-R) and recombinant human 

lactoferrin (hLF-R) produced in rice, in term infant formulas, pre-term infant formulas, 

“fortifiers”, and oral rehydration solutions for children up to three years of age. We have 

several important safety concerns regarding the addition of these proteins to formula 

and oral rehydration solutions: 

1. Potential risks: 

The first regards the potential that the human immune system will view these 

proteins as allergens. Drs. Jay Slater and Ron Rabin will address the potential 

allergenicity of such proteins in a separate report/memo. 

The second relates to the potential of these transgenic rice-produced 

recombinant human proteins, which have endogenous protein counterparts, to elicit 

immune responses that result in a breach in tolerance to the corresponding endogenous 

human proteins. Lactoferrin and lysozyme are normally present in multiple body fluids, 

particularly breast milk. They are considered an important component of the innate 

immune system with anti-infective, anti-cancer, and anti-inflammatory effects. 

Lactoferrin and Lysozyme are also prominent components of the secondary granules of 

neutrophils (PMNs) and are released in infected tissues and blood during inflammatory 

or infectious processes. Therefore development of antibodies to these proteins that 

either neutralize or change their bioactivity poses a significant risk. Indeed, several 

studies show that reduced levels of lactoferrin and/or granzyme are associated with 

increased susceptibility to infectious diseases (ref). 

Antibodies to both lactoferrin and lysozyme have been described in the context of 

several autoimmune disorders including inflammatory bowel disease, lupus (Caccavo, 

2005), Wegener’s granulomatosis (Pradhan, 2005) and rheumatoid arthritis (Manolova, 

2003). Early studies show that the presence of antibodies to lactoferrin may contribute 

to increased vascular permeability (Erga et al, 2000). However, their exact role in 

autoimmune pathology still unclear as the impact of such antibodies has not been 
 

 

 

 

 

 

 

 

 

extensively evaluated. Administration of LF to patients with inflammatory bowel disease 

is particularly concerning as it has a substantial probability to worsen disease by binding 

to high affinity, or even to lower affinity intestinal receptors, to which antibody could then 

bind and potentially fix complement, causing damage and destruction to the intestinal 

mucosa. The impact of hLF-R and hLZ-R on incidence and course of IBD in infants and 

children should be evaluated prior to general distribution in the population at large. In 

vitro modeling supports the activation of leukocytes by LF antibodies, due to the 

presence of LF on the cell surface of primed PMNs, as well as adherence of LF to 

cultured endothelial cells (Peen et al 1996) suggesting that PMNs adhering to vessel 

walls with exposed LF may become targets of circulating LF antibodies. The effect of 

orally administered LF in these patient populations is unknown. It may increase, 

decrease, or have no effect on antibody titer and may worsen, improve disease, or 

simply have no impact. This should be investigated. 

2. Neonates and infants are more prone to mounting an immune response to oral 

antigens: 

The risk of eliciting an immune response to these proteins is higher in neonates 

and infants, as studies have shown that the immature neonatal immune system has a 

higher capacity to form allergic immune responses to proteins delivered orally (refs). 

The presence of low titers of antibodies to LF in healthy, exclusively breast fed infants 

may further reflect the inherent immunogenicity of this protein (Lonnerdal et al 1998 

Adv. Exp Med and Biol). However , the presence of antibodies to lysozyme has never 

been evaluated in infants. Assessment of antibodies to hLf and hLZ should be 

undertaken in infants prior to consideration of allowing transgenic rice produced 

lysozyme or lactoferrin in formulas or ORSs. Should such antibodies be detected, the 

response should be followed over time and any correlation with disease states 

evaluated. 

Studies show that, the incidence of food allergy is substantially greater in children 

than in adults (Sampson H 2004 J. Allergy and Clin Immunol). Moreover, in neonatal 

rodent models, some proteins delivered orally have been shown to prime rather than 

tolerize the immune response. For example, oral administration of myelin basic protein 

to neonates exacerbates the subsequent course of experimental allergic 

encephalomyelitis, a disease similar to multiple sclerosis (Miller et al 1994 E. Jl. 

Immunol). The relevance of such observations in rodents to human infants is not clear, 

but does elicit concern. An additional concern when considering the administration of 

these proteins as ORS, is that exposure to LF and LZ proteins normally occurs in the 

context of breast milk, which is replete with cytokines, hormones and other 

immunomodulatory factors (Paramasivank et al 2006 Int J Fertil and Women Med). 

These factors may reduce or modify the immunogenicity of these proteins, or greatly 

moderate their potential to elicit immune related toxicity . Therefore, administration of 

hLF-R and hLZ-R in formula or ORS lacking such cytokines and immunomodulators 

may elicit a much more significant immune response than they would induce when 

delivered in human breast milk. As stated above, low levels of antibodies to LF have 

been reported in healthy infants, suggesting that low level antibodies to human LF are 

normal in infants, likely benign, and likely resolve over time. However administration of 

hLF-R, bearing foreign determinants may have the capacity to turn a benign response 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

into one with adverse consequences by increasing the affinity, the titer, causing isotype 

switching, or inducing a more sustained response. Lastly, delivery of these proteins in 

the setting of an inflamed and potentially compromised gut wall such as can happen in 

children with severe diarrhea may further facilitate the crossing of undegraded protein, 

believed to be more immunogenic than its degraded peptide fragments, into the gut 

associated lymphoid tissue where it may prime an immune response. Therefore, the 

development and fate of antibodies to human LF , in the presence or absence of 

exposure to rice produced hLF-R must be determined prior to generalized and 

uncontrolled use of ORS containing this agent. 

3. Product immunogenicity: 

From the data currently available it appears that the proteins produced in 

rice are not identical to their human, naturally occurring counterparts. 

Differences may include small differences in primary sequence, product related 

impurities due to post translational modifications (truncation, oxidation 

deamidation etc), process related impurities (such as rice related proteins, lipids 

or carbohydrates, or low levels of immune activators derived from adventitious 

agents such as bacteria or yeast, and altered glycosylation. All are of great 

concern as they can create novel epitopes or favor a pathogenic immune 

response to existing epitopes. To date, the published literature on hLF-R and 

hLZ-R, shows that only N-terminal sequencing and amino acid composition 

analysis has been performed. The presence of novel epitopes raises the concern 

that epitope spreading could ensue leading to breaking of tolerance to the fully 

human portions of the molecule and the generation of antibodies directed to the 

endogenous human protein. Thus, the full length of the hLF-r protein should be 

sequenced and not just the N-terminus. The primary data should be submitted for 

review by FDA. N-terminal sequencing may be acceptable as a release test for 

identity, but not as a test for determination of sameness to human LF. 

In addition, alternative or reduced glycosylation, as evidenced in the 

Ventria product could contribute to immunogenicity as glycosyl groups present in 

the endogenous protein may shield protein epitopes from access by the immune 

system, and changes in sugars may lead to exposure of cryptic epitopes and the 

generation of an immune response (Sinclair A and Elliot S 2005. J. Pharm Sci). 

Further, the presence of the plant glycans α1,2 xylose; β1,3 fucose on th hLF-R, 

could facilitate the breaking of tolerance to the endogenous human protein via 

collaboration of the plant glycan specific Th cells and autoreactive LF specific B 

cells, or via the IgE antibodies themselves, which in binding to antigen, may 

facilitate epitope spreading so that antibodies are generated to conserved human 

LF determinants (Bardor M et al 2003. Glycobiology). 

Similarly, for lysozyme produced in transgenic rice, even if it is allegedly 

not glycosylated (this needs to be confirmed through appropriate studies by 

Ventria), there may be post-translational modifications imposed by the rice 

expression system that may cause truncations, oxidation, deamidation, 

aggregation or other product related impurities, which may predispose to immune 

responses. As mentioned above, such modifcations leading to enhanced 
 

 

 

 

 

 

 

 

 

 

immunogenicity have been previously observed (Prescott V et al 2005. J. Agric 

and Food Chem) 

4. Testing: 

It should be pointed out that the failure to perform clinical trials that validate the 

safety of these proteins in infant formulas violates key principles set forth by the 

National Academy of Sciences regarding the evaluation of the safety of new ingredients 

in infant formulas: “Infant Formula: Evaluating the Safety of New Ingredients”, published 

in 2004(http://www.nap.edu/catalog/10935.html). This guideline underscores: 1) the 

unique vulnerability of infancy, 2) that infant formulas are consumed by the vast 

majority of infants and are the sole source of nutrition for a large segment of infants up 

to the first 6 months of life, 3) that manufacturers are increasingly interested in adding 

new ingredients to formulas in an attempt to mimic the perceived and potential benefits 

of human milk and finally, that 4) existing guidelines and safety regulations lack clarity 

and completeness in adequately addressing the unique growth and development 

requirements of infants and the vast diversity of potential new ingredients. In this 

guidance, it specifically states that though the “GRAS process is rigorous, flexible, 

credible and transparent..., its application does not clearly address possible 

concerns for the multitude of potential new ingredients in infant formulas.... 

including those derived from novel sources or processes (e.g. products of 

fermentation or biotechnology)”. The hLF-R and hLZ-R products clearly fall into the 

category of “new ingredients derived from novel sources”. It further specifically states 

that allergenicity is a factor that should be considered in a safety assessment: “Other 

factors that should be considered for safety are: tolerance, allergenicity, impact 

of gastrointestinal flora .....”. In that regard, there have been no evaluations of the 

allergenicity or immunogenicity of hLZ-R and hLF-R despite the presence on lactoferrin 

of plant glysocsyl groups known to be immunogenic/allergenic. This guidance clearly 

advocates for extensive testing of these proteins for their capacity to induce allergic and 

autoimmune responses to both rice produced and to the endogenous human LF and LZ 

prior to widespread use. The document describes a hierarchical approach to such 

evaluations and lists as the first two elements to be considered the “reversibility of 

potential harmful effects and the severity and consequences of adverse effects”. Allergic 

responses may be severe, life-threatening and not subject to elimination by standard 

immunotherapy. Also, they may be associated with vasculitis (). The document further 

recommends safety assessments of Organ Systems, Neurobiological Development and 

Behavior and specifically states that “..the committee recommends a two level 

assessment approach to assess organ, immunological and endocrinological systems”. It 

goes on to state that “In addition, some organ systems (e.g. immune and endocrine) are 

immature at birth; every effort must be made to ensure that ingredients new to infant 

formulas will not affect the development of these systems or expression of their 

function”. An autoimmune response that neutralizes LF or LZ could have a profound 

effect on the innate immune system (Welsh et al 2002 Nature), of which these factors 

are critical components, and could engender a suboptimal microbial gut flora with 

unknown consequences, both short and long term. 
 

 

 

 

 

 

 

 

 

We are puzzled as to the justification for the designation of “Generally 

Recognized as Safe”, as it is clearly not evidence based. In fact, hLF-R has only 

been administered to 47 children with diarrhea in Peru (45 of whom completed 

the study) (Zavaleta et al 2007 2007 J. Ped. Gastro and Nutr.44:258) and a total 

of 4 healthy females (Lonnerdal 2006 Am J Clin Nutr) who were dosed for 42 

days in the USA, while hLZ-R was only administered to children in the Peruvian 

study (Zavaleta et al 2007). Neither study was performed under IND and 

immunogenicity, including assessment of allergy was not evaluated. Indeed, the 

Peruvian study was followed by allegations of malpractice by the Peruvian 

Association of Physicians and the Peruvian Association for Human Rights 

according to the local press. 

Additionally, we think that there are implicit and potentially explicit drug 

claims regarding addition of these factors to the formulas mentioned: that they 

will either prevent infection with microbes causing diarrheal illness (presence in 

infant formulas), or enhance the recovery from such infection (oral rehydration 

solutions). These claims are based on the highly criticized clinical trial in which 

the sponsor purported to demonstrate enhanced recovery from diarrheal illness 

in Peruvian children (Zavaleta et al 2007.). They were further publicized on the 

Ventria website: “May 1, 2006: A Breakthrough for Second Leading Killer of 

Children Under Five a Medical Food for Acute Diarrhea”. A In press release it 

was stated that “Ventria believes that addition of Lactiva (rhuLF) and Lysomin 

(rhuLZ) to oral rehydration solutions may help improve the health of children 

suffering from diarrhea.” As explicit, but unverified claims have been made, these 

products must be studied for safety and effectiveness, particularly in the ORS 

setting. 

Further reason not to approve the GRAS designation of these products 

comes from the fact that by US laws and regulations, these products fall under 

the definition of “biological products” as they are analagous to human proteins 

present in multiple body fluids including serum. As interpreted in 21CFR600.3, 

which states that a biological product means any virus, therapeutic serum, toxin, 

anti-toxin, or analagous product applicable to the prevention, treatment, or cure 

of diseases or injuries of man, rice produced LF and LZ are biological products 

and require study under IND. Indeed, recombinant human lactoferrin products, 

produced in aspergillus are currently in clinical trials for presumed 

immunomodulatory properties in the settings of cancer and wound healing, and 

have been studied in the past for their effects on pathogenic microbes in the G.I. 

tract and on wound healing. 

In summary, we disagree with the draft FDA letter stating that there are 

“no concerns about autoimmune responses to hLF-r as a result of “allogenicity” 

or plant glycosylation because of the limited duration of use,“one to fourteen 

days”. This neglects the fact that these products will assuredly be used 

repetitively and not just on a one time basis (at least three times per year is an 

estimate). Moreover, if tolerance to endogenous human lactoferrin is broken, 

there may not be a further requirement for exposure to rice produced hLF-r or 

hLZ-r to perpetuate the response, as exposure to endogenous LF or LZ may 

perpetuate the response.. 
 

Thus, given the concerns listed above, and most importantly, given that these 

recombinant proteins have only been tested in a very small number of patients in a 

non-rigorous fashion, substantial risk exists and thus widespread uncontrolled use in the 

population, including healthy term and preterm infants, and in children recovering from 

diarrhea, likely comprising millions of children, is not justified. Should adverse events 

develop when this product is in widespread use, it could be devastating. In this case, 

risk can be mitigated to a very low level based on adequately sized and powered clinical 

trials assessing prevention of or time to recovery from infection. 
DEPARTMENT OF HEALTH & HUMAN SERVICES 

Food and Drug Administration 

Center for Drug Evaluation & Research 

Date: 6-17-08 

To: Dr. Steven Sundlof, Director, Center for Food Science and Nutrition 

From: Amy S. Rosenberg, M.D. and Daniela Verthelyi, Ph.D., M.D. 

Through: Dr. Steven Kozlowski, Director, OBP/OPS/CDER and Dr. Janet 

Woodcock, Director, Center for Drug Evaluation and 

Research 

Re: GRN 000235 and GRN 000191 GRAS Notices 

Introduction 

This document communicates our concerns regarding the decision not to contest the 

GRAS designation for recombinant human lysozyme (hLZ-R) and recombinant human 

lactoferrin (hLF-R) produced in rice, in term infant formulas, pre-term infant formulas, 

“fortifiers”, and oral rehydration solutions for children up to three years of age. We have 

several important safety concerns regarding the addition of these proteins to formula 

and oral rehydration solutions: 

1. Potential risks: 

The first regards the potential that the human immune system will view these 

proteins as allergens. Drs. Jay Slater and Ron Rabin will address the potential 

allergenicity of such proteins in a separate report/memo. 

The second relates to the potential of these transgenic rice-produced 

recombinant human proteins, which have endogenous protein counterparts, to elicit 

immune responses that result in a breach in tolerance to the corresponding endogenous 

human proteins. Lactoferrin and lysozyme are normally present in multiple body fluids, 

particularly breast milk. They are considered an important component of the innate 

immune system with anti-infective, anti-cancer, and anti-inflammatory effects. 

Lactoferrin and Lysozyme are also prominent components of the secondary granules of 

neutrophils (PMNs) and are released in infected tissues and blood during inflammatory 

or infectious processes. Therefore development of antibodies to these proteins that 

either neutralize or change their bioactivity poses a significant risk. Indeed, several 

studies show that reduced levels of lactoferrin and/or granzyme are associated with 

increased susceptibility to infectious diseases (ref). 

Antibodies to both lactoferrin and lysozyme have been described in the context of 

several autoimmune disorders including inflammatory bowel disease, lupus (Caccavo, 

2005), Wegener’s granulomatosis (Pradhan, 2005) and rheumatoid arthritis (Manolova, 

2003). Early studies show that the presence of antibodies to lactoferrin may contribute 

to increased vascular permeability (Erga et al, 2000). However, their exact role in 

autoimmune pathology still unclear as the impact of such antibodies has not been 
extensively evaluated. Administration of LF to patients with inflammatory bowel disease 

is particularly concerning as it has a substantial probability to worsen disease by binding 

to high affinity, or even to lower affinity intestinal receptors, to which antibody could then 

bind and potentially fix complement, causing damage and destruction to the intestinal 

mucosa. The impact of hLF-R and hLZ-R on incidence and course of IBD in infants and 

children should be evaluated prior to general distribution in the population at large. In 

vitro modeling supports the activation of leukocytes by LF antibodies, due to the 

presence of LF on the cell surface of primed PMNs, as well as adherence of LF to 

cultured endothelial cells (Peen et al 1996) suggesting that PMNs adhering to vessel 

walls with exposed LF may become targets of circulating LF antibodies. The effect of 

orally administered LF in these patient populations is unknown. It may increase, 

decrease, or have no effect on antibody titer and may worsen, improve disease, or 

simply have no impact. This should be investigated. 

2. Neonates and infants are more prone to mounting an immune response to oral 

antigens: 

The risk of eliciting an immune response to these proteins is higher in neonates 

and infants, as studies have shown that the immature neonatal immune system has a 

higher capacity to form allergic immune responses to proteins delivered orally (refs). 

The presence of low titers of antibodies to LF in healthy, exclusively breast fed infants 

may further reflect the inherent immunogenicity of this protein (Lonnerdal et al 1998 

Adv. Exp Med and Biol). However , the presence of antibodies to lysozyme has never 

been evaluated in infants. Assessment of antibodies to hLf and hLZ should be 

undertaken in infants prior to consideration of allowing transgenic rice produced 

lysozyme or lactoferrin in formulas or ORSs. Should such antibodies be detected, the 

response should be followed over time and any correlation with disease states 

evaluated. 

Studies show that, the incidence of food allergy is substantially greater in children 

than in adults (Sampson H 2004 J. Allergy and Clin Immunol). Moreover, in neonatal 

rodent models, some proteins delivered orally have been shown to prime rather than 

tolerize the immune response. For example, oral administration of myelin basic protein 

to neonates exacerbates the subsequent course of experimental allergic 

encephalomyelitis, a disease similar to multiple sclerosis (Miller et al 1994 E. Jl. 

Immunol). The relevance of such observations in rodents to human infants is not clear, 

but does elicit concern. An additional concern when considering the administration of 

these proteins as ORS, is that exposure to LF and LZ proteins normally occurs in the 

context of breast milk, which is replete with cytokines, hormones and other 

immunomodulatory factors (Paramasivank et al 2006 Int J Fertil and Women Med). 

These factors may reduce or modify the immunogenicity of these proteins, or greatly 

moderate their potential to elicit immune related toxicity . Therefore, administration of 

hLF-R and hLZ-R in formula or ORS lacking such cytokines and immunomodulators 

may elicit a much more significant immune response than they would induce when 

delivered in human breast milk. As stated above, low levels of antibodies to LF have 

been reported in healthy infants, suggesting that low level antibodies to human LF are 

normal in infants, likely benign, and likely resolve over time. However administration of 

hLF-R, bearing foreign determinants may have the capacity to turn a benign response 
 

into one with adverse consequences by increasing the affinity, the titer, causing isotype 

switching, or inducing a more sustained response. Lastly, delivery of these proteins in 

the setting of an inflamed and potentially compromised gut wall such as can happen in 

children with severe diarrhea may further facilitate the crossing of undegraded protein, 

believed to be more immunogenic than its degraded peptide fragments, into the gut 

associated lymphoid tissue where it may prime an immune response. Therefore, the 

development and fate of antibodies to human LF , in the presence or absence of 

exposure to rice produced hLF-R must be determined prior to generalized and 

uncontrolled use of ORS containing this agent. 

3. Product immunogenicity: 

From the data currently available it appears that the proteins produced in 

rice are not identical to their human, naturally occurring counterparts. 

Differences may include small differences in primary sequence, product related 

impurities due to post translational modifications (truncation, oxidation 

deamidation etc), process related impurities (such as rice related proteins, lipids 

or carbohydrates, or low levels of immune activators derived from adventitious 

agents such as bacteria or yeast, and altered glycosylation. All are of great 

concern as they can create novel epitopes or favor a pathogenic immune 

response to existing epitopes. To date, the published literature on hLF-R and 

hLZ-R, shows that only N-terminal sequencing and amino acid composition 

analysis has been performed. The presence of novel epitopes raises the concern 

that epitope spreading could ensue leading to breaking of tolerance to the fully 

human portions of the molecule and the generation of antibodies directed to the 

endogenous human protein. Thus, the full length of the hLF-r protein should be 

sequenced and not just the N-terminus. The primary data should be submitted for 

review by FDA. N-terminal sequencing may be acceptable as a release test for 

identity, but not as a test for determination of sameness to human LF. 

In addition, alternative or reduced glycosylation, as evidenced in the 

Ventria product could contribute to immunogenicity as glycosyl groups present in 

the endogenous protein may shield protein epitopes from access by the immune 

system, and changes in sugars may lead to exposure of cryptic epitopes and the 

generation of an immune response (Sinclair A and Elliot S 2005. J. Pharm Sci). 

Further, the presence of the plant glycans α1,2 xylose; β1,3 fucose on th hLF-R, 

could facilitate the breaking of tolerance to the endogenous human protein via 

collaboration of the plant glycan specific Th cells and autoreactive LF specific B 

cells, or via the IgE antibodies themselves, which in binding to antigen, may 

facilitate epitope spreading so that antibodies are generated to conserved human 

LF determinants (Bardor M et al 2003. Glycobiology). 

Similarly, for lysozyme produced in transgenic rice, even if it is allegedly 

not glycosylated (this needs to be confirmed through appropriate studies by 

Ventria), there may be post-translational modifications imposed by the rice 

expression system that may cause truncations, oxidation, deamidation, 

aggregation or other product related impurities, which may predispose to immune 

responses. As mentioned above, such modifcations leading to enhanced 
immunogenicity have been previously observed (Prescott V et al 2005. J. Agric 

and Food Chem) 

4. Testing: 

It should be pointed out that the failure to perform clinical trials that validate the 

safety of these proteins in infant formulas violates key principles set forth by the 

National Academy of Sciences regarding the evaluation of the safety of new ingredients 

in infant formulas: “Infant Formula: Evaluating the Safety of New Ingredients”, published 

in 2004(http://www.nap.edu/catalog/10935.html). This guideline underscores: 1) the 

unique vulnerability of infancy, 2) that infant formulas are consumed by the vast 

majority of infants and are the sole source of nutrition for a large segment of infants up 

to the first 6 months of life, 3) that manufacturers are increasingly interested in adding 

new ingredients to formulas in an attempt to mimic the perceived and potential benefits 

of human milk and finally, that 4) existing guidelines and safety regulations lack clarity 

and completeness in adequately addressing the unique growth and development 

requirements of infants and the vast diversity of potential new ingredients. In this 

guidance, it specifically states that though the “GRAS process is rigorous, flexible, 

credible and transparent..., its application does not clearly address possible 

concerns for the multitude of potential new ingredients in infant formulas.... 

including those derived from novel sources or processes (e.g. products of 

fermentation or biotechnology)”. The hLF-R and hLZ-R products clearly fall into the 

category of “new ingredients derived from novel sources”. It further specifically states 

that allergenicity is a factor that should be considered in a safety assessment: “Other 

factors that should be considered for safety are: tolerance, allergenicity, impact 

of gastrointestinal flora .....”. In that regard, there have been no evaluations of the 

allergenicity or immunogenicity of hLZ-R and hLF-R despite the presence on lactoferrin 

of plant glysocsyl groups known to be immunogenic/allergenic. This guidance clearly 

advocates for extensive testing of these proteins for their capacity to induce allergic and 

autoimmune responses to both rice produced and to the endogenous human LF and LZ 

prior to widespread use. The document describes a hierarchical approach to such 

evaluations and lists as the first two elements to be considered the “reversibility of 

potential harmful effects and the severity and consequences of adverse effects”. Allergic 

responses may be severe, life-threatening and not subject to elimination by standard 

immunotherapy. Also, they may be associated with vasculitis (). The document further 

recommends safety assessments of Organ Systems, Neurobiological Development and 

Behavior and specifically states that “..the committee recommends a two level 

assessment approach to assess organ, immunological and endocrinological systems”. It 

goes on to state that “In addition, some organ systems (e.g. immune and endocrine) are 

immature at birth; every effort must be made to ensure that ingredients new to infant 

formulas will not affect the development of these systems or expression of their 

function”. An autoimmune response that neutralizes LF or LZ could have a profound 

effect on the innate immune system (Welsh et al 2002 Nature), of which these factors 

are critical components, and could engender a suboptimal microbial gut flora with 

unknown consequences, both short and long term. 
We are puzzled as to the justification for the designation of “Generally 

Recognized as Safe”, as it is clearly not evidence based. In fact, hLF-R has only 

been administered to 47 children with diarrhea in Peru (45 of whom completed 

the study) (Zavaleta et al 2007 2007 J. Ped. Gastro and Nutr.44:258) and a total 

of 4 healthy females (Lonnerdal 2006 Am J Clin Nutr) who were dosed for 42 

days in the USA, while hLZ-R was only administered to children in the Peruvian 

study (Zavaleta et al 2007). Neither study was performed under IND and 

immunogenicity, including assessment of allergy was not evaluated. Indeed, the 

Peruvian study was followed by allegations of malpractice by the Peruvian 

Association of Physicians and the Peruvian Association for Human Rights 

according to the local press. 

Additionally, we think that there are implicit and potentially explicit drug 

claims regarding addition of these factors to the formulas mentioned: that they 

will either prevent infection with microbes causing diarrheal illness (presence in 

infant formulas), or enhance the recovery from such infection (oral rehydration 

solutions). These claims are based on the highly criticized clinical trial in which 

the sponsor purported to demonstrate enhanced recovery from diarrheal illness 

in Peruvian children (Zavaleta et al 2007.). They were further publicized on the 

Ventria website: “May 1, 2006: A Breakthrough for Second Leading Killer of 

Children Under Five a Medical Food for Acute Diarrhea”. A In press release it 

was stated that “Ventria believes that addition of Lactiva (rhuLF) and Lysomin 

(rhuLZ) to oral rehydration solutions may help improve the health of children 

suffering from diarrhea.” As explicit, but unverified claims have been made, these 

products must be studied for safety and effectiveness, particularly in the ORS 

setting. 

Further reason not to approve the GRAS designation of these products 

comes from the fact that by US laws and regulations, these products fall under 

the definition of “biological products” as they are analagous to human proteins 

present in multiple body fluids including serum. As interpreted in 21CFR600.3, 

which states that a biological product means any virus, therapeutic serum, toxin, 

anti-toxin, or analagous product applicable to the prevention, treatment, or cure 

of diseases or injuries of man, rice produced LF and LZ are biological products 

and require study under IND. Indeed, recombinant human lactoferrin products, 

produced in aspergillus are currently in clinical trials for presumed 

immunomodulatory properties in the settings of cancer and wound healing, and 

have been studied in the past for their effects on pathogenic microbes in the G.I. 

tract and on wound healing. 

In summary, we disagree with the draft FDA letter stating that there are 

“no concerns about autoimmune responses to hLF-r as a result of “allogenicity” 

or plant glycosylation because of the limited duration of use,“one to fourteen 

days”. This neglects the fact that these products will assuredly be used 

repetitively and not just on a one time basis (at least three times per year is an 

estimate). Moreover, if tolerance to endogenous human lactoferrin is broken, 

there may not be a further requirement for exposure to rice produced hLF-r or 

hLZ-r to perpetuate the response, as exposure to endogenous LF or LZ may 

perpetuate the response.. 
Thus, given the concerns listed above, and most importantly, given that these 

recombinant proteins have only been tested in a very small number of patients in a 

non-rigorous fashion, substantial risk exists and thus widespread uncontrolled use in the 

population, including healthy term and preterm infants, and in children recovering from 

diarrhea, likely comprising millions of children, is not justified. Should adverse events 

develop when this product is in widespread use, it could be devastating. In this case, 

risk can be mitigated to a very low level based on adequately sized and powered clinical 

trials assessing prevention of or time to recovery from infection. 
DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service 

 Food and Drug Administration 

1401 Rockville Pike 

Rockville, MD 20852-1448 

Memorandum 

To: Dr. Stephen F. Sundlof, D.V.M., Ph.D. 

 Director, CFSAN 

From: Ronald L. Rabin, M.D., DBPAP 

Office of Vaccines Regulation and Research, CBER 

By Ronald L. Rabin, M.D. at 2:47 pm, Jun 27, 2008

Through: Jay E. Slater, M.D., Deputy Director, DBPAP 

Office of Vaccines Regulation and Research, CBER 

Re: GRAS designation for recombinant human lysozyme and lactoferrin 

Date: June 27, 2008 

Ventria Biosciences proposes use of recombinant human lactoferrin (rhLF) and/or lysozyme (rhLZ) in 

an oral rehydration formula for infants with diarrhea. These two recombinant proteins are not perfectly 

identical to their endogenous counterparts, as there may be differences in glycosylation or other posttranslational modifications that in turn may be novel epitopes for T cell recognition and activation. 

While infectious diarrhea may be due to active secretion of solutes (and the water that follows) or an 

impairment in absorption of solutes (and water), the mucosal injury associated with infection and 

inflammation is frequently if not always accompanied by increased permeability of large molecules 

from the intestinal tract into the blood stream. Since infants may experience 3-6 episodes of diarrhea 

per year for the first two years of life, inclusion of rhLF and rhLZ in oral rehydration fluids has the 

potential for repeated intermittent systemic exposure to neoantigens. 

Repeated intermittent exposure is precisely the scenario that is known to induce allergic responses to 

exogenous proteins. Once a T cell response to a neoantigen is established, there is potential for the 

process of "antigenic spread" to other parts of the recombinant protein that are identical to their 

endogenous counterparts. Therefore, if the neoantigenic part of rhLF and rhLZ induce an allergic 

response, it may spread to endogenous LF and/or LZ. Antigenic spread is also associated with induction 

of autoimmunity that when directed, for example, against pancreatic islet beta cells, ultimately causes 

Type I diabetes mellitus. 

Therefore, it is our opinion that these two recombinants not be considered GRAS, as they have the 

potential of inducing in infants allergic responses to rhLF and/or rhLZ first, followed by an allergic 

response to their endogenous counterparts, and possibly may also induce autoimmunity. 
 

 

 

 

 

 

 

 

 

Page 1 of 1 

Fasano, Jeremiah 

From: Scott Deeter [sdeeter@ventria.com] 

Sent: Tuesday, July 15, 2008 1:09 PM 

To: Fasano, Jeremiah 

Subject: Plant Glycan - Lactoferrin GRAS 

Dear Jeremiah: 

The following paper showing the work we sponsored with Ronald van Ree and Adriano Mari regarding plant glycans and lactoferrin 

was published. As you know, Ronald was on our GRAS panel and is one of the leading experts in the world in this area of science and 

immunology. This data was previously discussed and presented as a poster session and I have made Rick Goodman aware of this 

paper, as he had not seen the poster presentation. 

I think this reinforces his presentation at the Toxicology Forum and would confirm the safety of Lactoferrin from rice as a GRAS 

ingredient for foods, especially for pediatric populations. 

See below: 

Mari A, Ooievaar-de Heer P, Scala E, Giani M, Pirrotta L, Zuidmeer L, Bethell D, van Ree R. 

Evaluation by double-blind placebo-controlled oral challenge of the clinical relevance of IgE antibodies against plant glycans. 

Allergy. 2008 Jul;63(7):891-6. 

PMID: 18588555 

Thank you, 

Scott E. Deeter 

President & CEO 

Ventria Bioscience 

(970) 420-9598 

www.Ventria.com 

Your Life. Our Passion. 

This message (including any attachments) may contain confidential information intended for a specific individual and purpose, and is protected by 

law. If you are not the intended recipient, you should delete this message. Any disclosure, copying, or distribution of this message, or the taking of 

any action based on it, is strictly prohibited. 

9/16/2008 
 

 

 

 

 

 

 

 

Page 1 of 2 

Fasano, Jeremiah 

From: Scott Deeter [sdeeter@ventria.com] 

Sent: Tuesday, July 15, 2008 8:45 PM 

To: McConagha, William; Commissioner FDA 

Cc: Mattia, Antonia; Fasano, Jeremiah 

Subject: Ventria GRAS - Meeting Follow-up 

Dear Commissioner Von Eschenbach and Mr. McConagha: 

I wanted to follow-up on our GRAS status and let you know that I attended the Toxicology Forum, which hosted the session: “human 

proteins as food ingredients”. Thank you for the heads-up regarding this meeting. Below is a recap of the meeting from our 

perspective and a request for the Commissioner to intervene so that sound science guides the decision-making process at FDA, 

rather than hypothetical or un-related issues. 

Toni Mattia (FDA/CFSAN) chaired the session and there were six speakers on the agenda with two speakers from FDA (Jeremiah 

Fasano-CFSAN and Daniela Verthelyi – Div. of Therapeutic Proteins). Jeremiah invited the speakers and arranged the session. 

Although he invited several members that were also members of the breastmilk protein (lactoferrin and lysozyme) GRAS panels, 

none were available to attend and speak at this meeting due to scheduling conflicts with the July 4th Holiday. I believe if they had 

been present, the level of scientific understanding regarding the subject would have been much improved. 

Interestingly, several of the speakers mentioned the published work of several of the breastmilk protein GRAS panel members, so 

the GRAS panel was well represented in that regard. Each speaker was provided 20 minutes plus 10 minutes of Q&A. The topic was 

introduced by Jeremiah Fasano. Jeremiah requested the audience to provide input regarding the GRAS status of products in this 

category. There was not a specific mention of the benefits of adding these ingredients to foods, nor was there a specific mention of 

which proteins are proposed to be added, although the audience was directed to FDA’s GRAS notices website where Ventria’s GRAS 

notifications for the breastmilk proteins, lactoferrin and lysozyme, are listed. 

Overall, the quality of discussion and dialogue at this meeting was introductory in nature and did not approach the scientific rigor 

that was employed by the GRAS panel when they reviewed the published data and science and made their conclusion that these 

proteins are GRAS. The issues that were relevant to the safety that were discussed at this meeting were thoroughly considered by 

the GRAS panel prior to reaching their conclusion. In this respect, the meeting was a confirmation that the GRAS panel addressed 

the relevant issues regarding safety of these proteins in foods and, in our view, this should clear the pathway for the completion of 

the GRAS review with a “no further questions” letter. 

Two presenters from biopharmaceutical companies discussed the safety considerations of injectible biopharmaceuticals. They 

mentioned areas of concern for injectible biopharmaceuticals including injection site reactions, changes in formulation of injectibles, 

and immunogenicity related to biologic drugs delivered by injection. Neither of these presenters had data related to oral delivery of 

proteins, and were quite unfamiliar with the scientific literature in this area. They both mentioned that they were not well suited to 

address the safety issues presented by proteins used in foods, as this was the first time they had been asked to review the topic. The 

audience also questioned the applicability and relevance of data that was presented by these speakers when considering safety of 

products for oral consumption. 

Another presenter briefly discussed lactoferrin and its application in human health, but spent most of his time discussing other 

human milk-derived proteins of interest for further development. 

Dr. Richard Goodman at FARRP (University of Nebraska), provided a clear approach to the safety assessment (suggested by FARRP) 

and considering the immunogenicity/allergenicity of protein-based foods. Dr. Goodman’s approach to the safety assessment of 

9/16/2008 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Page 2 of 2 

proteins as food ingredients was the only presentation to directly address the question raised by Jeremiah and Toni in the 

introduction. Dr. Goodman’s approach was consistent with the GRAS panel’s safety assessment and the safety conclusion by the 

GRAS panels regarding Ventria’s breastmilk protein products. 

Daniela Verthelyi, FDA-Div of Therapeutic Proteins mentioned several potential safety issues related to immunogenicity of injectible 

protein-based drugs. This is hardly relevant to oral consumption of proteins, as mentioned in Dr. Goodman’s presentation and as 

questioned by the audience at the meeting. Clearly, the safety issues for an injectible drug are quite unique due to this route of 

administration. Daniela claimed in her presentation that the safety issues could be the same, but she had no data or scientific 

literature to backup her assertion. Rather, it was a unfounded and hypothetical (at best) with no published scientific data to reach a 

meaningful or relevant hypothesis about the safety of oral consumption. 

After the session, a reception was held and myself and our VP of R&D introduced ourselves to Dr. Verthelyi. Very quickly, Dr. 

Verthelyi revealed her bias against the use of breastmilk proteins in foods and claimed that Ventria’s data was not strong enough to 

show benefit or safety. Of course, the issue currently being reviewed by FDA is the safety of these proteins in foods, not the 

efficacy/benefit. However, I felt compelled to describe the benefit of breastfeeding and the fact that millions of children are not 

breastfed for a variety of reasons, so improving infant formula with the addition of proteins found in breastmilk would be a 

significant benefit for pediatric nutrition. She claimed that Ventria did not have any human studies on this and no history of 

consumption. I mentioned that children have been consuming these proteins as part of breastmilk and also mentioned a recent 

published study in Journal of Pediatric Gastroenterology & Nutrition (Feb 2007) showing not only the safety of these proteins, but 

also the benefit of helping children with diarrhea to receive breastmilk proteins as part of a rehydration solution. The results were 

similar to those seen in children that have been breastfed. Daniela continued to claim that there were problems with our science 

and I asked her to explain, but she declined. When I repeated my request and suggested that we deserve an explanation, since she 

represents the FDA, she walked away from the conversation and would not address the question. 

This is a very concerning development for Ventria and the FDA. Out of concern for the process, I mentioned this interaction to 

Jeremiah Fasano and suggested that he share it with Toni Mattia. Jeremiah mentioned that he was “well aware” of the problem 

with Dr. Verthelyi, so I suspect this is an internal FDA issue and since the CFSAN group is separate from the Division of Therapeutic 

Proteins, resolution of this may require leadership from the Commissioner. 

From our perspective, it is very important that we use science to guide the regulatory process and decision-making utilizing currently 

available, published and credible science, rather than individual bias. 

Senator Harkin and other Congressional representatives have been informed of the above information. I look forward to following 

up with you on this issue so that we can move forward for the benefit of child health and nutrition. 

Very sincerely, 

Scott E. Deeter 

President & CEO 

Ventria Bioscience 

(970) 420-9598 

www.Ventria.com 

Your Life. Our Passion. 

This message (including any attachments) may contain confidential information intended for a specific individual and purpose, and is protected by 

law. If you are not the intended recipient, you should delete this message. Any disclosure, copying, or distribution of this message, or the taking of 

any action based on it, is strictly prohibited. 

9/16/2008 
 

 

 

 

 

 

 

   

  

                                     

                                               

                                         

                       

  

                                         

             

  

   

 

_______________________ 

Page 1 of 2 

Fasano, Jeremiah 

From: Fasano, Jeremiah 

Sent: Thursday, July 17, 2008 2:23 PM 

To: 'Scott Deeter' 

Subject: RE: Plant Glycan - Lactoferrin GRAS 

Mr. DeeterThank you for passing this on. I had seen a reference to the poster abstract a while back but was 

unable to readily obtain more information about it. I'll forward it to the team. 

Regards-

-Jeremiah Fasano 

Jeremiah Fasano, Ph.D. 

Consumer Safety Officer 

DBGNR/OFAS/CFSAN/FDA 

jeremiah.fasano@fda.hhs.gov 

Phone: 301-436-1173 

Fax: 301-436-2964 

HFS-255 

5100 Paint Branch Parkway 

College Park, MD 20740 

From: Scott Deeter [mailto:sdeeter@ventria.com] 

Sent: Tuesday, July 15, 2008 1:09 PM 

To: Fasano, Jeremiah 

Subject: Plant Glycan - Lactoferrin GRAS 

Dear Jeremiah:

The following paper showing the work we sponsored with Ronald van Ree and Adriano Mari regarding plant glycans and

lactoferrin was published. As you know, Ronald was on our GRAS panel and is one of the leading experts in the world in this

area of science and immunology. This data was previously discussed and presented as a poster session and I have made Rick

Goodman aware of this paper, as he had not seen the poster presentation.

I think this reinforces his presentation at the Toxicology Forum and would confirm the safety of Lactoferrin from rice as a

GRAS ingredient for foods, especially for pediatric populations.

See below:

Mari A, Ooievaar-de Heer P, Scala E, Giani M, Pirrotta L, Zuidmeer L, Bethell D, van Ree R. 

Evaluation by double-blind placebo-controlled oral challenge of the clinical relevance of IgE antibodies against plant glycans. 

7/17/2008 
  

 

  

Page 2 of 2 

Allergy. 2008 Jul;63(7):891-6. 

PMID: 18588555 

Thank you, 

Scott E. Deeter 

President & CEO 

Ventria Bioscience 

(970) 420-9598 

www.Ventria.com 

Your Life. Our Passion. 

This message (including any attachments) may contain confidential information intended for a specific individual and purpose, and is 

protected by law. If you are not the intended recipient, you should delete this message. Any disclosure, copying, or distribution of this 

message, or the taking of any action based on it, is strictly prohibited. 

7/17/2008 
 

 

 

 

Agennix Incorporated 

Eight Greenway Plaza, Suite 910 

Houston, Texas 77046 

Telephone (713) 552-1091 

Facsimile (713) 552-0795 

www.agennix.com 

August 14, 2008 

Laura M. Tarantino, Ph.D. (HFS-200) 

Director, Office of Food Additive Safety 

Center for Food Safety and Applied Nutrition 

Food and Drug Administration 

Room 3044, University Station 

5100 Paint Branch Parkway 

College Park, Maryland 20740 

Re: Request for Legal Conclusion that Recombinant Human Lactoferrin from 

Transgenic Rice GRN No. 000235 (resubmission of GRN No. 000162) Submitted by 

Ventria Bioscience is not Generally Recognized as Safe (GRAS) based on a “Severe 

Disagreement” among Qualified Experts 

Dear Dr. Tarantino: 

On behalf of Agennix, Inc. (Agennix) 1/, we write to urge the Food and Drug 

Administration (FDA) to reach the legal conclusion that recombinant human lactoferrin (rhLF) 

from transgenic rice is not generally recognized as safe (GRAS) for use in oral rehydration 

solutions and pediatric medical foods, due to a “severe disagreement” among qualified experts as 

to whether it is safe for these food uses. For that reason alone, GRN No. 235, submitted by 

Ventria Biosciences (“Ventria”) to FDA’s Center for Food Safety and Applied Nutrition 

(CFSAN), should be denied—based solely on legal grounds. 

1/ Agennix is a Houston, Texas-based biotechnology company and is the pioneer innovator of 

recombinant human lactoferrin as a pharmaceutical product. Agennix began clinical testing of rhLF in 1996 

under the FDA’s investigational new drug (IND) program. Agennix has completed blinded, placebocontrolled Phase II clinical trials with rhLF that met their primary endpoints in indications including non-small 

cell lung cancer and diabetic foot ulcers. In advanced renal cell carcinoma (RCC), rhLF has also been 

successfully tested in a Phase II open label trial to evaluate its effects in patients whose disease had progressed 

after receiving at least one prior regimen of systemic therapy. Additionally, the Company has initiated an 

NIH-funded, randomized, placebo-controlled, multi-center Phase II trial in patients with severe sepsis. 

Agennix obtained FDA Orphan Drug designation for rhLF for indications including graft versus host disease 

(Aug. 2003), non-small cell lung cancer (Aug. 2007), and renal cell carcinoma (Sept. 2006). Agennix also 

obtained Fast Track designation from the FDA for two different non-small cell lung cancer (NSCLC) 

indications (first-line in combination with chemotherapy [Sept. 2006] and third-line as monotherapy [Oct. 

2007]), and is starting Phase III trials in these indications. Agennix obtained approval of a Special Protocol 

Assessment (SPA) from the FDA for its first-line trial of rhLF in combination with chemotherapy in NSCLC 

patients (Nov. 2008). 
 

 

 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 2 

Agennix has already filed extensive scientific comments regarding significant, 

unresolved safety issues with the use of rhLF in food. 2/ Those submissions were supported by 

the opinions of 14 prominent scientific and medical experts that rhLF is not GRAS for these food 

uses. These scientific and medical experts are from disciplines directly applicable to the safety 

assessment of rhLF—including the fields of glycobiology, immunology, and medicine, 

particularly pediatric medicine. Moreover, these scientific and medical experts are leaders in 

their respective fields, based on their many years of experience, prestigious academic posts, 

extensive publications, and numerous positions on government panels and editorial boards. They 

are regularly sought after as speakers at national and international conferences precisely because 

they are thought leaders whose opinions are highly respected. 

Today’s submission is tantamount to a “motion for summary judgment” because there are 

no material facts in dispute (i.e., it is a matter of record that there are two groups of experts 

expressing diametrically opposing views) and so the Agency may rightfully decide this issue as a 

matter of law. Furthermore, this letter is based solely on the third prong of the GRAS test— 

namely, that there be a consensus among qualified experts that the food ingredient is safe. 3/ We 

are asking FDA to determine, as a matter of law, that rhLF from transgenic rice is not GRAS for 

use in oral rehydration solutions and pediatric medical foods because Ventria has failed to 

demonstrate that there is a scientific consensus among qualified experts that the substance is safe. 

The law is clear: a substance must meet all three prongs of the GRAS test to qualify as 

generally recognized as safe. An Agency determination that any one of the three elements is not 

met eliminates the need to evaluate and resolve the other two. As described below, Ventria so 

clearly fails to meet its burden of establishing a scientific consensus among experts that its 

GRAS notification for its rice-based rhLF must be denied on this basis alone. 4/ 

2/ Agennix submitted to CFSAN its original Scientific Assessment on GRN No. 000162 on November 9, 

2005, a subsequent response to additional Ventria comments on September 11, 2006, and a recent 

Supplemental Scientific Assessment to address new data submitted by Ventria regarding a South American 

pediatric rhLF clinical trial on June 3, 2008. 

3/ This letter does not rely on either of the first two prongs of the GRAS test—namely, that there be 

technical evidence of safety and that the data relied upon be publicly available. Those prongs are addressed in 

previous comments filed by Agennix to the scientific staff in CFSAN. Because all three prongs are required 

for a GRAS determination, the Agency does not need to reach a conclusion on the first two prongs if FDA 

determines, as a matter of law, that the third prong of expert consensus is not met. 

4/ Should the FDA agree that there is a severe disagreement among qualified experts, not only would 

there be no need for FDA to reach a conclusion on the complex scientific issues surrounding its technical 

evidence of safety, but FDA also would not have to reach a conclusion on the effect of Section 912 of the Food 

and Drug Administration Amendments of 2007 (FDAAA) on Ventria’s GRAS notification (see letter of 

October 31, 2007 from Joseph A. Levitt, Counsel to Agennix). 
 

 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 3 

I. The GRAS Standard Requires A Consensus Among Qualified Experts 

As you are aware, a substance added to food is a “food additive” for which FDA premarket approval is required unless the substance is GRAS or qualifies for another statutory 

exemption. The intended use of a substance is GRAS if it is— 

generally recognized, among experts qualified by scientific training and 

experience to evaluate its safety, as having been adequately shown 

through scientific procedures (or, in the case of a substance used in food 

prior to January 1, 1958, through either scientific procedures or experience 

based on common use in food) to be safe under the conditions of its 

intended use . . . 5/ 

As the statutory language states, a GRAS determination may be based on “scientific 

procedures.” FDA has advised that a GRAS determination based on scientific procedures 

requires three elements: 

1. Evidence that a substance is safe for its intended use; 

2. A basis for concluding that such evidence of safety is generally available; 

and 

3. A basis for concluding that such evidence of safety is the subject of scientific 

consensus among qualified scientific experts. 

FDA refers to the first element as “technical evidence of safety”; the second and third 

criteria collectively constitute the “common knowledge” element of the GRAS standard. All 

three elements must be demonstrated or the GRAS notice is considered incomplete. 6/ Further, 

the common knowledge elements of scientific consensus and publication apply to all of the 

evidence that is the basis for the determination of safety. 7/ 

Technical evidence of safety requires a showing that “there is a reasonable certainty in 

the minds of competent scientists that the substance is not harmful under the intended conditions 

of use.” 8/ This is frequently paraphrased as demonstrating that there is a “reasonable certainty 

of no harm.” The second element, general availability, requires publication of key data or 

information in peer-reviewed scientific journals, general reference materials, textbooks, or other 

5/ FFDCA § 201(s). 

6/ 62 Fed. Reg. at 18937, 18948 (Apr. 17, 1997) (stating “A notice summary that fully describes the 

technical evidence of safety, but does not provide a basis to conclude that the technical evidence is generally 

available and accepted [by experts], would be incomplete”). 

7/ Id. 

8/ 21 C.F.R. § 170.3(i); 62 Fed. Reg. at 18948. 
 

 

 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 4 

appropriate sources. 9/ Although we believe that Ventria also fails on the first two counts of the 

GRAS standard, this submission is limited to the third prong of the GRAS standard—the 

common knowledge element of scientific consensus among qualified experts. 

II. A Scientific Consensus Does Not Exist If There Is A “Severe Disagreement” Among 

Qualified Scientific Experts 

It is well-settled law that a “consensus” of qualified experts does not exist if there is a 

“severe disagreement” among such experts as to whether the food ingredient is safe for its 

intended use. The very fact that Agennix has identified 14 prominent, highly qualified scientific 

and medical experts who all believe there are significant, unresolved safety issues and that rhLF 

has not been shown to be safe for its intended uses, unequivocally demonstrates that a “severe 

disagreement” exists on this pivotal point. Accordingly, Ventria has failed to demonstrate that 

the safety of its proposed uses of rhLF from rice is the subject of expert consensus. 

FDA’s 1997 proposed rule on “Substances Generally Recognized as Safe” provides clear 

guidance on criteria for the basis of concluding expert consensus, 10/ and that the existence of a 

“severe conflict’ among experts will preclude a GRAS determination. 11/ 

As discussed in FDA’s GRAS proposal and the pertinent case law, a proponent of a 

GRAS claim bears the burden of establishing expert consensus (i.e., that experts “generally” 

consider the ingredient at issue to be safe). The courts and FDA have interpreted this to mean 

that, although a mere divergence of views will not necessarily preclude GRAS status (as “even 

properly conducted studies may produce disagreement” 12/) a “severe conflict” of expert opinion 

will prevent a finding of general recognition. 13/ 

Although there is no bright-line test for identifying what constitutes a “severe conflict,” 

courts have readily found a “severe conflict” to exist after evaluating the facts at hand. In one 

case, even where the proponent of a GRAS claim presented the testimony of seven experts 

supportive of GRAS status, general recognition was found to be lacking in light of persuasive 

9/ 21 C.F.R. § 170.30(b); 62 Fed. Reg. at 18942-43. 

10/ 62 Fed. Reg. at 18948-49. 

11/ See 62 Fed. Reg. at 18939 (citing United States v. An Article of Drug . . . 4,680 Pails, 725 F.2d 976, 

990 (5th Cir. 1984); Premo Pharma. Labs. v. United States, 629 F.2d 795, 803 (2d Cir. 1980). Significantly, 

according to the Proposed Rule, “an ongoing scientific discussion or controversy about safety concerns . . . 

would make it difficult to provide a basis about the safety of a substance for an intended use.” Id. at 18949. 

12/ See, e.g., United States v. Articles of Food and Drug . . . “Coli-Trol 80,” 518 F.2d 743, 746 (5th Cir. 

1975). 

13/ 62 Fed. Reg. at 18939 (citing United States v. Articles of Drug . . . 5,906 boxes, 745 F.2d 105, 119 n. 

22 (1st Cir. 1984); 4,680 Pails, 725 F.2d at 990; Coli-Trol 80, 518 F.2d at 746 (5th Cir. 1975); United States v. 

Articles of Drug . . . Promise Toothpaste, 624 F. Supp. 776, 782 (N.D. Ill. 1985), aff’d 826 F.2d 564 (7th Cir. 

1987)). 
 

 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 5 

opposing views offered by “several” government experts. 14/ In another case, “sharply divided 

testimony” was found to present a severe conflict of opinion. 15/ Expert testimony critical of 

general recognition in that case suggested that the studies presented did not prove safety or meet 

other criteria contained in FDA’s regulations. 16/ Another court failed to find a consensus where 

there was a “sharp difference of opinion” between experts regarding the methods and results of 

the available studies. 17/ Although these and other cases addressing expert consensus involve 

drug products, the expert consensus standard is exactly the same for both food and drugs. 18/ 

For both food products and drugs, the key is whether there is a “severe disagreement” of views 

among qualified experts. 

As described further below, these judicial characterizations of “sharply divided 

testimony” and “sharp difference of opinion” perfectly describe the current case—i.e., whether 

rhLF is generally recognized as safe for its intended food uses. The experts presented by Ventria 

express one view, and the experts presented by Agennix express the very opposite view. Indeed, 

it is hard to imagine a scenario where the experts are any more “sharply divided.” In such cases, 

the courts have consistently found that expert consensus does not exist, and FDA should reach 

the same conclusion here. 

Expert credentials play an important role when assessing whether expert consensus exists. 

In one case evaluating the status of a drug for a particular treatment, the court gave great weight 

to the opinions of several chairmen of leading medical departments from that specialty area. The 

court stated that “it cannot be denied that the affidavits of five of the leading doctors in the field 

which deny general recognition creates more than a ‘mere’ conflict . . . [i]t is inconceivable that a 

drug such as this could be considered generally recognized in the face of such learned nonrecognition.” 19/ 

Once again, the court has very much described the current case. As detailed below, and 

reinforced in the collection of expert CVs already on file with CFSAN 20/, the 14 scientific and 

medical experts presented by Agennix have national and international stature. They hold 

prestigious academic posts, direct cutting edge scientific and medical centers, serve on important 

14/ See, e.g., Pails, 725 F.2d at 990 (holding that presentation by the United States of the views of 

“several experts” that a drug was not generally recognized as effective showed a “severe conflict” in the expert 

testimony and precluded general recognition). 

15/ United States v. An Article of Drug . . . X-Otag Plus Tablets, 441 F. Supp. 105, 113-114 (D. Colo. 

1977). 

16/ Id. at 113. 

17/ Premo Pharma. Labs., 629 F.2d 795 at 804. 

18/ See, e.g., 62 Fed. Reg. at 18938-18939 (citing drug and food precedent in discussion of meaning of 

GRAS standard under section 201(s) of the FFDCA). 

19/ United States v. An Article of Drug . . . “Mykocert,” 345 F. Supp. 571, 575 (N.D. Ill. 1972). 

20/ These CVs were all submitted to CFSAN with the June 3, 2008 Supplemental Scientific Assessment. 
 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 6 

governmental committees, and publish extensively in leading journals. In short, they are 

quintessential examples of “leading doctors [and scientists] in the field” so that a finding of 

GRAS is virtually precluded “in the face of such learned non-recognition.” 

Agennix, the clear worldwide leader in research, development and production of rhLF, 

has consulted leading national and international experts on lactoferrin and issues relevant to the 

safety of rhLF from transgenic rice. These experts are primarily from the fields of: (a) 

glycosylation/glycobiology; (b) immunology; and (c) medicine, including pediatric medicine. 

Included among these are experts who have conducted research directly with recombinant human 

lactoferrin, so they have first hand knowledge of its safety profile. These 14 highly qualified 

experts have expressed serious and specific concerns regarding the safety of the Notifier’s 

proposed uses of rhLF from rice, demonstrating a “severe conflict” with the expert opinions and 

conclusions submitted by Ventria. We feel strongly that all of our experts are qualified to opine 

on various issues related to the GRAS status of rhLF from rice and their credentials speak for 

themselves. These are notable opinion leaders in various fields of science and medicine 

expressing widely-held safety concerns. We believe their opinions—as contrasted to those of 

Ventria’s experts—demonstrate there is a “severe disagreement” among qualified experts and 

that there is no “consensus” of the scientific community on the safety of rhLF for its intended 

uses. 

III. Agennix has Provided the Opinions of 14 Prominent Physicians and Scientists that 

Rice-based Recombinant Human Lactoferrin is Not GRAS. 

Agennix has provided FDA with the opinions of 14 prominent physicians and scientists 

that rhLF is not GRAS for its intended uses. These experts were selected based on their 

recognized subject matter expertise, professional reputation, and experience in areas that have a 

high degree of relevance to the safety, biologic activity, and mechanism of action of rhLF, 

including glycobiology, immunology, and medicine (including pediatrics). These experts 

include renowned professors at universities in the United States, Europe and Australia, chairs of 

their respective departments or group, directors of scientific or medical centers, and practicing 

physicians. Collectively, they have published over 1,500 scientific articles, abstracts or book 

chapters, including a number of studies on recombinant human lactoferrin. The background and 

experience of each of these 14 experts may be summarized as follows: 

1. Richard D. Cummings, Ph.D.: Dr. Cummings is a preeminent leader in the field 

of Glycobiology with over 30 years of research and academic experience. He is William 

Patterson Timmie Professor and Chair of the Department of Biochemistry at Emory University 

School of Medicine. He and his research labs have made numerous significant discoveries and 

contributions at the forefront of this emerging field. Dr. Cummings founded and directed two 

major centers for Glycobiology at Emory University School of Medicine and the University of 

Oklahoma Health Sciences Center. He is co-editor of the first textbook on Glycobiology. Dr. 

Cummings has published over 170 peer-reviewed articles, over 30 review articles, eleven 

textbook chapters, and owns 27 different U.S. patents. 
 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 7 

Dr. Cummings is an internationally known lecturer and speaker on issues related to 

Glycobiology. He has been an invited speaker of over 125 organizations and institutions. He 

has organized or chaired various national and international meetings and symposia on glycomics. 

He is a former President of the Society of Glycomics and is active in numerous professional 

societies. Dr. Cummings has been awarded various prestigious research fellowships from the 

National Institutes of Health (NIH) and National Science Foundation. He has served in an 

editorial capacity on ten different scientific journals. Dr. Cummings and his labs have been the 

recipient of seven current and seventeen prior NIH research grants, and twelve other research 

grants from various public and private institutions. He has provided government service in many 

different roles as an NIH reviewer, panel member, and study section member. 

2. James Michael Pierce, Ph.D.: Dr. Pierce is a Professor of Biochemistry and 

Molecular Biology at the University of Georgia and Director of the University of Georgia Cancer 

Center. He is a tenured professor with over 25 years in academia. Dr. Pierce’s research focuses 

on the function of complex carbohydrates in human health with an emphasis on cancer 

progression and diagnosis. He has conducted extensive research in the area of glycobiology. He 

is the editor of the Handbook of Glycomics and an officer in the Society of Glycobiology. Dr. 

Pierce’s work has been supported by the NIH and the National Cancer Institute. He has 

published over 65 peer-reviewed articles. He has served as a reviewer for various NIH, NCI, and 

American Cancer Society study sections and project reviews. Dr. Pierce is also a reviewer at 

leading publications including Nature, Biochemistry, Gene, Glycobiology, Glycoconjugate 

Journal, and the International Journal of Cancer. Dr. Pierce has been an invited speaker or 

lecturer at over 70 major seminars/symposia in the U.S. and abroad. He also holds eleven U.S. 

patents. 

3. Irma van Die, Ph.D.: Dr. van Die is Head of the Glycoimmunology Group in the 

Department of Molecular Cell Biology & Immunology at Vrije University Medical Center in 

Amsterdam. She has written over 100 publications in the areas of glycobiology and immunology 

and has been a professor for over fifteen years. Dr. van Die has done extensive work for various 

sections of the Netherlands Organization for Scientific Research (NWO), the Dutch government 

organization that funds research at top universities and institutes. She is a regular reviewer for 

major journals including: European Journal of Biochemistry, Glycoconjugate Journal, 

Glycobiology, Journal of Biological Chemistry and a grant reviewer for the NWO. She has been 

a board member and is the current Secretary of the Dutch Society of Glycobiology, and is a 

member of various other professional societies. Dr. van Die’s research is supported by numerous 

major public and private grants. Research at her glycoimmunology department has made a 

significant contribution to the present understanding and knowledge of glycan function. 
 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 8 

4. Hubertus Schellekens, M.D.: Dr. Schellekens is a professor of Pharmaceutical 

Sciences at Utrecht University in the Netherlands. Dr. Schellekens has written more than 200 

peer-reviewed journal articles concerning the preclinical development of biotechnology-derived 

therapeutic proteins. His most recent work focuses on immunogenicity of therapeutic proteins 

and biosimilars. He is the editor-in-chief of Biotherapy. Dr. Schellekens is very active in the 

Netherlands Commission on Genetic Modification (COGEM), serving as chairman of several 

subcommittees. COGEM provides scientific advice to the government on the risks to human 

health and environment regarding the production and use of bioengineered compounds. He also 

serves as an expert in rDNA pharmaceuticals for the European Medicines Agency (EMEA), and 

as chairman of the Dutch Society of Microbiology’s Committee for Biological Safety and deputy 

chair of its Committee on Biotechnology in Animals. 

5. Arno Kromminga, Ph.D.: Dr. Kromminga serves as Director of Immunology at 

the Institute for Immunology, Clinical Pathology, and Molecular Medicine (IPM) in Hamburg, 

Germany. IPM’s work focuses on resolving immunogenicity issues by antibody detection 

against biopharmaceuticals using a broad range of methods and different assay formats. It is 

dedicated to the development, validation and application of innovative methods in molecular and 

immunological diagnostics including immunogenicity. He is an international leader in the field 

of immunology. Dr. Kromminga has written over 25 publications and presented over 40 lectures 

at major symposia around the world. 

6. Michael P. Sherman, M.D.: Dr. Sherman is a Professor of Pediatrics at Southern 

Illinois University School of Medicine and Professor Emeritus at the University of California, 

Davis. He has practiced academic medicine for over thirty years with a focus on neonatology. 

Dr. Sherman has a longstanding interest in lactoferrin and is uniquely qualified to express 

medical opinions on the use of rhLF in humans and the potential risks to children and neonates (a 

proposed use by Ventria). 

Dr. Sherman’s research has been published in over 80 peer-reviewed publications. He 

has written 19 book chapters and holds two U.S. patents. He has been a reviewer or member of 

several NIH study sections, a reviewer for thirty-six scientific journals and a member of the 

editorial board of three journals. He has been an invited lecturer at over fifty conferences/ 

symposia since 1988. A sample of the subjects he has lectured on includes: “Lactoferrin and 

Neonatal Gut Related Infections,” “Lactoferrin and Macrophage Biology and Biochemistry,” and 

“Neonatal Small Bowel Epithelia: Fortifying Anti-bacterial Defense with Lactoferrin and 

Lactobacillus GC.” Dr. Sherman has obtained NIH and Children’s Miracle Network grants for 

research specific to lactoferrin. 

Dr. Sherman has published or submitted manuscripts for publication for several articles 

on various issues related to lactoferrin. Some of these articles include: “Effect of lactoferrin and 

lactobacillus prophylaxis on small bowel infection by Escherichia coli in newborn rats,” 

“Lactoferrin-enhanced Anoikis: A Defense against Neonatal Necrotizing Enterocolitis,” 

“Lactoferrin protects neonatal rats from gut-related system infection,” and “Lactoferrin and 

recognition of enteric bacteria by rat bronchoalveolar macrophages.” In addition, he has 

presented twenty-eight abstracts or poster presentations concerning lactoferrin. 
 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 9 

7. E.D. Weinberg, Ph.D.: Dr. Weinberg is Professor Emeritus in Microbiology at 

Indiana University and the Scientific Advisory Board Chair for the Iron Disorders Institute. He 

was a professor for over 40 years for more than 15,000 students. He has published over 150 

research papers or book chapters. Two of his papers have been designated as Benchmark Papers 

in Microbiology. Dr. Weinberg has presented thirty-six invited lectures at national and 

international meetings and attended over forty invited seminars throughout the world. 

Dr. Weinberg has conducted important research on lactoferrin over decades and is 

particularly qualified to advise on the safety issues related to human use of rhLF. Three of his 

publications include: “Human lactoferrin: a novel therapeutic with broad spectrum potential,” 

“Therapeutic potential of human transferrin and human recombinant lactoferrin,” and “The 

therapeutic potential of lactoferrin.” 

8. Sidney E. Grossberg, M.D.: Dr. Grossberg is Walter Schroeder Professor of 

Microbiology and Molecular Genetics and Professor of Medicine at the Medical College of 

Wisconsin. He served as Chairman of the Department of Microbiology for thirty-one years and 

has been a medical professor for over fifty years. Dr. Grossberg has been published in over 170 

peer-reviewed publications. He has served as an advisor or reviewer for the National Cancer 

Institute, National Institute of Allergy and Infectious Diseases, the World Health Organization, 

and the National Board of Medical Examiners. His expertise includes microbiology and 

immunology. 

9. Marco van de Weert, Ph.D.: Dr. van de Weert is a professor in the Department 

of Pharmaceutics and Analytical Chemistry and is Biomacromolecules Group Leader at the 

Danish University of Pharmaceutical Sciences. He has been a professor for six years and focuses 

his research on protein formulation and drug delivery. He has written over 20 publications and 

three book chapters. Dr. van de Weert is a regular reviewer for scientific journals, including the 

European Journal of Pharmaceutical Sciences, the Journal of Pharmaceutical Sciences, and the 

International Journal of Pharmaceutics. He is also a member of the European Working Party on 

Biosimilars, the group that advises the European Medicines Agency on issues related to 

comparability testing for follow-on biologics and any other clinical and non-clinical matters 

relating directly or indirectly to the safety and efficacy of biosimilar therapies. 

10. Wolfgang E.B. Jelkmann, M.D.: Dr. Jelkmann is Professor of Physiology and 

Director of the Institute of Physiology at the University of Luebeck in Germany. He has over 

thirty years of academic medical experience and focuses his research on the production and 

action of inflammatory cytokines and hemopoietic growth factors, with an emphasis on 

erythropoietin. Dr. Jelkmann has written over 120 original publications, over fifty book chapters 

and reviews, and edited three books regarding the pathophysiology, pharmacology, molecular 

biology and clinical use of erythropoietin. He is on the editorial board of six journals. 

11. Martin K. Kuhlmann, M.D.: Dr. Kuhlmann is an Associate Professor of 

Medicine and Nephrology and Director of Internal Medicine - Nephrology at Vivantes Clinical 

Center-Friedrichshain in Berlin. He has been a professor of nephrology for fifteen years, with 
 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 10 

research focusing on various issues related to hemodialysis, peritoneal dialysis, and 

cytoprotection from ischemic/toxic renal injury. Dr. Kuhlmann is a reviewer for fourteen 

different scientific journals. He has written thirty peer-reviewed publications, over forty review 

articles, and has been an invited presenter at over 100 international conferences and symposia. 

12. Simon D. Roger, M.D.: Dr. Roger is a renal physician and Director of 

Nephrology at Gosford Hospital in Australia and a Clinical Associate Professor in the 

Department of Medicine and Health Sciences at Newcastle University. He has written over forty 

publications and a book chapter. Dr. Roger’s research focuses on the management of 

anemia/chronic kidney disease, erythropoietin use and renal failure, and biosimilars. 

13. Ashfar I. Mikhail, M.D.: Dr. Mikhail is a renal physician at Morriston Hospital 

and Senior Clinical Tutor at Swansea University in Wales. Dr. Mikhail’s main areas of research 

include the impact of introducing biosimilar epoetins on the quality of anemia management in 

hemodialysis patients and the role of cytokines in modulating the response to erythropoietin 

therapy. He has published fourteen articles in peer-reviewed journals and two book chapters. 

14. Nicole Casadevall, M.D.: Dr. Casadevall is Professor of Hematology at Saint 

Antoine Hospital in Paris. Her areas of research have centered on hemodialysis with special 

emphasis on erythropoiesis, erythropoietin, and myeloproliferative and myelodyspastic 

syndromes. She has served a member of the Medical Committee for the French Health Products 

Safety Agency (AFSSAPS) and as Scientific President of the French Society of Hematology. 

Agennix sought out these experts solely for the purpose of obtaining an independent 

evaluation of the safety of rhLF for use in food. In doing so, Agennix sought a broad range of 

perspectives and experience including: (1) topical experts from research and academia (experts 

who are leaders in their respective fields and who are familiar with state-of-the art in these fields); 

(2) seasoned medical professionals in academia (physicians from teaching hospitals and/or 

medical professors); (3) practicing medical doctors (providing a perspective from frontline 

clinicians); and (4) experts in proteins, in general, and recombinant human lactoferrin, in 

particular. The mix was selected to provide both technical and practical depth. Complete CVs 

of these experts are already on file with CFSAN. 

Although the opinions of just a few of these experts would be compelling, the opinions of 

this broad array of experts concurring in their scientific assessments unambiguously 

demonstrates a “severe conflict” that precludes GRAS status. 
 

 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 11 

IV. These Expert Opinions Create a “Severe Disagreement” with those of Ventria’s 

Experts on the Key Issues Affecting GRAS Evaluation. 

The opinions of 14 prominent experts submitted by Agennix quite clearly demonstrate 

there is a “severe disagreement” among experts regarding whether the use of rhLF from rice in 

oral rehydration solutions and pediatric medical foods is safe. These experts have raised 

legitimate concerns regarding important, unanswered safety questions as well as regarding the 

safety of long-term use of rhLF in food. Thus, given that these experts have expressed an 

opinion diametrically opposed to that offered by Ventria’s experts, a consensus definitely does 

not exist in the medical and scientific communities. 

The expert opinions provided by Agennix raise concerns in a number of areas, 

particularly concerning: (1) risks specifically associated with the glycosylation of rhLF from 

rice; (2) risks of immunogenicity and allergenicity with rhLF from rice; and (3) risks associated 

with feeding rice-based rhLF to young children, including infants. 21/ These 14 prominent 

scientific and medical experts have all endorsed the entire Supplemental Scientific Assessment 

submitted to FDA on June 3, 2008. The summary below highlights particular expertise that 

certain experts bring to each of the major issues presented. 

Fundamental to the concerns raised by these experts is the genuine opinion and belief that 

the safety of this compound cannot be established in the absence of appropriately powered longterm human clinical studies. Of particular concern was the need to determine (again through 

appropriately powered long-term human clinical studies) rhLF’s safety in uniquely vulnerable 

patient populations, including children and immunocompromised subjects such as those with 

autoimmune disease. Moreover, the opinions of these experts, many of whom have been 

evaluating this particular issue since 2005, have not wavered during the intervening 3 years, 

despite attempts by Ventria to reposition its GRAS filing. 

1. Risks specifically associated with the glycosylation of rhLF from rice. 

Our experts strongly disagree with Ventria’s experts on whether the safety profiles of 

rice-derived lactoferrin and native human lactoferrin are equivalent and whether the structural 

differences and major changes in glycosylation patterns can pose significant, long-term health 

risks. We have consulted some of the most prominent leaders in the field of glycobiology (Dr. 

Cummings, Dr. Pierce, and Dr. Schellekens) who concluded that the data presented in Ventria’s 

GRAS notice did not substantiate the safety of rice-produced rhLF. Rather, comprehensive 

studies characterizing the long-term safety risks related to exposure to foreign rice glycans are 

necessary before any consensus on its safety can be reached. The glycosylation issue is of 

particular concern, according to these experts, because Ventria’s rhLF consists of allergenic plant 

glycans attached to a human protein sequence. As these experts have explained in submissions 

21/ These experts have also expressed concern about the absence of adequate safety studies conducted 

with rhLF from rice; risks of rice-based rhLF exacerbating autoimmune disease; and other risks associated 

with extended dosing with any rhLF, including the risk of toxicity in individuals with iron overload. 
 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 12 

to CFSAN, evaluation of the safety of plant glycans and of human lactoferrin separately does not 

replace the need to evaluate the safety of rhLF that combines plant glycosylation with the human 

protein sequence. Rather, these experts believe that the novel structure of rice glycosylated 

human lactoferrin may create new risks relating to the recombinant protein’s processing and 

recognition by the human immune system that can only be adequately assessed by long-term 

human clinical studies with the rice-derived recombinant protein. 

Dr. Cummings is one of the preeminent scholars on glycosylation and the resulting effect 

on the function of and safety of therapeutic proteins. As noted above, he holds the prestigious 

position as the William Patterson Timmie Profession at the Emory University School of 

Medicine, where he also chairs the Department of Biochemistry. He founded and directed two 

major centers for glycobiology at leading universities. He has published over 170 peer-reviewed 

articles and is co-editor of the first textbook on Glycobiology. He is also a former President of 

the Society of Glycomics. In short, any “who’s who” in the field of glycobiology would start 

with Dr. Cummings. 

Dr. Pierce is also a prominent expert on glycobiology and carbohydrates. He has spent 

25 years in academia and is currently a Professor of Biochemistry and Molecular Biology at the 

University of Georgia and is Director of the University’s Cancer Center. He has published over 

65 peer-reviewed articles, is the editor of the Handbook of Glycomics and is a reviewer for 

several leading scientific journals, including Nature and Glycobiology. 

Dr. Schellekens is a physician and a professor of pharmaceutical sciences at Utrecht 

University in the Netherlands. He has extensive experience on the effect of glycosylation on the 

immunogenicity of proteins. He has published more than 200 peer-reviewed journal articles and 

is editor-in-chief of Biotherapy. He serves as an expert to the European Medicines Agency and 

is chairman of the Dutch Society of Microbiology’s Committee for Biological Safety. 

In the individual and collective opinions of these experts, there is no justification for 

Ventria’s experts to ignore evidence that foreign glycoforms may have an effect on the safety of 

rhLF from rice. Further, our experts disagree with Ventria’s experts’ basic assertions that 

carbohydrates are not generally considered allergens and have poor biological activity. 

Moreover, according to our experts, risks related to plant-derived glycans including IgEmediated responses may even be amplified by the administration of rice-based lactoferrin which 

could serve as a vector to deliver cross-reactive plant glycans directly to immune cells in the gut. 

Our experts also believe there is a further increase in immunogenicity and allergenicity risk in 

the context of infantile or childhood gastroenteritis, where there is an increase in gut 

permeability. 

These unresolved safety issues present an “ongoing scientific discussion or controversy 

about safety concerns” as stated in the Agency’s 1997 Proposed Rule, that should clearly stand in 

the way of establishing the safety of an intended use. The impeccable credentials of our 

glycosylation experts should solidify the validity of their opinions and preclude a finding of 

scientific consensus, as established by the Mycocert court. In that case, it was “inconceivable” 

that a substance could be GRAS given the “learned non-recognition” of several chairmen of 
 

 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 13 

leading specialty medical departments. 22/ Here, too, we have a severe disagreement among 

prominent experts and a sharp difference of opinion on the key issue of the potential 

consequences of the glycosylation of rice-derived rhLF. Failure of these learned experts to 

recognize Ventria’s rhLF as GRAS is demonstrative of a “severe disagreement” in the scientific 

community. 

2. Risks of immunogenicity and allergenicity with rhLF from rice. 

Drs. van Die, Kromminga, and Schellekens are well-known and esteemed experts in the 

field of immunology, and Drs. Weinberg and van de Weert are notable researchers who have 

addressed protein immunogenicity in their published work. These experts all strongly disagree 

that Ventria has provided sufficient human data to resolve the safety concerns of 

immunogenicity, induction of anti-lactoferrin antibodies and exacerbation of autoimmune 

diseases that are associated with anti-lactoferrin antibodies. Indeed, these experts believe that 

Ventria and its experts may be basing their conclusions on a dated understanding of the 

mechanism and activity of human lactoferrin. Our experts have evaluated several published, 

peer-reviewed studies conducted by Agennix which have further strengthened their conclusion 

that long-term human studies are needed to accurately understand the actual safety profile of 

rhLF. 

Dr. van Die is Head of the Glycoimmunology Group in the Department of Molecular Cell 

Biology & Immunology at Vrije University Medical Center in Amsterdam. She has been a 

professor for over 15 years and has written over 100 publications in the areas of glycobiology 

and immunology. She is a regular reviewer for major scientific journals and is a grant reviewer 

for the Netherlands Organization for Scientific Research. She is a former board member and 

current Secretary of the Dutch Society of Glycobiology. 

Dr. Kromminga is Director of Immunology at the Institute of Immunology, Clinical 

Pathology, and Molecular Medicine in Hamburg, Germany, where he focuses on resolving 

important immunogenicity issues. He is an international leader in the field and has written over 

25 publications and presented over 40 lectures at major symposia around the world. 

Dr. Schellekens’ extensive scientific and medical expertise is summarized in the previous 

section. Dr. Weinberg has researched lactoferrin for decades and has noted immunogenicity and 

other risks from lactoferrin administration in scientific publications. Dr. van de Weert’s research 

and publications on the development of protein-based drugs include relevant concerns relating to 

immunogenicity. 

Our experts strongly disagree with Ventria’s experts’ assertion that possible allergenic 

properties of rhLF cannot be the basis to deny a GRAS petition. Known allergenic/immunogenic 

properties are a significant safety concern and should be questioned when determining if a 

substance is GRAS. Our experts have provided the equivalent of the “sharply divided 

22/ United States v. An Article of Drug . . . “Mykocert”, 345 F. Supp. 571, 575 (N.D. Ill. 1972). 
 

 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 14 

testimony” from the X-Otag case on the issue of whether exogenous lactoferrin can cause 

allergenic responses in humans. 23/ According to our experts, long-term studies are the only 

credible way to identify and quantify health risks associated with immunogenicity and 

allergenicity. Our experts fervently believe that the conclusions reached in Ventria’s GRAS 

Notice are not supportable. Thus, an ongoing scientific controversy clearly exists on these issues, 

and the experts from Ventria and Agennix maintain an unresolved and severe conflict of opinion 

on these subjects. 

3. Risks to young children, including infants. 

Ventria specifically proposes to use its rhLF in pediatric medical foods. As detailed in 

our June 2008 submission, our experts opined that the trial conducted by Ventria in South 

America in a relatively small number of children receiving very short term administration did not 

establish the safety of pediatric use of rice-derived rhLF, and, in fact, raised more safety 

questions than it answered. 

Dr. Sherman is a highly respected pediatrician and academic with extensive research 

experience with lactoferrin and with gut infections in neonates. He is a Professor of Pediatrics at 

Southern Illinois University of Medicine and Professor Emeritus at the University of California, 

Davis. He has practiced in the field for over 30 years and has a specialty in neonatology. He has 

published over 80 peer-reviewed articles and has written 19 book chapters. Importantly, he is a 

true expert on lactoferrin and on gut infections in neonates, having conducted NIH-funded 

research in both areas and having written and presented extensively on the subject. It is 

particularly significant that Dr. Sherman, who has published research specifically on the 

beneficial effect that lactoferrin has in neonatal animal models, still believes strongly that it 

would not be appropriate to consider rhLF as GRAS without evidence from long-term clinical 

studies. 

Dr. Sherman is joined by a host of other practicing physicians we consulted, including Dr. 

Sidney Grossberg (Medical College of Wisconsin), Wolfgang E. B. Jelkmann (University of 

Leubeck in Germany), Martin Kuhlmann (Director of Internal Medicine-Nephrology at Vivantes 

clinical Center-Friedrichshain in Berlin), Simon Roger (Newcastle University), Ashfar Mikhail 

(Swansea University in Wales) and Nicole Casadevall (Saint Antoine Hospital in Paris, France). 

These experts strongly disagree with Ventria’s experts’ view that the results of the 

pediatric clinical trial with rice-based rhLF conducted in South America support a conclusion 

that Ventria’s rice-based rhLF is safe for its intended use. In particular, these experts believe that 

Ventria’s trial in South America was not designed to address the serious safety concerns they had 

identified. The experts cited the fact that the children received only a single cycle of only a few 

days of treatment, that the number of children receiving treatment with Ventria’s rhLF was small, 

and that the children did not receive adequate follow-up. Moreover, according to these experts, 

23/ United States v. An Article of Drug . . . X-Otag Plus Tablets, 441 F. Supp. 105, 113-114 (D. Colo. 

1977). 
 

 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 15 

published reports of allergic reactions in the trial – even though the trial involved administration 

of Ventria’s rhLF to only a small number of children and for only a few days of treatment – only 

adds to the safety concerns. The possibility of acute allergic reactions was raised previously by 

many of these experts in the initial Scientific Assessment we submitted to CFSAN dated 

November 9, 2005. It was also concerning to these experts that insufficient follow-up 

monitoring was conducted to determine whether other delayed reactions or allergic sensitization 

may have occurred. 

These experts had a number of other concerns, which were articulated in the 

Supplemental Scientific Assessment dated June 3, 2008, about the way the trial was conducted 

(including among other things, informed consent issues, and the use of a “control group” that 

received in about half the cases an ORS that is well known to be inferior to the ORS base 

received by all the infants in the rhLF/rhLZ “treated group”). They were also concerned that the 

occurrence of allergic reactions, and the higher frequency of bacterial pathogen isolation in the 

stool of children receiving the rhLF/rhLZ-ORS, do not appear to have been disclosed by Ventria 

to CFSAN when they would clearly be relevant to Ventria’s GRAS petition. 

Furthermore, even if there had not been serious safety concerns raised by the South 

American trial, these experts strongly believe that long-term human studies are necessary to 

assess the risks of immunogenicity. Some of the immunogenicity risks include: 

• the risk of immunogenicity and the breaking of B-cell tolerance, which may 

take over a year to manifest; 

• the risk of inducing anti-lactoferrin antibodies, which could both crossneutralize endogenous lactoferrin with negative biological effects and 

neutralize the efficacy of exogenous lactoferrin, which could compromise 

future treatments; and 

• the risk of exacerbating autoimmune diseases that are associated with antilactoferrin antibodies. 

This impressive list of medical experts all agree that the safety concerns related to 

glycosylation and immunogenicity/allergenicity are magnified when targeting vulnerable 

pediatric populations. These experts believe that autoimmune diseases and other 

immunogenicity concerns may be a greater threat to infants and children with developing 

immune systems, particularly those with gastrointestinal infections where gut permeability can 

be further increased. These qualified experts do not believe that administration of compounds 

containing Ventria’s rhLF is considered safe for neonates and children. 

Thus, like in the Premo Pharmaceutical Laboratories case cited above, there is a “sharp 

difference of opinion” between experts regarding the methods and results of the available 

study. 24/ A severe disagreement exists concerning whether rice-derived rhLF is safe for use in 

24/ Premo Pharma. Labs., 629 F.2d at 804. 
 

 

 

 

Laura M. Tarantino, Ph.D. 

August 14, 2008 

Page 16 

children, and much more robust clinical data is needed to establish any type of informed 

consensus on the issue. 

In summary, the clear lack of scientific consensus that rhLF is GRAS is evidenced by the 

compelling opinions of these 14 prominent scientific and medical experts, raising legitimate 

safety questions about the safety of feeding rice-based rhLF to young children and infants. That 

so many, and such highly qualified, experts have repeatedly expressed serious concern about the 

proposed uses of rhLF demonstrates a “severe conflict” of expert opinion and precludes GRAS 

status for rhLF from rice. 

III. Conclusion 

Based on Ventria’s failure to demonstrate that there is a scientific consensus among 

qualified experts that rhLF from transgenic rice is GRAS, we are asking CFSAN to determine, as 

a matter of law, that rhLF from transgenic rice is not GRAS for use in oral rehydration solutions 

and pediatric medical foods. 

Agennix appreciates CFSAN’s consideration of this important information as Ventria’s 

GRAS notification for rhLF from rice is considered. Please do not hesitate to contact us if there 

are any questions or if additional information would be useful.

 Sincerely,

 Rick Barsky

 Chief Executive Officer 

cc: Jeremiah Fasano (HFS-255) 

Consumer Safety Officer 

Division of Biotechnology and GRAS Notice Review 

Stephen F. Sundlof, D.V.M., Ph.D. (HFS-001) 

 Director, CFSAN 

Michael M. Landa (HFS-001) 

Deputy Director for Regulatory Affairs, CFSAN 

Gerald F. Masoudi (GCF-1) 

 FDA Chief Counsel 
 

 

 

 

 

 

 

 

 

 

------------------------------------------------------------------------------

Page 1 of 2 

Fasano, Jeremiah 

From: Levitt, Joseph A. [JALevitt@HHLAW.com] 

Sent: Friday, August 15, 2008 12:36 PM 

To: Fasano, Jeremiah 

Cc: Tarantino, Laura M 

Subject: Agennix "Summary Judgment" Letter on GRN 235 

Attachments: Agennix Summary Judgment letter aug 14.pdf 

Dear Jeremiah--

Attached is an electronic copy of a letter being delivered to your office today. The letter requests that FDA reach 

the legal conclusion that recombinant human lactoferrin (rhLF) from transgenic rice, GRN No. 000235 (resubmission of 

GRN No. 000162) submitted by Ventria Bioscience, is not Generally Recognized as Safe (GRAS) based on a “severe 

disagreement” among qualified experts. 

Agennix has approached this as being tantamount to a legal motion for summary judgment because there are no material 

facts in dispute (i.e., it is a matter of record that there are two groups of experts expressing diametrically opposing views) 

and so the Agency may rightfully decide this issue as a matter of law. Furthermore, this letter is based solely on the third 

prong of the GRAS test—namely, that there be a consensus among qualified experts that the food ingredient is 

safe. Agennix is asking FDA to determine, as a matter of law, that rhLF from transgenic rice is not GRAS for use in oral 

rehydration solutions and pediatric medical foods solely because Ventria has failed to demonstrate that there is a scientific 

consensus among qualified experts that the substance is safe. 

The letter also notes that, if FDA were to take this approach, then it would obviate the need to address the rhLF issue in the 

context of Section 912 of the FDAAA. 

Please let me know if you have any questions. FYI, I am sending similar notes to others named as cc's on the letter. 

Best regards,

 Joe 

JOSEPH LEVITT, PARTNER 

HOGAN & HARTSON LLP 

Columbia Square, 555 Thirteenth Street, NW, Washington, DC 20004 

direct +1.202.637.5759 | tel +1.202.637.5600 | fax +1.202.637.5910 

jalevitt@hhlaw.com | http://www.hhlaw.com 

"EMF <HHLAW.COM>" made the following annotations. 

This electronic message transmission contains information from this law firm which may be confident 

8/20/2008 
Page 2 of 2 

copying, distribution or use of the contents of this information is prohibited. 

If you have received this electronic transmission in error, please notify us by telephone (+1-202-6 

============================================================================== 

8/20/2008 
 

 

 

 

 

 

 

 

_______________________ 

Page 1 of 2 

Fasano, Jeremiah 

From: Fasano, Jeremiah 

Sent: Wednesday, August 20, 2008 11:27 AM 

To: 'Levitt, Joseph A.' 

Subject: RE: Agennix "Summary Judgment" Letter on GRN 235 

Mr. LevittI just wanted to acknowledge receipt of both the electronic version of your letter and the hard copy, 

which has now reached me. We will add the letter to our files and consider its contents. 

Regards-

-Jeremiah Fasano 

Jeremiah Fasano, Ph.D. 

Consumer Safety Officer 

DBGNR/OFAS/CFSAN/FDA 

jeremiah.fasano@fda.hhs.gov 

Phone: 301-436-1173 

Fax: 301-436-2964 

HFS-255 

5100 Paint Branch Parkway 

College Park, MD 20740 

From: Levitt, Joseph A. [mailto:JALevitt@HHLAW.com] 

Sent: Friday, August 15, 2008 12:36 PM 

To: Fasano, Jeremiah 

Cc: Tarantino, Laura M 

Subject: Agennix "Summary Judgment" Letter on GRN 235 

Dear Jeremiah--

Attached is an electronic copy of a letter being delivered to your office today. The letter requests that FDA reach 

the legal conclusion that recombinant human lactoferrin (rhLF) from transgenic rice, GRN No. 000235 

(resubmission of GRN No. 000162) submitted by Ventria Bioscience, is not Generally Recognized as Safe (GRAS) 

based on a “severe disagreement” among qualified experts. 

Agennix has approached this as being tantamount to a legal motion for summary judgment because there are no 

material facts in dispute (i.e., it is a matter of record that there are two groups of experts expressing diametrically 

opposing views) and so the Agency may rightfully decide this issue as a matter of law. Furthermore, this letter is 

based solely on the third prong of the GRAS test—namely, that there be a consensus among qualified experts that 

the food ingredient is safe. Agennix is asking FDA to determine, as a matter of law, that rhLF from transgenic rice is 

not GRAS for use in oral rehydration solutions and pediatric medical foods solely because Ventria has failed to 

demonstrate that there is a scientific consensus among qualified experts that the substance is safe. 

9/16/2008 
 

 

 

 

 

 

 

 

------------------------------------------------------------------------------

Page 2 of 2 

The letter also notes that, if FDA were to take this approach, then it would obviate the need to address the rhLF issue 

in the context of Section 912 of the FDAAA. 

Please let me know if you have any questions. FYI, I am sending similar notes to others named as cc's on the letter. 

Best regards,

 Joe 

JOSEPH LEVITT, PARTNER 

HOGAN & HARTSON LLP 

Columbia Square, 555 Thirteenth Street, NW, Washington, DC 20004 

direct +1.202.637.5759 | tel +1.202.637.5600 | fax +1.202.637.5910 

jalevitt@hhlaw.com | http://www.hhlaw.com 

"EMF <HHLAW.COM>" made the following annotations. 

This electronic message transmission contains information from this law firm which may be conf 

copying, distribution or use of the contents of this information is prohibited. 

If you have received this electronic transmission in error, please notify us by telephone (+1-

============================================================================== 

9/16/2008 



__________________________________________ 

Fasano, Jeremiah 

From: Fasano, Jeremiah 

Sent: Monday, March 02, 2009 11:25 AM 

To: 'edward.allera@bipc.com' 

Subject: Re: Meeting request on behalf of Ventria 

Mr. AlleraI'm Jeremiah Fasano, the Consumer Safety Officer assigned to arrange the meeting you've requested in your February 

24th letter to Laura Tarantino. I'm still checking availability of a few parties who might attend, but I wanted to let you know 

that I'm working on it and to give you my direct contact information. The week of the 9th looks pretty promising, and I will 

likely be back in touch in the next day or so to lock in a date. Are there any days or times of day during that week that 

would definitely not work for you? 

My understanding (based on a few words from Dr. Tarantino) is that you would like to come in and discuss with us the 

history of Ventria's submissions to date and their current status. Is this basically correct? Please let me know at your 

convenience if that's so, or if I've missed something getting it second-hand. Also, will anyone else be with you? (I need to 

provide names to the lobby guard). 

I'll be in touch very soon. 

Regards-

-Jeremiah Fasano 

Jeremiah Fasano, Ph.D. 

Consumer Safety Officer 

Division of Biotechnology and GRAS Notice Review 

Office of Food Additive Safety 

Center for Food Safety and Applied Nutrition 

Food and Drug Administration 

Phone: 301-436-1173 

Fax: 301-436-2964 

Email: jeremiah.fasano@fda.hhs.gov 

Mailing Address: 

HFS-255 

5100 Paint Branch Parkway 

College Park, MD 20740 

This e-mail is intended for the exclusive use of the recipient(s) named above. It may contain information that is protected, privileged, 

or confidential, and it should not be disseminated, distributed, or copied to persons not authorized to receive such information. If you 

are not the intended recipient, any dissemination, distribution or copying is strictly prohibited. If you think you have received this email message in error, please e-mail the sender immediately at jeremiah.fasano@fda.hhs.gov. 

1

 

__________________________________________ 

From: Fasano, Jeremiah 

To: "Allera, Edward John"; "Scott Deeter"; 

cc: Gaynor, Paulette M; 

Subject: Confidentiality of recent correspondence associated with GRN 191/235 

Date: Wednesday, June 24, 2009 7:59:04 PM 

Attachments: 2009-02-

24 - Letter from Ventria to OFAS requesting meeting and notifying of new counsel. 

pdf 

2009-03-06 - Letter from Ventria confirming new counsel.pdf 

Mr. Allera and Mr. DeeterWe recently received a Freedom of Information Act request that would encompass 

two recent letters our office received from you (attached), both marked 'Confidential.' 

Before preparing our response to this FOIA request, we wanted to consult with you, 

in accordance with our regulations governing such requests, about the aspects and 

content of these letters that you would consider confidential. 

Dr. Paulette Gaynor and I are each managing one of the relevant GRAS notices and 

will both be away from our desks with different schedules for the next several weeks, 

so please direct your response, at your convenience, to both of us. 

Sincerely-

-Jeremiah Fasano 

Jeremiah Fasano, Ph.D. 

Consumer Safety Officer 

Division of Biotechnology and GRAS Notice Review 

Office of Food Additive Safety 

Center for Food Safety and Applied Nutrition 

Food and Drug Administration 

Phone: 301-436-1173 

Fax: 301-436-2964 

Email: jeremiah.fasano@fda.hhs.gov 

Mailing Address: 

HFS-255 

5100 Paint Branch Parkway 

College Park, MD 20740 

This e-mail is intended for the exclusive use of the recipient(s) named above. It may contain 

information that is protected, privileged, or confidential, and it should not be disseminated, 
distributed, or copied to persons not authorized to receive such information. If you are not the 

intended recipient, any dissemination, distribution or copying is strictly prohibited. If you 

think you have received this e-mail message in error, please e-mail the sender immediately at 

jeremiah.fasano@fda.hhs.gov. 
From: Gaynor, Paulette M 

To: "Scott Deeter"; Allera, Edward John; 

cc: Fasano, Jeremiah; 

Subject: RE: Confidentiality of recent correspondence associated with GRN 191/235 

Date: Thursday, June 25, 2009 1:56:09 PM 

Dear Mr. Deeter, 

Thank you for getting back to us about the confidential information in these two 

letters. 

Sincerely, 

Paulette Gaynor, Ph.D. 

From: Scott Deeter [mailto:sdeeter@ventria.com] 

Sent: Thursday, June 25, 2009 12:07 AM 

To: Fasano, Jeremiah; Allera, Edward John 

Cc: Gaynor, Paulette M 

Subject: RE: Confidentiality of recent correspondence associated with GRN 

191/235 

Dear Jeremiah: 

It is good to hear from you. The contents of the letter that are confidential are the 

firm name, contact name, signature and contact information referencing our 

counsel (Buchanon, Ingersoll & Rooney and Ed Allera). Otherwise, the rest of the 

information is not confidential. 

Sincerely, 

Scott Deeter 

President & CEO 

Ventria Bioscience 

From: Fasano, Jeremiah [mailto:Jeremiah.Fasano@fda.hhs.gov] 

Sent: Wednesday, June 24, 2009 5:59 PM 

To: Allera, Edward John; Scott Deeter 

Cc: Gaynor, Paulette M 

Subject: Confidentiality of recent correspondence associated with GRN 191/235 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

__________________________________________ 

Mr. Allera and Mr. DeeterWe recently received a Freedom of Information Act request that would encompass 

two recent letters our office received from you (attached), both marked 

'Confidential.' Before preparing our response to this FOIA request, we wanted to 

consult with you, in accordance with our regulations governing such requests, about 

the aspects and content of these letters that you would consider confidential. 

Dr. Paulette Gaynor and I are each managing one of the relevant GRAS notices 

and will both be away from our desks with different schedules for the next several 

weeks, so please direct your response, at your convenience, to both of us. 

Sincerely-

-Jeremiah Fasano 

<<2009-02-24 - Letter from Ventria to OFAS requesting meeting and notifying of 

new counsel.pdf>> <<2009-03-06 - Letter from Ventria confirming new counsel. 

pdf>> 

Jeremiah Fasano, Ph.D. 

Consumer Safety Officer 

Division of Biotechnology and GRAS Notice Review 

Office of Food Additive Safety 

Center for Food Safety and Applied Nutrition 

Food and Drug Administration 

Phone: 301-436-1173 

Fax: 301-436-2964 

Email: jeremiah.fasano@fda.hhs.gov 

Mailing Address: 

HFS-255 

5100 Paint Branch Parkway 

College Park, MD 20740 

This e-mail is intended for the exclusive use of the recipient(s) named above. It may contain 

information that is protected, privileged, or confidential, and it should not be disseminated, 

distributed, or copied to persons not authorized to receive such information. If you are not 

the intended recipient, any dissemination, distribution or copying is strictly prohibited. If 

you think you have received this e-mail message in error, please e-mail the sender 

immediately at jeremiah.fasano@fda.hhs.gov. 

From: Scott Deeter 

To: Fasano, Jeremiah; Allera, Edward John; 

cc: Gaynor, Paulette M; 

Subject: RE: Confidentiality of recent correspondence associated with GRN 191/235 

Date: Thursday, June 25, 2009 12:07:25 AM 

Dear Jeremiah: 

It is good to hear from you. The contents of the letter that are confidential are the 

firm name, contact name, signature and contact information referencing our 

counsel (Buchanon, Ingersoll & Rooney and Ed Allera). Otherwise, the rest of the 

information is not confidential. 

Sincerely, 

Scott Deeter 

President & CEO 

Ventria Bioscience 

From: Fasano, Jeremiah [mailto:Jeremiah.Fasano@fda.hhs.gov] 

Sent: Wednesday, June 24, 2009 5:59 PM 

To: Allera, Edward John; Scott Deeter 

Cc: Gaynor, Paulette M 

Subject: Confidentiality of recent correspondence associated with GRN 191/235 

Mr. Allera and Mr. DeeterWe recently received a Freedom of Information Act request that would encompass 

two recent letters our office received from you (attached), both marked 

'Confidential.' Before preparing our response to this FOIA request, we wanted to 

consult with you, in accordance with our regulations governing such requests, about 

the aspects and content of these letters that you would consider confidential. 

Dr. Paulette Gaynor and I are each managing one of the relevant GRAS notices 

and will both be away from our desks with different schedules for the next several 

weeks, so please direct your response, at your convenience, to both of us. 

Sincerely-

-Jeremiah Fasano 

<<2009-02-24 - Letter from Ventria to OFAS requesting meeting and notifying of 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

__________________________________________ 

new counsel.pdf>> <<2009-03-06 - Letter from Ventria confirming new counsel. 

pdf>> 

Jeremiah Fasano, Ph.D. 

Consumer Safety Officer 

Division of Biotechnology and GRAS Notice Review 

Office of Food Additive Safety 

Center for Food Safety and Applied Nutrition 

Food and Drug Administration 

Phone: 301-436-1173 

Fax: 301-436-2964 

Email: jeremiah.fasano@fda.hhs.gov 

Mailing Address: 

HFS-255 

5100 Paint Branch Parkway 

College Park, MD 20740 

This e-mail is intended for the exclusive use of the recipient(s) named above. It may contain 

information that is protected, privileged, or confidential, and it should not be disseminated, 

distributed, or copied to persons not authorized to receive such information. If you are not 

the intended recipient, any dissemination, distribution or copying is strictly prohibited. If 

you think you have received this e-mail message in error, please e-mail the sender 

immediately at jeremiah.fasano@fda.hhs.gov. 
 

 

 

 

 

 

 

 

 

 

 

_______________________ 

From: Fasano, Jeremiah 

To: "Scott Deeter"; 

Subject: RE: Counsel to FDA - Ventria GRAS Submissions 

Date: Monday, November 23, 2009 5:04:52 PM 

Mr. DeeterThank you for keeping us up to date. I'll pass the information along to the appropriate parties as necessary. 

Regards-

-Jeremiah Fasano 

Jeremiah Fasano, Ph.D. 

Consumer Safety Officer 

DBGNR/OFAS/CFSAN/FDA 

jeremiah.fasano@fda.hhs.gov 

Phone: 301-436-1173 

Fax: 301-436-2964 

HFS-255 

5100 Paint Branch Parkway 

College Park, MD 20740 

From: Scott Deeter [mailto:sdeeter@ventria.com] 

Sent: Friday, November 20, 2009 1:45 PM 

To: Fasano, Jeremiah 

Subject: FW: Counsel to FDA - Ventria GRAS Submissions 

Dear Jeremiah: 

FYI. Please inform others at FDA, if necessary. 

From: Scott Deeter 

Sent: Friday, November 20, 2009 11:43 AM 

To: Allera, Edward John 

Cc: Ann Swan; Randy Semadeni 

Subject: Counsel to FDA - Ventria GRAS Submissions 

Dear Ed: 

Thank you for your advice related to our GRAS submissions. By way of this email, I wanted to inform you that we no longer 

require Buchanan, Ingersoll & Rooney’s counsel on this matter and our relationship is no longer active. Please inform your 

team and if required, inform any contacts you made at FDA on our behalf. I enjoyed working with you and your team. 

Thanks for your help. Maybe we can work together in the future. 

All the best, 

Scott Deeter 

President & CEO 

(970) 420-9598 

Ventria Bioscience 

Pediatric Health 

This message (including any attachments) may contain confidential information intended for a specific individual 

and purpose, and is protected by law. If you are not the intended recipient, you should delete this message. 
Any disclosure, copying, or distribution of this message, or the taking of any action based on it, is prohibited. 

From: Scott Deeter 

To: Fasano, Jeremiah; 

cc: Nancy L. Buc; 

Subject: Letter 

Date: Tuesday, December 15, 2009 11:28:21 AM 

Attachments: Letter-FDA-Buc-BeardsleyNotice-Dec09.pdf 

Dear Jeremiah: 

I hope this finds you well. We look forward to seeing you on Jan 15th to discuss the 

notices. Thank you for allowing us your time for this meeting. Attached, please find 

a formal notice of our representation by Buc & Beardsley, LLC. 

Have a happy holiday! 

Sincerely, 

Scott E. Deeter 

President & CEO 

Ventria Bioscience 

(970) 420-9598 

www.Ventria.com 

Your Life. Our Passion. 

This message (including any attachments) may contain confidential information intended for 

a specific individual and purpose, and is protected by law. If you are not the intended 

recipient, you should delete this message. Any disclosure, copying, or distribution of this 

message, or the taking of any action based on it, is prohibited. 


From: Nancy L. Buc 

To: Fasano, Jeremiah; 

cc: "Scott Deeter"; 

Subject: Followup to our meeting 

Date: Monday, January 25, 2010 8:39:59 PM 

Dear Dr. Fasano -

Scott Deeter, Bill Rutter, and I appreciated the opportunity on behalf of my client, 

Ventria Biosciences, to meet with you and your collagues to discuss issues 

pertaining to the two Ventria GRAS notices, GRN 235 for recombinant human 

lactoferrin dervied from rice, and GRN 291 for recombinant human lysozyme 

dervied from rice, both for use in pediatric medical foods and other pediatric 

foods such as infant formula. We found the discussion both enlightening and 

helpful. 

At the meeting, Ventria asked to be allowed to make further submissions to the 

pending GRAS notices before CFSAN takes any acation on them, and you 

agreed to that so long as the submission is made on or before March 22, 2010. 

Ventria also agreed that if it has not made its submission(s) by that date, it will 

withdraw the GRAS notice(s) for which a submission has not been made. 

I will get you the above in hard copy as soon as possible, and may also want to 

ask some further questions and make some further suggestions about how to 

proceed from here. In the meantime, please accept this e-mail version. 

Thank you. 

Nancy L. Buc 
 

 

 

______________________ 

From: Fasano, Jeremiah 

To: Nancy L. Buc; 

cc: "Scott Deeter"; Cheeseman, Mitchell A; 

Mattia, Antonia; 

Subject: RE: Followup to our meeting 

Date: Wednesday, January 27, 2010 3:44:18 PM 

Ms. BucWe wanted to take this opportunity to clarify our understanding of the agreement 

we reached at our January 15th meeting. As a minor point, we understood that 

Ventria would provide a substantive amendment by the 19th of March, rather 

than the 22nd. More importantly, Ventria's GRAS notices would be considered 

automatically withdrawn without any further action on Ventria's part if a 

substantive amendment is not received by close of business on the final day of 

the agreed-upon timeframe. This is not clearly articulated in the email you sent to 

us. 

We would be willing to respond to specific questions or comment on suggestions 

if that will be helpful to you in assembling a substantive amendment, though we 

would not consider such interactions to comprise a substantive amendment 

sufficient to preclude automatic withdrawal of the GRAS notices, or to "extend 

the clock" past the agreed-upon timeframe. 

We would appreciate it if the formal letter you send to us is explicit about these 

points. 

Although FDA is very interested in continuing to engage constructively with 

industry on issues associated with the use of human proteins as food 

ingredients, if the substantive amendment submitted by Ventria does not resolve 

the issues we discussed at our January 15th meeting, we do not intend to 

engage in any further iteration within the framework of these two specific GRAS 

notices. 

Please feel free to contact me with any questions you may have. 

Sincerely, 

Jeremiah Fasano 

Jeremiah Fasano, Ph.D. 

Consumer Safety Officer 
 

 

 

 

 

 

 

 

DBGNR/OFAS/CFSAN/FDA 

jeremiah.fasano@fda.hhs.gov 

Phone: 301-436-1173 

Fax: 301-436-2964 

HFS-255 

5100 Paint Branch Parkway 

College Park, MD 20740 

From: Nancy L. Buc [mailto:nlb@bucbeardsley.com] 

Sent: Monday, January 25, 2010 8:35 PM 

To: Fasano, Jeremiah 

Cc: 'Scott Deeter' 

Subject: Followup to our meeting 

Dear Dr. Fasano -

Scott Deeter, Bill Rutter, and I appreciated the opportunity on behalf of my client, 

Ventria Biosciences, to meet with you and your collagues to discuss issues 

pertaining to the two Ventria GRAS notices, GRN 235 for recombinant human 

lactoferrin dervied from rice, and GRN 291 for recombinant human lysozyme 

dervied from rice, both for use in pediatric medical foods and other pediatric 

foods such as infant formula. We found the discussion both enlightening and 

helpful. 

At the meeting, Ventria asked to be allowed to make further submissions to the 

pending GRAS notices before CFSAN takes any acation on them, and you 

agreed to that so long as the submission is made on or before March 22, 2010. 

Ventria also agreed that if it has not made its submission(s) by that date, it will 

withdraw the GRAS notice(s) for which a submission has not been made. 

I will get you the above in hard copy as soon as possible, and may also want to 

ask some further questions and make some further suggestions about how to 

proceed from here. In the meantime, please accept this e-mail version. 

Thank you. 

Nancy L. Buc 




 

 

 

 

 

 

 

 

 

 

 

_______________________ 

From: Fasano, Jeremiah 

To: "Scott Deeter"; 

Subject: RE: Withdrawal of GRAS Notices 

Date: Friday, March 12, 2010 12:11:12 PM 

Mr. DeeterI just wanted to let you know that we have received your withdrawal letter. A 

more formal acknowledgement should be on its way soon. 

Regards-

-Jeremiah Fasano 

Jeremiah Fasano, Ph.D. 

Consumer Safety Officer 

DBGNR/OFAS/CFSAN/FDA 

jeremiah.fasano@fda.hhs.gov 

Phone: 301-436-1173 

Fax: 301-436-2964 

HFS-255 

5100 Paint Branch Parkway 

College Park, MD 20740 

From: Scott Deeter [mailto:sdeeter@ventria.com] 

Sent: Saturday, March 06, 2010 4:11 PM 

To: Fasano, Jeremiah 

Subject: Withdrawal of GRAS Notices 

Dear Jeremiah: 

This email confirms notice is being sent to you for the withdrawal ofGRN 291 and 

GRN 235. A formal withdrawal letter is on its way to you. 

Sincerely, 
Scott E. Deeter 

President & CEO 

Ventria Bioscience 

(970) 420-9598 

www.Ventria.com 

Your Life. Our Passion. 

This message (including any attachments) may contain confidential information intended for 

a specific individual and purpose, and is protected by law. If you are not the intended 

recipient, you should delete this message. Any disclosure, copying, or distribution of this 

message, or the taking of any action based on it, is prohibited.