FDA: Biotech Mandatory Consultation 05-03-01 - Organic Trade Association
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FDA: Biotech Mandatory Consultation 05-03-01


FDA Mandatory Consultation Process An Improvement But Still Not Strong Enough

Comments of the Organic Trade Association on Docket Number 00N-1396, “Premarket Notice Concerning Bioengineered Foods”

Submitted by
Tom Hutcheson,
Associate Policy Director

May 3, 2001 

General Comments

The Organic Trade Association (OTA) thanks FDA for this opportunity to comment on the structure of the consultation process for bioengineered foods.

OTA strongly supports making this consultation mandatory.  The current lack of such a requirement allows private entities to make decisions affecting public safety regarding risk analysis.  These decisions are based on private interests and should not be the basis for food safety decisions. Of course companies do not wish to market unhealthy products, as this would interfere with their profitability, but there is always a countervailing pressure to bring products to market as quickly as possible to maintain competitive advantage.  The over-riding concern of all companies is profit, not the disinterested search for better knowledge.  When this results in better products, society benefits, but when fundamental scientific questions remain regarding any particular technology, it is the task of public agencies to set the bounds of behavior which affects the public welfare.

There are several over-arching principles necessary for a neutral evaluation of novel foods.  These include ensuring the disinterested review of novel products; recognizing the implications of there not being a one-to-one correspondence between genes and traits; adequately detecting and preventing any harm from unintended consequences of genetic engineering; recognizing that the peer-reviewed literature is thin in many significant areas; ensuring that companies take full responsibility for their products; and misleading marketing.

Disinterested review

The foremost practical principle is that the role of FDA is that of a disinterested reviewer.  In order to fulfill this function, FDA needs objective data and analysis.  The case mentioned on pages 4709-10 of the proposed rule regarding the allergenicity of genetically engineered Brazil nuts refers to a company testing its product for known allergens.  This is not the problem—if companies are not doing this, they should of course be prohibited from marketing their products.  The problem comes from a lack of sufficient methods for identifying not only potential allergens but other unknown and potentially harmful effects of genetic engineering.  The commercial application of this technology is outpacing the health science related to it.  It is FDA’s job to prevent problems arising from this condition.  The burden of proof on the company is to prove that the product is safe; the burden of proof on FDA is to prove that the information the company uses is valid.  The mere assertion that the information is valid is unacceptable.

FDA should not rely on private concerns for its access to information.  Private information leading to decisions affecting food safety must be scrutinized for any evidence that the information being presented is partial to the commercial success of the product.  Since there is by definition a paucity of independent, peer-reviewed work in proprietary areas, FDA should consider all information from private sources to be best-case projections.  This is not sufficient, though, to protect the public interest.  The only way to protect the public interest is to mandate an independent assessment of any novel product’s characteristics.

Genes and traits, and the adequate prevention of unintended consequences

OTA applauds FDA for considering in its consultation process any changes known to occur in metabolic pathways which could lead to the production of substances known to be toxic to humans.

Because genes have complex relationships within the chromosome, perhaps the most important theoretical principle to be considered is that there is not a one-to-one correspondence between genes and traits.  FDA makes an excellent point on pages 4710-4711 that unintended consequences must be identified and any problems solved.  This point, however, does not seem to be fully integrated into the proposed rule.  OTA notes that there is very little objective data on the non-target effects of genetic engineering, and that independent peer review is the only way to demonstrate FDA’s diligence in seeking such information.

Stephen Palumbi, curator of invertebrates at the
Museum of Comparative Zoology at Harvard University, contrasts traditional breeding techniques (artificial selection) with the “brute force” of genetic engineering.  His recent article in “The Chronicle of Higher Education” illuminate precisely the difficulties in assessing the full consequences of genetically engineered products.  They are worth repeating at length[i]:

“The major difference between artificial selection and brute-force genetic manipulation lies in the complexity of interlocking, multiple evolutionary changes that underlies most of the important differences we see between species.  Brute-force manipulation seeks to alter a solitary gene in a small number of plants and immediately produce a populationwide desirable trait—but selection almost never works so single-mindedly.

“Usually, several genes contribute to any given trait, including many that control trait expression in an organism….

“Artificial selection simultaneously selects for the genes providing a trait plus all the genes that control it.  This inclusion of regulatory genes in the evolutionary process happens automatically because selection acts on the whole organism, not just a single gene.  Desirable features and any potentially undesirable complications are balanced by the process of selection….As a result, artificial selection must work on the end-product of all of an organism’s genes as they act together to produce stems, roots, and flowers.  The sum total is the most important—the way the pieces fit together determining success….

“These three differences between selection and engineering—inclusion of the necessary regulatory genes, selection for whole-organism success over several generations, and large population sizes with multiple variants—result in very different evolutionary processes and potentially very different outcomes….

“The complex and species-specific set of genes that control the timing of gene expression—or the tissues in which expression occurs—are unknown.”

Palumbi is concerned mainly with the evolution of genetically engineered crops.  FDA must also think critically and avoid reductionism, considering the whole organism when developing the criteria for demonstrating that a novel product will not have harmful unintended consequences.

Thin literature

Industry knowledge cannot be considered full and complete by FDA if FDA is to be a worthy steward of the public trust.  Peer reviewed knowledge is necessary for the adequate assessment of a novel product of genetic engineering.  FDA’s statement on page 4708 of the proposed rule that “there does not appear to be any new scientific information that raises questions about the safety of bioengineered foods currently being marketed” seems to indicate that FDA believes that all the significant questions about bioengineered foods have been answered.  As Palumbo’s article makes abundantly clear, many of those questions have not yet begun to be asked.

The only questions that have been asked are the very narrow questions regarding intended effects.  Answers to questions related to the effect of the placement of the introduced gene or genes are not well known; indeed, only since the very recent decoding of various genomes has the idea that gene placement is relatively important in determining trait expression been widely acknowledged.  Again, it is not in the interest of biotechnology companies to devote considerable resources to such complex questions, as the state of knowledge regarding the subject is so weak.  Their job is not science but technology, not theory but application.  Rushing forward with first- or even second-generation applications without a good understanding of the importance of gene placement is not prudent.  What good is it to make a decision based on current understanding when current understanding is so poor?  Only public agencies are in a position to govern the actions of biotechnology companies for the public interest, and FDA should assess its knowledge of genetics carefully before making decisions based on that knowledge.

Full responsibility

OTA applauds the point in FDA’s 1992 policy that “developers of new foods have a responsibility to ensure that biotech companies should take full responsibility for their products”.  As FDA has recognized in its proposed rule, this policy has implications for the process of approval, a number of which are considered below.

Misleading marketing

FDA must also ensure that food produced through biotechnology is not labeled or marketed in a misleading manner.  The marketing of “golden rice” is an example of misleading marketing, in that positive effects of the vitamin A are claimed which are in fact realized only when additional dietary items are ingested.  This is another example of thinking in terms of specific intended results rather than the effects of interactions of the product with other systems.  In this case, it lead to a claim that was questioned even by the product’s funder [ii] [iii].  FDA should not have allowed such a marketing claim for “golden rice”, and it should require all such claims to be independently evaluated before being allowed.

Specific Comments

I.  Background


On page 4707 of the proposed rule, FDA writes that comments suggest processes “to ensure that {FDA] remains aware of new bioengineered foods entering commercial distribution”.  OTA believes that FDA should not only be aware of the food American eat, it should regulate the introduction of those foods.


On page 4708, FDA mentions the use of antibiotic resistance markers.  This practice may not be conducive to public health and should be prohibited.  Ideally, each biotechnology product should have a unique and biologically and ecologically benign genetic marker for identification.


On page 4708, FDA says that “the resolution of these and other scientific issues entailed the use of nontraditional approaches to the evaluation of food safety”.  OTA suggests that because bioengineering is a nontraditional approach to the production of food, the parameters for evaluating food safety must be reassessed, along with the state of knowledge regarding genetic expression.  Gaps in knowledge must be identified and producers of novel foods must be required to satisfy valid scientific questions regarding the effects of their products.  If producers cannot answer questions regarding the effects of their bioengineering, the products of such bioengineering should not be allowed in the food chain.  “Reasonable” test procedures cannot be based in any way on commercial viability.  Additionally, all vectors into the food chain of unapproved products of bioengineering, including genetic drift, must be considered by FDA in assessing the safety of a bioengineered food.  This is the only way to prevent further food chain disruptions such as those presented by the apparent escape into the environment of the Cry9C gene from StarLink corn.


On page 4708, FDA writes that “there does not appear to be any new scientific information that raises questions about the safety of bioengineered products currently being marketed”.  OTA respectfully notes that 1) many questions do remain regarding genetics, let alone the effects of genetic engineering; 2) much of the science being conducted is for very narrow purposes, and is really application, or technology, rather than disinterested scientific investigation.  In short, there are an abundance of scientific questions about the effects of genetic engineering in general, of which questions regarding any specific product are only a subset.  The only conclusion that is certain is that the state of knowledge regarding the effects of genetic engineering is poor.

II.  Legal Authority

On page 4709, FDA refers to “the directed modification” of the composition of foods.  As much as those producing biotechnology products would like to present the process as precise, or directed, commercial techniques are essentially random.  The only aspect that is purposeful is the selection of the genes to be modified and the gene or genes to be added.  In practice, the placement of the gene is still imprecise.  OTA cautions FDA against adopting of biotechnology industry perspectives when the fundamental issues are still being debated within the scientific community.


Similarly, FDA refers on page 4709 to “specific, well-characterized genetic material”.  This is the only specific, well-characterized aspect of the whole process.  The material’s eventual placement on the target chromosome and all of the myriad relations the new genetic material has to other genes are not at all well understood.


Also, when FDA writes that “transferred genetic material can be presumed to be GRAS”, OTA cautions FDA against failing to consider the dynamic nature of biological organisms.  Elsewhere, FDA recognizes the effects genes may have upon metabolic pathways and that there may be unintended consequences; the composition of the specific genetic material is not the question.  This is like saying that because all matter is composed of electrons, protons, and neutrons, all matter is essentially the same.  It is the relationship of genes to their chromosome that is in question.  Furthermore, this statement is incompatible with FDA excellent point on pages 4710-4711 that unintended consequences must be identified and any problems obviated.


On page 4711, FDA asked for comments “as to whether it should include foods developed from wide crosses or any other breeding methods in the scope of any final rule based upon this proposal.  OTA fully supports FDA in not including these considerations; the reasons FDA gives on the same page are sufficient.


OTA does not agree that the only changes which should change the legal status of the food are those which deal with the composition of the plant.  What may arguably be an insignificant change in the composition of a plant may have a significant effect on the expression of various life processes.  OTA requests that if FDA adopts this policy, that the policy reflect both the composition and the life processes of the plant.  Further, any condition of substantial equivalence should be demonstrated and not merely assumed based on analogy.  Because of the lack of knowledge regarding whole-organism effects of genetic engineering, OTA proposes that FDA require premarket approval for all foods developed using rDNA technology and introduce an across-the-board requirement that all such foods bear special labeling, until such time as the whole-organism effects of genetic engineering are well known.


On page 4712, FDA writes that “FDA believes that the food products of rDNA technology are appropriately made subject to greater regulatory scrutiny by FDA in the form of enhanced agency awareness of all such foods intended for commercial distribution”.  OTA would agree with this only under the condition that such enhanced agency awareness includes consideration of a scientific review of the foods in question which is independent of commercial interests.


OTA supports FDA’s proposal on page 4712 that “the notification program that is described in this document be mandatory”.  OTA further proposes that independent review of commercial information be required, and that it is the responsibility of the producer to bear the expense of such review.  For obvious reasons of conflict of interest, the producer should not administer the program; therefore, associated costs would include the costs necessary for FDA to oversee such a program.

III.  Scope

OTA approves of the scope proposed, but requests FDA consider a rule prohibiting animal-derived bioengineered foods.

IV.  Definitions

OTA requests that the term “bioengineered food” should include any food which contains ingredients which have been produced through biotechnology.


OTA further requests that FDA include in the definition of “transformation event” specific examples for clarity, such as the clarifying sentence “Such events would include recombinant DNA, cell fusion, and micro- and macro-encapsulation”.

V.  Requirement for a Premarket Biotechnology Notice

OTA opposes excluding a bioengineered food from the notification requirement on the grounds that it “derives from a plant line that represents a transformation event that has been addressed in a notice previously submitted to FDA”.  This policy would not recognize that plants evolve, and that the results of one transformation event, or one generation of events, is likely to undergo changes over successive generations.  See Palumbi (op. cit.) for an overview of the issues of the evolution of genetically engineered organisms.

VI.  Recommendation for Premarket Consultation

OTA supports FDA in encouraging “developers of bioengineered plants that are not intended for use in food or feed, but that theoretically could enter the food supply, to participate in the consultation program described in this proposed rule” (p. 4714).  OTA notes that genetic drift can and does occur between species and that genes introduced into relatives of plants intended for food may well cross into food plants.


OTA supports the provisions under “A. Presubmission Consultation Program”, “B. Public Disclosure”, and “C. Standards Procedures”, with the understanding that all recommendations will become requirements.

VII:  Premarket Biotechnology Notice:  Administrative Information

OTA supports the provisions under this section, again with the understanding that all recommendations will become requirements.  OTA notes that if a company lacks the means to submit information electronically, FDA should seriously question that company’s ability to perform responsible genetic research and development.

VIII.  Premarket Biotechnology Notice:  Required Parts

Under the proposed Section 192.25(g), or perhaps under a new Section 192.25 (h), FDA should require information not only regarding specific substances produced by the introduction of new genetic material, but also regarding the relationship between all introduced genes and the whole organism, including a discussion of the effect of the genetic material on the receiving organism’s metabolism; the function of the sequence of genes into which the new genetic material was inserted; and any other information which increases understanding of changes in the structure or function of the organism receiving new genetic material.


Regarding subsection 4 in the preamble, OTA believes that producers of novel foods should not be allowed to claim a lack of scientific data for not including “other relevant information”.  It is the responsibility of the producer to ensure that the results of genetic engineering are safe  Producers should be required to demonstrate that they have systematically examined the ways in which new genetic material can and does affect the whole organism.  If necessary, FDA should publish guidelines for such a review to ensure that both producers and the public can know what criteria are being used to evaluate novel products.  This provision would also provide the scientific community with consistency in the comparison of various data.


OTA strongly supports “a requirement that a premarket notice for a bioengineered food [should] include methods by which the food [may] be detected”.  It is essential for organic producers to be able to verify that their products have not been contaminated by materials produced through “excluded methods” (genetic engineering).  Clearly, antibiotic markers are inappropriate for this purpose because of the public health implications.  OTA further proposes that each producer use a distinct, unique marker to assist in tracing material to its developer.


Under subsection 5, “Narrative”, OTA proposes requiring producers to include a discussion of the effect of any new genetic material introduced on the whole organism, including any interactions it has with other genes and any effects it has on the organism’s metabolic pathways.


XI.  Proposed Regulations Regarding Bioengineered Foods That Would Be Used In Animal Feed


OTA strongly supports the additional requirements under this section and requests FDA to require producers to consider the effect of the new genetic material on the whole organism.

XV.  Environmental Impact

While OTA recognizes that requiring producers of biotechnology foods to engage in premarket consultation with FDA will not significantly affect the human environment, OTA notes that the approval of new organisms has already had a significant effect, especially on the producers of organic foods and fiber.


OTA also encourages FDA to act in the public interest by engaging in inter-agency consultation with EPA and USDA.  Genetic engineering bridges the perceived gaps between agriculture, food, health, and our environment.  No one agency can oversee the entire biotechnology industry, but instead of drawing distinct boundaries between the responsibilities and concerns of various agencies, agencies should create consultations in which areas of mutual concern may be addressed as part of a greater whole.

[i] Palumbi, Steven R.  The High Stakes Battle Over Brute-Force Genetic Engineering.  The Chronicle of Higher Education, 4/13/01.


[ii] Pollan, Michael.  The Great Yellow Hype.  The New York Times Magazine, 3/4/01.


[iii] Hesman, Tina. Bioengineered rice loses glow as vitamin A source.  St. Louis Post-Dispatch, 3/4/01.


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