FDA Policy: 1994 to the Present 

JAMES MARYANSKI, Ph. D. , Biotechnology Coordinator for Food Safety and Applied Nutrition, FDA 
at the Public Meeting 
"Biotechnology in the Year 2000 and Beyond" 13dec99

The meeting was convened in the Auditorium, Federal Building, Oakland, California, at 9:00 a.m., Sharon Smith Holston, Deputy Commissioner for International and Constituent Relations, Food and Drug Administration, presiding.

DR. MARYANSKI: Thank you, Ms. Holston. Good morning, ladies and gentlemen.

I'm Jim Maryanski. I have the honor this morning of explaining to you what we do with foods that are produced by modern biotechnology, and some of the experiences that we've had over the past several years. We'd like to give you a little context for the discussion that we will be having throughout the day today.

If I might have the slides, please.

Just to sort of tell you a little bit about who we are, the Food and Drug Administration, as many of you know, is an agency in the Department of Health and Human Services. And just to give you an idea of where we fit in the scheme of things, there are other public health agencies that make up this department, including the National Institutes of Health and the Centers for Disease Control and Prevention. And, so, FDA and NIH and CDC are health-protection agencies within this larger department.

The law that FDA has responsibility for carrying out and insuring the safety of the products that it regulates is the Federal Food, Drug and Cosmetic Act.

This is the law that Ms. Holston mentioned has been in place since 1938, and provides the basis for the oversight that FDA has for assuring the safety of foods and other products that we regulate.

I think I will explain to you in a few minutes just what those products are that this law covers. But I think it's important to understand that this law is very broad, covers many aspects of consumer protection, and it is consumer protection that is our mission.

Our approach to protecting consumers is based on the best science that is available. So our policies and regulations are science-based policies. And we regulate foods that are interstate commerce. We don't regulate foods that are in research; but we do regulate foods that are for sale, both imported into the U.S. and on the market in the U.S. So it is the commercial part of the food chain that FDA has responsibility for.

I'd like to give you a little sense of how products of modern biotechnology fit within the broader federal system in the U.S., because there are a number of agencies that have responsibilities for various aspects of the safety of these products. Of course, FDA is responsible for the safety of foods, and that means we are responsible for most foods. The Department of Agriculture has oversight over meat, poultry and egg products, in terms of inspecting those products. But FDA has oversight over all the other things in the grocery store. And, so, if you think about the diversity of the products in the grocery store, and that includes all the substances that are added to foods, you think about the ingredient package labeling, all the substances that are added to foods, fall under FDA's authority.

So, in terms of biotechnology products, the same applies. Those products fall under the act just as other products produced by other methods. There is no difference in the way FDA exerts its oversight.

The Department of Agriculture is responsible for many of the issues that relate to environmental concerns. They, of course, have authority to insure that plant pests are not introduced into agriculture, both in terms of plants and seeds that are transported in the U.S., as well as materials that come into the U.S.

The Environmental Protection Agency, or EPA, has responsibility for pesticides in the food supply and, of course, elsewhere. So, if a substance is introduced into food that is a pesticide, EPA is responsible for assuring its safety, for setting tolerances for its use in food, or for exempting it from those tolerances. But all pesticides must be registered by EPA before they're used in food.

Soy now, let me give you an example of a product produced by modern biotechnology, but falls under all three agencies in some aspects. The BT Corn, the corn that has been developed to produce its own pesticide substance. That corn is a product that the company would discuss and take through the process at USDA, for consideration of plant pest characteristics and a number of the environmental issues that would be associated with that plant. They would-also, of course, have to have the pesticide as produced by that plant registered by EPA before it could be used in food. And EPA's process for registration addresses both human safety of exposure to that pesticide and environmental issues related to the use of that pesticide. And, of course, FDA has responsibility for food products that are derived from that corn. So, for example, high fructose corn syrup is a product that is produced through the processing of corn that's used in soft drinks and other products. And, of course, most of the corn that is produced today from plants developed by modern biotechnology is used for animal feed. So both human food products and animal feed products fall under FDA. As I described our policy for foods today, I will be speaking of feeds at the same time. We consider them in the same manner.

In the late 1980s, FDA began to receive a lot of questions about the use of modern biotechnology in agriculture. At that time, as you have heard, we had already had experience both with pharmaceutical products and with the first food products, such as the enzyme rennet, or caymosun, that's used to make cheese. But we realized that the real large impact of biotechnology was going to be in agriculture, and really on things that we think of as whole foods. And, so, FDA convened a group of scientists within the agency to look at all aspects of this technology. And these scientists were asked to consider all possible impacts of this technology on the food supply. They were not given any restrictions whatsoever in terms of the law or any other constraints in terms of bringing the policy together. But they were asked to look at all possible impacts on health, and then to consider that within the framework of the Food, Drug and Cosmetic Act.

The purpose of that exercise was so that we could, first of all, understand the impact of this new technology on the food supply: How would these foods be similar, how would they be different from other foods; and therefore, how should FDA carry out its responsibility of public health protection? Also to answer the questions from industry about what kind of safety testing would be needed for these products, and what kind of regulatory process should be in place for these products to come to market. In other words, would they be regulated like other foods that are placed in the grocery store?

So the 1992 policy was intended to answer the questions that we were receiving at the time. It was not intended to look forward five or ten years later. We wanted the policy to be flexible. We knew this was a new technology. We wanted to be able to answer the questions at the time based on the types of products that were coming then, and leaving ourselves sufficient flexibility so that we could adjust if there were changes in the future. This, of course, is a policy based on the Food, Drug and Cosmetic Act, and the policy applies to foods derived from plants developed by all methods of plant breeding. There are many methods. We're familiar with cross-hybridization and the sexual processes of mating plants, but breeders have many other different methods of introducing, coaxing plants to do things that they would like them to do that will be beneficial in agriculture and food production.

Our conclusion was that the Food, Drug and Cosmetic Act applies to all foods, and that all foods should meet the same standards. So we do not have a different standard for products of modern biotechnology. So the policy applies to plants produced by all methods of plant breeding. And it applies to human foods and animal feeds. This policy explains the regulatory framework and the scientific approach for assessing safety for products, such as fruits and vegetables, and cereals, and the products that are derived from those types of plants, such as vegetable oils and food starches.

The policy that we published in 1992 really explained how foods have always been regulated, and how foods that are produced by modern biotechnology can fit within that framework. FDA has two tools that it uses primarily to insure the safety of foods in the grocery store. If a food would pose a health problem to consumers, if we know something about that food, that we know that it will be unsafe, we have very broad enforcement authority to remove that product from the market. That system works because, of course, companies do not want to be in that situation, nor do their customers, who will ask to make sure that the product is okay with FDA before it goes to market. And, of course, it works because FDA has very strong enforcement authority. We, of course, can issue injunctions and seizures against products, and we can even initiate criminal prosecution against those who place an illegal product on the market. So the law is a very strong law in terms of enforcement. Foods are not required to undergo pre-market approval by FDA. So new varieties of corn, for example, or soy beans, do not necessarily - do not come to FDA for approval before they go to market. But the Act places the legal responsibility for the safety of these products on the developer, on the purveyor of the product. And FDA's job, then, is to provide the guidance to make sure that these products are safe, to make sure that the purveyors know what the standards are; and, of course, to remove products from the market if they do not meet the standards.

There is pre-market approval for substances that are added to food that are food additives. These would include substances such as new flavors, thickeners, preservatives, any substance that is added to food that isn't otherwise exempt from this part of the Act. Pesticides, for example, are exempt because they are regulated by EPA. But there's also a large category of substances that we call GRAS substances, G-R-A-S, Generally Recognized as Safe. Congress has established this exemption because they're are many substances that have been used safely in foods, such as flavors, spices, vinegars, sugar, food processing enzymes, and so forth, and did not intend that all of those, that type of substance, would undergo pre-market review. But this gives us the tool to insure that any substance introduced into food through modern biotechnology that is not generally recognized as safe will be reviewed and approved by FDA before the food goes to market. And we have said that there are many substances introduced into food through plant breeding, and that many of, those substances have been safely consumed. And to the extent that a substance is introduced into food through modern biotechnology or other means, and it's derived from food where it's been safely consumed, we will presume that that substance is really exempt from the Food Additive requirement.

On the other hand, we have also said that there are many substances that are very similar to substances found in food, even though they come from very diverse organisms. And to the extent that that is the case, those substances are also considered to be, presumed to be, GRAS. But we have the legal hook. If someone can put a substance into food using this, or any other technology, for which there is not a basis for us to presume that that substance is GRAS, it will be required to undergo pre-market review. And we've published extensive guidance for developers.

This is really the crux of the 1992 policy: to make sure that developers know the kind of safety issues that should be taken into account in evaluating new varieties for commercial food use. And it really is this part which was new in 1992 in the sense that what we said wasn't new. We think that there are practices that breeders normally follow, but we put it down on paper so there could be no mistake about what the standard is that FDA expects for these products to meet. And we also set up a consultation process to make sure that companies had an opportunity to make sure that they knew all the steps that need to be taken so that they could. meet their legal duty in bringing these products to market.

This was something that evolved after the publication of the 1992 policy and our review of the first product, the FlavrSavr Tomato. FDA conducted a full review of that product at the request of the company. That review was a review that lasted about three or four years, and we worked with the company right in the beginning, helping them design the tests. Because, in fact, this was the first time that anyone had come to FDA and said: Well, how do we apply modern biotechnology, or modern science, rather, to a food? In other words, most foods have been accepted on the basis of experience and use. Now the question was: Well, actually, we would like to provide some additional assurance and use modern analytical and other methods to assure the safety of these foods. How will we do that?

We're very used to looking at the safety of single chemicals as food additives, that are added to food. We realized that this was a very different question because a food is composed of many substances. And, so, we had to think about that quite hard in terms of developing a process to assure that this food would be safe, as safe as other foods in the market. And we discussed the approach that we presented in the 1992 policy with our Food Advisory Committee in 1994, which is a committee of experts from outside of FDA and includes academic, consumer and industry representatives. Those committee members felt that the approach that had been used for the FlavrSavr, and that we were proposing for other similar products, was scientifically sound; but they also said to us that, given the nature of the FlavrSavr product, and other products that we were seeing at the time, they did not, in fact, raise substantial safety issues, and that FDA might better use its resources by having some sort of process that was more abbreviated where we would still have some oversight of this new technology, but not commit the kind of resources that we did to this full scientific review of the Flavr Savr Tomato. And we felt that, given the nature of the products we were seeing at the time, that was appropriate.

We developed what we now call the "consultation procedures," and discussed those again with our Food Advisory Committee, and our committee that assists us in areas on veterinary medicine, such as animal feeds. And again, the Committees felt that the consultations that we have in place were an appropriate mechanism given the nature of the products.

The way consultations work is: Our guidance is there for companies to use and to consult with us on particular scientific issues, such as evaluation of nutritional changes, or assessment of possible allergenicity. What we do ask companies to do is to provide us a comprehensive summary of the information that they have developed when they feel they have completed all the work that they need to do. That information - which usually is a hundred to several hundred pages in length - gives the FDA scientists an opportunity to make sure that all safety issues have been resolved before those products go to market. And that is the system that has been in place since 1994, and there are about 45 products that are now listed on our home page, where companies have completed their food safety and nutritional assessment discussions with FDA.

I'd like to just give you a little bit of sense of some of the principles that underlie our approach to safety assessment.

The products that we're seeing, of course, are familiar food crops. They're corn, soy beans, potatoes, tomatoes. They're not something that we've never seen in food before. And we felt that, because these are products that have been modified, but they're based on conventional crops, that the food that we have today should be the standard. FDA should not ask developers to prove that tomatoes are safe to eat, or that corn is safe to eat. In fact, we know that, if one subjected many of our foods to the kinds of extensive toxicological testing, they might not pass because they contain many different substances that can cause effects in food.

What we thought was important is that the food, as the standard, should be what is used to compare the new variety. The new variety should be looked at in terms of what is similar, what is different about this new variety in terms of food safety, and that we would have to use a different approach than we normally use for single chemical, such as food additives. We would have to look at many different kinds of information. Plant breeders do extensive evaluations of new varieties over a period of time during development, and that that agronomic and the quality characteristics that plant breeders evaluate for individual crops is a very important process in determining whether a product is suitable to come to market.

We also have some new tools. Modern biotechnology gives the tools to develop new products. It also gives us a way to know more about those products, to know the identity of the genetic material, to know the identity and the function of the proteins and other substances that are new in food as a result of the use of that technology. And so that that information would be very important to the assessment of the safety of these products.

In addition, we recommend to companies that they take some extra steps that are not normally done in plant breeding. That they develop information to show that, in fact, the foods have not been changed in the ways that are important in terms of their nutrients, and other components of the food, the vitamins, minerals, that I will show you in a moment. But really to assess whether the food is, in fact, the same as what is expected in addition to, of course, whatever change had been made in that food.

There could be circumstances where we would recommend that further testing be done. And I will give you some examples. But we don't generally recommend that animal tests be conducted with these foods, because the tests are very difficult to design, and they cannot be done in the same way that we do for standard chemical toxicity testing.

Maybe if I could -- it looks a little out of focus, but there could be situations where we would have a new protein expressed by a gene introduced into a plant that would be very different from the proteins that have been safely consumed. So there would likely have to be additional tests that would be done for that substance, or other new chemicals that would be in the food as a result of genetic alterations. If a new substance showed similarity to an allergen, or to a toxin, there would have to be additional testing to assure that that product was safe.

To give you an example, you may have heard in the news about a potato developed in Europe that contained a substance called Lectin. Lectin is a substance that, as a class, there are a number of those substances that are very toxic. If that product were presented to FDA, there would have to be extensive toxicity testing in order to establish that the substance, that the potato, was actually safe for consumers. So there can be a number of circumstances where there would be additional testing. These, of course, are just some examples.

I would just. like to give you a sense of the kind of information that is being developed on products of modern biotechnology. This is really our recommendations for foods derived from all methods of plant breeding. But it takes into account the change that has been made in the plant that is the intended change that has been made, and whether there would be any new substances introduced into the finished food by that modification, and what would be the identity structure and function of that substance? Is it, of course, safe to consume? Will it present allergic reactions to consumers? Is it a substance that is present in food at very high levels? To date, most of the substances, all of the substances, in fact, that have been introduced into food have been present at very low levels. They're enzymes.

Remember, FDA does not look at the pesticide substances. EPA has oversight over those. All of the substances that fall un-der FDA to date, in terms of new substances in food, have been enzymes. They're present at very low levels in the food. They've been shown to be very readily digestible and not similar to any known toxins or allergens.

There could also be nutritional changes in the food that would be important. This is an issue that is particularly important in animal feed, because animals often have a diet that consists primarily of one crop.

And, so, a change in the nutrition of that crop can have potential ramifications in feed use. But that, of course, could also be true in humans, a human diet. And we have to look at changed in nutrition with respect to the overall diet that people consume.

In addition to the intended changes, we ask companies to consider what unintended or unexpected changes might occur in the plant and ultimately in the food. It is well known, of course, that, in plant breeding, there often are unintended or unexpected effects that occur, and plant breeders take that into account in terms of the observations in bringing new varieties to the market.

But we have suggested some additional steps to minimize the likelihood of unexpected changes. First of all, by insuring that any inserted genetic material in the plant is stablely inserted so that it's not moving around, perturbing the chromosome.

And secondly, companies are doing extensive analytical studies to insure that the important, or the key components of the plant, are what is expected for commercial varieties of that crop.

I would like to just give you briefly some examples that we have taken from some of the information that has been submitted to us. I'm going to show you essentially composite information because there's quite a bit of information that we have, but just to give some examples of the kinds of things that are looked at in bringing a product to market.

Typically, of course, there are many characteristics, such as plant morphology, flower color, time of flowering, resistance to disease, the percent of oil and quality of protein that are observed for soy beans. And I'm using soy bean as an example because it's one of the major crops that has been developed by modern biotechnology. But these, of course, would be dependent on the type of crop and where it will be grown, and the breeder normally will do tests over several years in several different locations and field sites in order to assure that this plant is performing in the way that it's expected to perform. These are just a few of the characteristics that are taken into account during this process.

There are also, of course, a number of types of information that are accumulated during development based on the molecular change, that is, the change using modern biotechnology techniques. What kind of information has been introduced into the plant and is it stable? Does the plant reproduce from generation to generation in the manner that would be expected? And, of course, I've already discussed the safety of new proteins, nutrients, anti-nutrients. Soy beans in particular, of course, are known to cause allergic reactions in some individuals, and companies have actually done analyses to assure that the native, or normal, allergens that are present in soy beans have not been increased in these new varieties. In addition, companies also do wholesomeness studies in feeding to animals to be sure that the animals growth, and so forth, is typical for these new foods.

I'm going to go through several slides fairly quickly, but I would just like to give you a sense of the kinds of information that companies submit to FDA as part of a consultation. That, of course, reflects the kind of testing that they are doing.

This shows what is called the proximate analysis of seed, but this is carbohydrate fat protein, and these are fiber analyses for digestibility of the seeds. And, of course, it's typical to control the product of modern biotechnology with its appropriate counterpart that is not modified. But these values are also looked at in terms of the range that is typical for this crop. Because various parameters vary considerably depending on environmental conditions, growth conditions, genetic background, and so forth. And, so, it's very important to look at these values in terms of what has been accepted commercially, what is typical of this crop. Analyses are done for minerals that are typical of the crop in the same manner. oils, or course, is very important to insure that the fatty acid composition, the composition of the vegetable oil, is what is expected.

The same for the proteins where the protein will be an important food ingredient derived from the soy bean. These are just a few examples of the amino acid analysis that would be done to assure that the protein quality of the protein derived from the soy bean will be typical of what is expected. And there are other substances that can affect nutrition of both humans and animals that are typical of soy beans. Analyses are also being performed on those types of substances.

Those are just some of the kinds of information that companies are generating to assure that these products are as safe as other foods. To date, there are actually a limited number, but a growing number of crops that have been produced through modern biotechnology. There are sugar beets, canola, corn, cotton, potato, soy bean, flax, radicchio, squash and tomato. These are the crops that, to date, companies have completed food safety discussions with FDA. So you can see that actually there are some major crops, but it's also a relatively limited number of crops at this time.

To give you a sense of what some of the changes are that are introduced into these crops, they're also limited in terms of the types of modifications that are being done. This is just the beginning of this technology. And, so, many of the crops - in fact, the majority - are herbicide tolerant; others are resistant to insects or viruses. Some have altered ripening, such as the modified tomatoes. And then there are other products, such as vegetable oils, that have been modified.

We have two examples where there are completely new products, in the sense that they've been modified such that they are not similar to their traditional counterpart. One is a product that is a.soy bean oil that has been modified to increase one of the fatty acids that's typical of soy bean, oleic acid. And that product, that now has a very high level of oleic acid, as a result of the genetic change, is very different than soy bean oil. It's an oil that can be used for high-temperature frying without processing before it's -- soy bean oil typically has to be processed before it can be used for high-temperatures. So this product is a very new product. It, of course, has a different name. It's called High Oleic Soy Bean Oil.

There is a second product called Lauric Canola, which is a variety of canola oil in which a fatty acid lauric acid has been introduced into the canola plant, and that again produces a very different product. Lauric acid is not a new substance. in food. It is found in tropical oils, such as palm oil. But the canola oil that contains this lauric acid is very different. It's not a vegetable oil that you typically think of as the bottle on the shelf in the grocery store. This oil is used in confections and coffee whiteners. It actually has a relatively limited use in food.

So we have two products that are fairly different. Most of the products, of course, are more typical of agriculture. It's typical for plant breeders to want varieties that resist insects and disease, and to be tolerant of other agricultural conditions. In the future, we expect to see a number of different health-enhanced varieties. But these are the products that we have seen to date.

I'd also like to give you a sense of the time period, and just what happens when companies bring these products to market. Usually, it is typical - what we're showing here is the time frame in months on this side (indicating), so this is 15 months, for example; and presubmission is what it says on the bottom. That really is the time that companies discuss these products with FDA before they complete all of their safety assessment data. And you can see that, while it varies considerably, it's not unusual for companies to spend a year, or two years, talking to FDA. Because, what typically happens is: They come to the agency and talk to our scientists about the kinds of test they're planning to do. And that gives our scientists an opportunity to suggest different tests or modifications of the kinds of tests. In other words, to help them design appropriate kinds of testing. For some products that we have seen before, often the consultations may be very brief.

What we do tell companies we expect is for them to consult with us, to provide us substantial information about the testing that has been done when they have completed it, so that we have a chance to make sure that all the proper testing has been done. You can see this time frame is more in the five to several months period that FDA spends looking at the submission that the company feels is a complete package.

When we are satisfied that the company, in our view, based on the information we have seen, has answered all the questions, we do provide the company with a letter that says not very much. What the letter says is: We don't have anymore questions based on what we know today. And we remind the company that it is their continuing obligation to insure that these products meet all the provisions of the Food, Drug and Cosmetic Act.

So this is the process that has been in place. This process of consultation is described on our home page. Currently, there are about 45 products that are also listed there for which companies have completed this process.

So, what do we expect? We expect that new foods will be as safe as the foods that are in the grocery store today. And what does that really mean? It means, of course, that the food cannot have an unimproved food additive in it. It must -- that would be an illegal product. So there cannot be a new food additive. It cannot contain a substance that would be harmful to humans or the food would be adulterated. FDA would have to initiate actions to take the product off the market. It would have to meet all the provisions of the Food, Drug and Cosmetic Act. This is what we mean when we'say that the food must be as safe as today's foods that are on the market.

Thank you for your attention. [Applause.] .

COMMISSIONER HOLSTON: Thank you so much, Jim, for your presentation.

All right. We're a little ahead of schedule, which is a good thing. So, right now, we are going to take a 15-minute break; and, then, when the break is over, we will begin the panel discussion on the scientific, the safety, and the regulatory issues.

It is now 10 minutes to 10:00 according to my clock; and, so, we are going to ask that everyone return and be back in place at 5 minutes after. Let me remind you of something that I should have reminded about before, and that is: There are no foods or drinks, including water, allowed in the auditorium. So please remember that when you return from the break.

Thank you.

source: 101 page PDF file http://www.fda.gov/ohrms/dockets/dockets/99n4282/tr0003a.pdf 2nov02