THE FOOD ADDITIVES AMENDMENT OF 1958

III. THE FOOD ADDITIVES AMENDMENT OF 1958

The concept of the 1958 Amendment was quite simple. Congress divided the food supply into four categories. First, it made a distinction between food itself and the substances added to food. Second, it set forth three categories of added substances: (1) added sub- stances approved by FDA or USDA during 1938–1958 (which have come to be called prior-sanctioned substances) (14), (2) added substances that are generally recognized as safe (which have come to be called by the acronym GRAS), and (3) all of the remaining added substances in the food supply, which are neither subject to a prior sanction nor GRAS, which were defined as food additives. For food itself and for prior-sanctioned and GRAS substances, simple policing controls were retained and no premarket approval was required. In contrast, food additives were required to be the subject of premarket testing;

a petition had to be submitted to FDA to request the establishment of safe conditions of use; and the promulgation by FDA of a food additive regulation establishing the specific conditions under which the additive can be used in the food supply had to be made (15).

The Food Additives Amendment covered two different kinds of additives—direct additives (incorporated directly into the food supply) and indirect additives (used in vari- ous types of food-contact applications, such as packaging and food machinery). The 1958 Amendment also covered additives used in animal feed and pet food. This chapter deals primarily with the subject of food additives and food substances that are directly added to human food.

A. The Transitional Provisions

One of the first policy choices that must be faced in enacting any new regulatory statute is how the statute will be applied to products already on the market. Congress handled that in two different ways under the 1958 Amendment. First, it excluded from the definition of

a food additive, and therefore from the requirement of premarket approval, all food and all substances that were subject to a prior sanction or were GRAS. Accordingly, these substances were permanently excluded from premarket approval (except to the extent that

a GRAS substance subsequently lost its status as GRAS). Second, for those pre-1958 substances that were not prior-sanctioned or GRAS, and thus properly fell within the a GRAS substance subsequently lost its status as GRAS). Second, for those pre-1958 substances that were not prior-sanctioned or GRAS, and thus properly fell within the

The 1958 Amendment became law on September 6, 1958. New Section 409 of the FD&C Act, regulating food additives, became effective six months later. One year after that, all pre-1958 additives were required to have obtained FDA approval and promulga- tion of a food additive regulation. FDA was authorized to extend that period for an addi- tional year. Thus, all pre-1958 food additives were required to be the subject of food additive regulations promulgated by FDA no later than March 1961.

This schedule proved impossible to meet. In 1961, Congress therefore enacted legis- lation allowing a further extension for any specific food additive to June 30, 1964 (16). By another law enacted in 1964, this was again extended to December 31, 1965 (17). No further statutory extensions were granted. Accordingly, Congress ultimately provided just slightly over seven years for industry to prepare and to submit to FDA food additive petitions, and for FDA to review these petitions and promulgate food additive regulations, for all of the pre-1958 food additives. During the same time, FDA was required to deal with the prior-sanction and GRAS provisions of the new statute and to handle food additive petitions for post-1958 food additives.

The handling of all of the pre-1958 direct human food additive petitions in seven years reflected a heroic effort by FDA. It required the development and organization of

a group of dedicated scientists within FDA, close daily cooperation between FDA and the regulated industry, and a commitment by everyone involved to work through the inevitable problems that arose in a practical and realistic way. No one either in industry or in FDA had the luxury of sitting around for months or years on end, debating theoretical issues. There was a job to be done, and it was done extraordinarily efficiently and with unprece- dented success. Not a single additive that was approved during that time has since been removed from the market for lack of safety. The people who participated in that effort, many of whom still are alive today, deserve far greater recognition than they have been given to date.

By the time this transitional process was completed, FDA had promulgated 185 separate direct human food additive regulations, along with an additional 93 indirect food additive regulations, five regulations governing radiation of food, the lists of GRAS sub- stances, and additional lists of prior-sanctioned substances (18). All of these substances were evaluated by FDA, regulations were promulgated, and effective dates were con- firmed. It was an extraordinary outpouring of regulatory science. The productivity of FDA at that time in history stands in stark contrast to the inefficiency and paralysis of today.

B. The GRAS List

At the same time that it was laboring to implement the transitional provisions for food additives, FDA also sought to respond to the need to clarify the scope of the GRAS exclusion from the definition of a food additive (19). Based upon the personal knowledge of FDA scientists and a limited survey of academic experts, FDA proposed and promul- gated regulations that collectively became known as the GRAS list, consisting of some 450 direct human food GRAS substances (20).

The statue and its legislative history were clear, however, that the FDA GRAS list was not definitive or all-inclusive. Indeed, there was no statutory requirement that FDA even publish a list of GRAS substances (21). The statute excluded GRAS substances from The statue and its legislative history were clear, however, that the FDA GRAS list was not definitive or all-inclusive. Indeed, there was no statutory requirement that FDA even publish a list of GRAS substances (21). The statute excluded GRAS substances from

Four decades after its enactment, many important aspects of the scope of the cover- age of the 1958 Amendment, and the GRAS exclusion, remain unexplored and uncertain. No court has ever addressed the question whether a food loses its status as a food, and becomes subject to analysis under the 1958 Amendment, when it is combined with other food and food substances in a processed product (23). No court has ever addressed the issue whether deliberate genetic selection, or recombinant DNA technology, to change the characteristics of raw agricultural commodities results in that food losing its status as

a food and becoming a food additive. Issues like these, which have major implications for food technology and food policy in our country, are yet to be resolved. As a practical matter, it is the GRAS exclusion that has covered all of these developments, and that has largely made them moot up to this time.

C. The GRAS List Review

In the fall of 1969, Abbott Laboratories announced to FDA that an animal bioassay had shown a combination of saccharin and cyclamate to be carcinogenic. Cyclamate had origi- nally been the subject of a new drug application, but became reclassified as a food sub- stance and was included in the GRAS list promulgated in 1961 (24). FDA promptly re- moved cyclamate from the GRAS list (25) and, after a futile attempt to restore its status as a drug (26), banned it from the food supply (27). In his consumer message of November 1969, President Nixon ordered FDA to review the GRAS list to assure the American public that the food substances on that list were in fact GRAS and were not subject to safety concerns similar to those for cyclamate (28).

This began another heroic effort, comparable to the seven-year review of pre-1958 transitional food additives. This time, however, FDA turned to an outside organization to do the job (29).

The Food and Drug Administration contracted with the Life Sciences Research Of- fice (LSRO) of the Federation of American Societies for Experimental Biology (FASEB), which established a Select Committee on GRAS Substances (SCOGS) to conduct the GRAS List Review. The Select Committee on GRAS Substances was organized in June 1972. Under strong and able leadership, it held fifty 2-day executive sessions over a 5- year period, and reviewed and prepared substantial GRAS reports on some 400 substances on the FDA GRAS list (30). This was an extremely efficient and effective process. FASEB convened teams of experts who reviewed the published literature, conducted hearings to obtain the views of interested citizens and scientists, considered unpublished data submit- ted by the regulated industry, and arrived at documented conclusions in well-written re- ports, all in a very short period of time. By the end of the 1970s, FASEB had completed its job. The remarkable productivity and success of this venture stands alongside the FDA implementation of the transitional provisions of the Food Additives Amendment 15 years earlier.

By this time, however, the ability of FDA to handle its end of the process had begun By this time, however, the ability of FDA to handle its end of the process had begun

Even beyond this technical problem, however, the agency simply lost the capacity to process the FASEB determinations in a timely fashion. In spite of the fact that FASEB completed its work more than 20 years ago, as of today FDA has not only failed to com- plete its much more limited role in this process, but the end is still not even in sight. It has been a disgrace to the agency. Like the food additive matters that remain unresolved within FDA, this matter received no priority, no management attention, and thus no resolu- tion, until the Institute of Food Technologists and then Congress focused public attention on it in 1995. Recent attempts by FDA to reform the GRAS process are discussed in Section III.F.

D. Direct Human Food Additive Regulations

Once FDA completed its work on pre-1958 transitional food additives, it seems the agency lost heart on food additive matters. Since that time the record of FDA approval of new food additives is appalling. It is useful to review the FDA record on approving new direct human food additives over the past thirty years, from 1970 to the present. Research indi- cates only eight new direct human food additives during that time:

4. Acesulfame K, 1988 (35)

5. Gellan gum, 1990 (36)

6. Olestra, 1996 (37)

7. Sucralose, 1998 (38)

8. Sucrose acetate isobutyrate, 1999 (39) Eight direct human food additives in thirty years (40). That is embarrassing. It represents

a serious problem for food technology in the United States. Just at the time when we are learning more about the relationship between diet and health, and new food ingredients could contribute greatly to healthy improvements in our daily diet, we have adopted a regulatory system that has virtually destroyed the incentive to innovate and the ability to get new food additives to the market.

Let us also examine the history of one of the new food additives that languished in the FDA pipeline almost nine years prior to FDA approval: olestra. Information published on olestra shows that it was invented in 1968, the first meetings with FDA were held in the early 1970s, and it was the subject of continuing testing and negotiations with FDA until approved in 1996 (41). The story of the incredible journey of olestra through the food additive quagmire in FDA was so compelling that Congress enacted a statute to Let us also examine the history of one of the new food additives that languished in the FDA pipeline almost nine years prior to FDA approval: olestra. Information published on olestra shows that it was invented in 1968, the first meetings with FDA were held in the early 1970s, and it was the subject of continuing testing and negotiations with FDA until approved in 1996 (41). The story of the incredible journey of olestra through the food additive quagmire in FDA was so compelling that Congress enacted a statute to

The lesson taught by the problems encountered by these hapless compounds has been learned by the entire food industry. The food additive approval process in America is dead. It has been killed by FDA. No food company of which I am aware would even consider beginning research today on a new food additive.

The lesson learned is that there is only one type of food substance worth considering:

a GRAS substance that can immediately be marketed. If a new food substance cannot be determined to be GRAS, it is simply discarded. Only if it can be regarded as GRAS will it be pursued.

It is easy to be misled about the efficiency of FDA regulation of food additives by counting the Federal Register food additive notices during the past 30 years and not look- ing behind them. The vast majority of these notices relate to indirect food additives that have no possible bearing upon the public health. Indirect food additives are important, serve a highly useful purpose, and should not be given inadequate attention. At the same time, they do not deserve the same degree of scrutiny and FDA priority as new food additives added in significant amounts directly to the food supply. It is apparent that a completely separate and different process, with far less government involvement, is appro- priate for the category of indirect food additives. Recent FDA and statutory reforms in the regulation of indirect food additives are discussed in Section III.G.

Once a new direct human food additive is approved, there are always a large number of follow-on amendments that gradually expand its use to additional categories of food and perhaps for additional functional purposes. This is a direct result of the extraordinary conservatism of FDA in reviewing and approving the initial regulation. It is easy to read these and be misled that they represent real work and real progress. In fact, they are a direct reflection of the lack of any realistic evaluation of a new food additive by FDA and an extraordinary amount of sheer busywork as each new food use for an already- approved food additive must be the subject of yet another lengthy petition and review process.

Even as the ability of FDA to handle food additives was disintegrating, the agency announced an initiative—not required by the FD&C Act—to expand its food additive work. In January 1977, FDA presented to Congress an ambitious new program of cyclic reevaluations of previously approved food additives (44). Although FDA continued to pursue plans for the cyclic review for another five years (45), it died a natural death by the mid-1980s. In light of the agency’s inability to deal with new food additives, the objective of reviewing prior safety decisions was clearly unachievable. Common sense ultimately prevailed. The agency concluded that prior safety decisions would be reviewed when specific problems arise.

With the development of biotechnology, FDA has been forced to consider how new food substances made through recombinant DNA technology, and traditional plant and animal sources altered through that technology, will be handled under the food additive provisions of the FD&C Act. To its credit, the agency has avoided a rigid response and has instead adopted a very flexible and workable approach. Under the FDA policy an- nounced in 1986 (46) and 1992 (47), FDA clearly stated that the safety of a food or food substance, and not the process by which it is developed, will be the focus of the agency. Food derived from biotechnology will therefore be treated no differently than traditional food, except to the extent that the process of biotechnology adds a substance to the food With the development of biotechnology, FDA has been forced to consider how new food substances made through recombinant DNA technology, and traditional plant and animal sources altered through that technology, will be handled under the food additive provisions of the FD&C Act. To its credit, the agency has avoided a rigid response and has instead adopted a very flexible and workable approach. Under the FDA policy an- nounced in 1986 (46) and 1992 (47), FDA clearly stated that the safety of a food or food substance, and not the process by which it is developed, will be the focus of the agency. Food derived from biotechnology will therefore be treated no differently than traditional food, except to the extent that the process of biotechnology adds a substance to the food

The new food substances created by biotechnology have primarily been handled as GRAS (48), not pursuant to food additive regulations. For the first genetically altered food, a tomato, FDA required a food additive regulation only for the enzyme produced by the marker gene added to the food (i.e., the translation product), but not for the gene or the genetically altered food itself (49).

One of the most serious contributing factors to the decline of the FDA food additive process has been the development of rigid rules for evaluation of food additives. This concept has a long history. Dr. Dale Lindsay, Associate Commissioner for Science in FDA during the late 1960s, was the original proponent of establishing written guidelines for review of food substances, largely to guide the GRAS List Review. Industry strongly opposed this for the reasons that have later turned out to be correct—guidelines may begin as flexible recommendations, but they can all too easily become rigid requirements for which there is no exception. Scientific judgment is too often replaced by rules. Those rules, moreover, are designed to deal with every last possibility. Thus, tests are cascaded upon tests, anticipating any conceivable possibility that might arguably occur in the future. Using cookbook toxicology rather than informed judgment, guidelines can rapidly become

a reflection of the lowest common denominator, that is, incorporating every imaginable test, whether or not each test is fully justified from a scientific standpoint for any particular food substance involved (50).

The Lindsay approach was rejected in the late 1960s and early 1970s precisely for these reasons. In June 1980, however, an industry-sponsored Food Safety Council recom- mended a flexible decision tree approach to determining appropriate testing for food addi- tives (51), and in the early 1980s FDA concluded to prepare its own testing guidelines as an answer to the need for consistent FDA action. The resulting Red Book of food toxicology rules has become exactly what industry and food scientists feared—a rigid compendium of required tests designed more to protect an FDA reviewer from criticism than to protect the consuming public against an unsafe additive. The Red Book was adopted without any opportunity for notice and public comment of the type required for formal regulations (52). A draft of a revised version was made publicly available for comment in 1993 (53), but has never been subject to full public peer review and has not been finalized. Nonetheless, it is as rigidly applied as any provision in the statute or FDA regulations (54).

One of the major failings of FDA, as an institution, is that it cannot admit that it has ever made a wrong decision. There is no better example of this than the ill-fated non-nutritive sweetener cyclamate. Following its ban in 1969, the manufacturer sought repeatedly to obtain reapproval from FDA on the basis of substantial new scientific evi- dence (55). Cyclamate is now widely regarded as safe, within both the general scientific community and among FDA scientists themselves (56). To admit that the agency had made a mistake in banning it, however, would surely be politically incorrect. Even the recommendations of internal FDA scientists for reapproval have failed to result in re- turning this substance to the market.

As long as safety evaluation remains solely the domain of FDA, it is extremely difficult, if not impossible, to break down this institutional intransigence. Only if safety As long as safety evaluation remains solely the domain of FDA, it is extremely difficult, if not impossible, to break down this institutional intransigence. Only if safety

E. GRAS Affirmation

When FDA established its GRAS affirmation procedures as part of the GRAS List Review in the early 1970s (57), the agency recognized that it did not have the statutory authority either to preclude self-determination of GRAS status or to prevent marketing while the agency reviewed a self-determination of GRAS. In establishing its GRAS affirmation pro- cedure, the agency deliberately and explicitly adopted a policy of recognizing that industry had the legal right to market a new food substance following a self-determination of GRAS, even if the manufacturer then concluded to submit a GRAS affirmation petition to FDA. The purpose of the agency was to encourage submission of GRAS affirmation petitions to FDA in order to assist the agency in its surveillance of the food supply and to settle any safety issues that might arise with the use of new food substances. This was

a purposeful tradeoff. FDA gave industry the assurance that it could market products after

a self-determination of GRAS, and in return industry began to submit GRAS affirmation petitions in order to demonstrate to potential customers and to FDA that the new substance had been thoroughly evaluated and was in fact GRAS.

While reasonable in concept, FDA implementation of this program broke down almost from the beginning. GRAS affirmation was a process created by FDA, not by statute. There was no statutory deadline for FDA action and thus no priority within FDA. In many instances, FDA seemed to be more intent upon receiving a GRAS affirmation petition than it was upon evaluating and acting upon it. As a result, FDA became simply

a dumping ground for GRAS affirmation petitions. The backlog of GRAS affirmation petitions for direct food substances, in various stages of consideration, grew every year. These could undoubtedly have been handled swiftly by FASEB, but the agency was inca- pable even of delegating this function.

Nonetheless, the program was still a resounding success from the standpoint of pub- lic policy, precisely because FDA involvement was not needed to make it work. Self- determination of GRAS permits immediate marketing, whether or not a GRAS affirmation petition is filed and whether or not FDA ever acts on it.

As a general rule, FDA evaluation of GRAS affirmation petitions—although ex- tremely tardy—was reasonable and did not result in taking safe and useful products off the market. In one instance, FDA did deny a GRAS affirmation petition for a non-nutritive sweetener from a natural plant source (58), resulting in the bankruptcy of the small com- pany that sought to market it (59).

Perhaps there is no better example of the success of the GRAS approach than the history of high fructose corn syrup. High fructose corn syrup was the subject of a thorough scientific evaluation and a self-determination of GRAS in the mid-1960s. It was immedi- ately marketed, without asking FDA for an opinion or even informing the agency. Once one manufacturer began to market it, others followed suit. By the early 1970s, it was in widespread use throughout the food industry. It proved to have excellent functional proper- ties and to be an extremely important addition to the food supply.

By the time that FDA realized that high fructose corn syrup had become ubiquitous in the food supply, it was simply too late, as a practical matter, to insist that it be taken off the market and made the subject of a food additive petition. The agency had no basis

GRAS. The agency therefore requested submission of a GRAS affirmation petition. The industry agreed, a petition was prepared and submitted, and FDA published a notice of filing in 1974 (60). For the next nine years, there was endless discussion about the matter. Finally, in 1983, FDA recognized the obvious and published three separate regulations for this substance (61). Even then the matter was not finished. A further proposal was published in 1988 and was not the subject of a final regulation until eight years later (62).

One should stop to consider what would have happened if high fructose corn syrup had been handled through a food additive petition rather than a self-determination of GRAS. By any standard, this substance is what we now refer to as a macronutrient. It can be consumed at a substantial level in the daily diet, if one selects a diet of processed food sweetened only with this substance (an assumption that FDA routinely makes in evaluating food additives). High fructose corn syrup was a contemporary of olestra. These two macronutrients were subject to initial research and development at the same time, during the mid-1960s. One took the GRAS superhighway to market, and the other followed the meandering food additive path through the FDA woods. One was freely marketed more than 25 years for unlimited food use before the other was allowed to be marketed for very limited food use. In many ways, this simple comparison tells the entire story.

F. Recent Reform for Direct Food Additive and GRAS Substances

By 1995, it was apparent that the FDA GRAS affirmation process was no longer operable. At its June 1995 meeting, the Institute of Food Technologists sponsored a major sympo- sium to analyze food regulatory policy. Three of the papers presented at that symposium focused on the major problems with the current regulation of food additives and GRAS substances in the United States (63). Congress held a hearing (64) to investigate the matter later that month (65) and subsequently issued a report highly critical of the FDA perfor- mance (66). A year later the International Society of Regulatory Toxicology and Pharma- cology (ISRPT) sponsored a workshop on optimizing the review process of food additive and GRAS petitions (67). The following year, the Institute of Medicine Food Forum held

a workshop on the subject, focusing on a major commissioned academic analysis of the entire food additive/GRAS process (68). Although it was difficult to interpret the FDA data presented at the House hearings and the ISRTP workshop, it was clear that the FDA backlog for direct and indirect food additive petitions and GRAS affirmation petitions was very large and increasing each year. As of June 1995, there was a backlog of 295 pending petitions. This backlog was broken down into approximately 70 direct food addi- tive petitions, 150 indirect food additive petitions, and 75 GRAS affirmation petitions. The oldest food additive petition was filed in 1971 and the oldest GRAS affirmation peti- tion was filed in 1972. At the ISRTP workshop a year later, the FDA data presented a slightly improved picture but FDA was quick to point out that the situation was still inadequate.

At the House hearings and the ISRTP workshop, FDA presented proposals for re- form in the handling of direct food additives, indirect food additives, and GRAS affirma- tion petitions. This section of the chapter covers direct food additive and GRAS affirmation petitions. The next section handles indirect food additive and GRAS affirmation petitions.

For direct food additive petitions, FDA presented a plan to Congress that focused on reorganization of the FDA Center for Food Safety and Applied Nutrition (CFSAN) to place the petition review resources under one central manager, set performance goals to For direct food additive petitions, FDA presented a plan to Congress that focused on reorganization of the FDA Center for Food Safety and Applied Nutrition (CFSAN) to place the petition review resources under one central manager, set performance goals to

Partly as a response to the findings about the deterioration of the FDA process for review of food petitions, Congress included in the Food and Drug Administration Modern- ization Act of 1997 (70) a new section (909 of the FD&C Act), explicitly authorizing FDA to enter into contracts with outside experts to review and evaluate any application or submission (including a petition or notification) submitted under the FD&C Act, includ- ing those for food additives and GRAS substances. This provided explicit statutory author- ity for the plan announced by FDA in 1995 to expedite review of food additive and GRAS affirmation petitions. Nonetheless, because the underlying FDA requirements for approval of a direct food additive remain unchanged, and it does not appear that the resources allocated by FDA to this process have substantially increased, this new statutory provision by itself cannot be expected to make a major impact on the pending backlog.

Congressional frustration with the inability of FDA to handle food additive petitions undoubtedly reached its peak when Congress included in the Food and Drug Administra- tion Modernization Act of 1997 an explicit statutory requirement that no later than 60 days following the date of enactment FDA must make a final determination on a pending food additive petition to permit the irradiation of red meat (71). FDA promptly approved the petition (72).

Recognizing that substantial progress on reducing the backlog of direct food additive petitions is unlikely in the near future, FDA sought in 1999 to blunt continuing criticism of its program by announcing that the agency would give ‘‘expedited review’’ to any food additive petitions designed to decrease the risk of foodborne illness (73). The agency was careful to point out, however, that this means merely that the expedited petitions would

be reviewed first (thus placing other petitions at a disadvantage) and that the standards for review would not change. For GRAS affirmation petitions for direct food substances, in contrast, FDA chose quite a different approach. In 1997, FDA proposed to replace the entire GRAS affirmation process with a GRAS notification procedure. Under the proposed new procedure, a person would submit a GRAS notification based on the person’s determination that a substance is GRAS for its intended use. The GRAS notification would include a detailed summary of the scientific data on which the GRAS determination is based, but not the raw data. Within 90 days of receipt of the notification, FDA would be required to respond in writing either that the agency has no current objection to the notification or that it does have an objection. Although FDA has not yet promulgated a final regulation for this procedure, it has declined to accept new GRAS affirmation petitions, has encouraged those who submitted old GRAS affirmation petitions to convert them to GRAS determination notifi- cations, and has accepted new GRAS determination notifications and taken action on them.

Without question, the new GRAS determination notification process has the poten- tial for substantially reducing or even eliminating the GRAS affirmation petition backlog very quickly. That potential would be maximized if FDA would agree to delegate primary review of these notifications to FASAB or a comparable organization, and to evaluate only the recommendation made by that outside organization. Even without the benefit of outside expertise, however, the streamlined procedure will result in prompt and efficient FDA decisions if the agency resists the temptation to review these notifications in the same way that it has reviewed GRAS affirmation petitions in the past.

G. Recent Reform for Indirect Food Additive and GRAS Substances

As enacted in 1958, the definition of a food additive broadly includes ‘‘any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food’’ (74). Thus, this term has always been under- stood to include indirect as well as direct food additives. As discussed, the majority of food additive petitions submitted to FDA in the past four decades have been for indirect rather than direct food additives. And if one counts only substances (rather than multiple uses of the same substance), undoubtedly more than 90% of all food additive petitions have been for indirect use. Although these uses are important, they clearly do not need the same level of FDA review as a new direct food additive.

The concept of limiting the number of indirect food additives that would require FDA review was first discussed by industry and agency officials as early as 1968 (75). After 25 years of consideration, a proposal that has come to be called the ‘‘threshold of regulation’’ approach was finally published in 1993 (76) and promulgated in 1995 (77). Even then, it contained a classic example of the refusal of FDA to let go of even the most trivial issue. Instead of simply providing that any indirect food additive that met the regulatory criteria for exclusion from regulation could immediately be marketed, FDA has required that this decision, in itself, result in a submission to FDA and an explicit FDA exemption. Indirect food additive petitions have thus been replaced by indirect food additive exemption petitions. No more graphic example of government over-regulation can be found.

By 1995, the FDA backlog of indirect food additive petitions had reached approxi- mately 150. With inadequate resources, a lower priority than direct food additives, and a threshold of regulation policy that suffered from the same deficiencies as indirect food additive petitions themselves, it was apparent that a new approach was needed.

Three approaches have emerged to reduce the resources and time required for FDA handling of petitions for indirect food additives and GRAS substances. First, industry has simply taken the position that any substance that it determines meets the FDA threshold of regulation policy is also, by that fact alone, GRAS for its intended use. In short, the threshold of regulation policy itself establishes a definition of GRAS status for an indirect food substance. The vast majority of substances that meet the threshold of regulation policy therefore are not submitted to FDA at all. This has been a highly successful result of the threshold of regulation policy, even though FDA unquestionably did not intend this result.

Second, the proposed new GRAS determination notification procedure discussed with respect to direct food substances also applies to indirect food substances. This new procedure therefore has a substantial potential for reducing the FDA backlog for indirect

Third, and most important, Congress was persuaded to include in the Food and Drug Administration Modernization Act of 1997 an entirely new and different approach for handling indirect food additives (78). Under the 1958 Amendment, no distinction was made between direct and indirect food additives. Under the 1997 Act, however, a new premarket notification procedure is established for indirect food additives to replace the present premarket approval procedure that applies for direct food additives. The new pre- market notification procedure represents the result of a successful negotiation between the regulated industry and FDA on this matter.

The new law provides that a manufacturer or a supplier of an indirect food additive may, at least 120 days prior to shipment, notify FDA of the identity and intended use of the substance and of the determination that it is safe for its intended use. All pertinent information must be submitted with this notification. The notification becomes effective 120 days after the date of receipt by FDA, and the substance may be shipped thereafter, unless FDA makes a determination within that period that use of the substance has not been shown to be safe. The Food and Drug Administration may also promulgate regulations prescribing a procedure by which the agency may deem a notification to be no longer effective, based on new information.

Existing indirect food additive regulations remain in effect. The agency may also require that a food additive petition rather than a notification be submitted when the agency determines that this is necessary to provide adequate assurance of safety. It seems likely, however, that a food additive petition will rarely be required.

The legislation initially included user fees to provide adequate resources to FDA for the regulation of indirect food additives. These were deleted by the Conference Com- mittee, which stated that the new procedure is to be implemented by appropriated funds but that ‘‘implementation is to be triggered only when the FDA receives an appropriation sufficient to fund the program’’ (79). The agency has issued a report to Congress on the anticipated costs of this program (80) and has held a public meeting to consider implemen- tation of the new procedure (81), but required appropriation has not yet been enacted. If implemented as intended by Congress, this new procedure would substantially reduce FDA resources needed to handle indirect food additive petitions and could eliminate the backlog of these petitions in the near future.

H. Dietary Ingredients in Dietary Supplements

Since the 1920s, when dietary supplements were first marketed, FDA and the dietary supplement industry have been in a continuous regulatory war about both the promotional claims and the safety of these products (82). When FDA sought to impose stricter standards for dietary supplements in the 1960s and early 1970s, Congress enacted the Vitamin– Mineral Amendments of 1976 (83) to overrule the FDA restrictions. The 1976 Amend- ments, however, made no change in the safety standards applicable to dietary supplements.

Following enactment of the Nutrition Labeling and Education Act of 1990 (84), FDA sought to use this statutory authority to impose new limitations for dietary supple- ments. Ignoring a congressional invitation to establish separate standards and requirements for dietary supplements (85). FDA instead used the new statutory authority to deny all disease prevention claims for dietary supplements (86), and threatened to impose stringent food additive requirements on important dietary supplement ingredients (87). The dietary supplement industry marshalled its formidable political power and obtained enactment of Following enactment of the Nutrition Labeling and Education Act of 1990 (84), FDA sought to use this statutory authority to impose new limitations for dietary supple- ments. Ignoring a congressional invitation to establish separate standards and requirements for dietary supplements (85). FDA instead used the new statutory authority to deny all disease prevention claims for dietary supplements (86), and threatened to impose stringent food additive requirements on important dietary supplement ingredients (87). The dietary supplement industry marshalled its formidable political power and obtained enactment of

I. The Lack of Market Protection

There are two basic ways for FDA or any other federal agency to regulate new products as they come on the market. The first way is to use a product-specific license, and to require that each new version of the product be the subject of its own petition in order to obtain its own license based upon its own data. This is the way that new drugs have been regulated. When Congress sought to permit increased competition in pharmaceutical products in 1984, it authorized the approval of generic versions of pioneer drugs only after the pioneer drug has exhausted its patent life or a five-year period of market exclusiv- ity (90). For orphan drugs, the period of market exclusivity was established at seven years (91). Thus, a manufacturer could be assured of a period of market protection during which no other company could rely upon its license and data in order to obtain its own marketing approval.

The second means of regulating new products is through a public regulation which, absent a patent, permits competitors to market the product immediately without the need for any type of license or the protection of any period of market exclusivity. This is the approach taken by Congress in 1958 for food additives. The conclusion was that any market protection must come from a patent. Failing that, competitors are free to use the food additive regulation to manufacture and market their own version of the new product.

The economic fallacy in this second approach is obvious. Except in those few in- stances where strong patent protection is available, there is a substantial disincentive for any person to invest significant resources in research and development on new food sub- stances. Regardless of the potential benefit to public health from new food substances, it is not feasible to recoup any investment made in them because competitors can immedi- ately enter the market at a price that does not need to reflect any investment at all. Not surprisingly, all of the eight new direct food additives listed alone, approved by FDA during the past thirty years, are patented.

If there is a patent for the new food additive, it will, of course, prevent competitors from entering the market until the patent expires. Recognizing that the FDA food additive process erodes the effective patent life for a new patented food additive, Congress provided for patent term extension for food additives as part of the Drug Price Competition and

For food additives that are unpatented or whose research, development, and FDA review extend up to or beyond the end of patent protection, however, Congress failed to provide any form of nonpatent market exclusivity or other market protection for food additives in the 1984 Act. The food industry is now directly confronted with the reality not only that there is no possible economic justification for investing even one cent in a new food additive for which a patent cannot be obtained, but also that, with horror stories like olestra, even patent protection is illusory. Thus, there is no incentive to innovate in the field of new direct human food additives, however valuable those additives might be to the health of the American public. If one manages to survive the food additive regulatory process, it is likely that the patent will have expired, or be close to expiration, and the enormous investment that has been made in the additive will be lost.

This problem cries out for a legislative solution. Without a statutory period of market exclusivity, American industry cannot be expected to invest in new food additives that cannot be patented, even if the regulatory process itself is reformed. Some form of market protection must be provided in order to assure industry that there will be a reasonable time to recoup the investment before generic competitors are allowed on the market.

We have thus seen a promising new approach to food safety be killed by the dead hand of FDA regulation. The implications are too important for public health to allow this situation to continue. A new system must be found to replace the present one.