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What's changing? Industry initiative for enhanced self-regulation of GRAS practices is likely.
April 17th will mark 18 years since FDA published its 1997 proposal to modify the operating procedures for Generally Recognized as Safe (GRAS) evaluations.1 Besides providing a wealth of information on the GRAS concept with detailed guidance on the requisite information to support a valid GRAS determination, FDA’s 1997 publication proposed discontinuing the GRAS petitioning process while instituting voluntary GRAS notification procedures. Interestingly, FDA began implementing the procedures shortly after they were proposed in the Federal Register document, presumably in anticipation that the procedures would be finalized without substantial changes. The proposed GRAS procedures that are operational with FDA today have not been finalized.
First, an Abbreviated History of GRAS Status
The GRAS category of food substances was created with the 1958 congressional passage of the Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act. GRAS substances were deemed exempt from FDA’s pre-market approval requirements that were instituted for food additives; furthermore, declaring GRAS status for substances is not the sole domain of FDA but, instead, such findings can be proclaimed by individuals who are qualified to do so by virtue of their training and experience. These features-in concert with the legislative origin of GRAS status-are important in light of the current state of affairs with GRAS procedures and the associated questions and challenges that have surfaced in recent years.
The proposed 1997 GRAS procedures have been well-received by the regulated food industry and FDA, as reflected by the recognition that 562 GRAS notifications have been voluntarily submitted to FDA between 1997 through the end of 2014. The number of GRAS notifications submitted to FDA now totals about 50 annually.2 In addition, companies can continue to make their own self-determined GRAS determinations that need not be reported to or shared with FDA as originally established by Congress in 1958, as long as such self-determined GRAS conclusions are conferred by appropriately credentialed individuals. The number of total GRAS determinations made-FDA notifications and self-determined GRAS evaluations-cannot be determined with accuracy since no requirement exists for firms pursuing self-determined GRAS status to provide any public declaration of such action. It is highly likely that the number of self-determined GRAS evaluations exceeds the number of GRAS notifications that have been submitted to FDA.
Challenges to 1997 Proposed GRAS Procedures
Since FDA issued its proposed GRAS procedures in 1997, a number of challenges have been aimed at the agency and its handling of GRAS procedure.
Challenges directed at various aspects of the proposed GRAS procedures of 1997 surfaced with a February 2010 final report by the U.S. Government Accountability Office (GAO) entitled “FDA Should Strengthen Its Oversight of Food Ingredients Determined to be Generally Recognized As Safe (GRAS).”3 The GAO’s in-depth review scrutinized the 1997 procedures that addressed the GRAS operations, as well as the actual associated agency practices. Explicitly identified within the GAO report are concerns over the fact that the proposed 1997 GRAS procedures proffered had not been finalized as well as over the continued allowance by companies to utilize self-determined GRAS evaluations to fulfill food ingredient regulatory requirements-without FDA notification or awareness.
One of GAO’s primary objectives was to review practices regarding FDA oversight of new GRAS determinations to ensure the safety of the subject materials. On this topic, GAO declared that FDA does not ensure the safety of all new GRAS determinations, only those that are voluntarily submitted to FDA, and that because self-affirmed GRAS determinations are not the subject of the FDA notification process, they thereby escape FDA oversight. The GAO report also stated that some self-GRAS determinations are shallow and are of inadequate depth and scope, thereby creating potential safety vulnerabilities.
Ultimately, the GAO report said that GRAS safety evaluations must be open and transparent to FDA and the public. The GAO deemed allowing self-determined GRAS evaluations without any form of FDA review or oversight unacceptable. Further, it observed, the fact that FDA is very likely to not even be aware of such self-determined GRAS evaluations compounded the concern.
The GAO report also cited worry over potential conflicts of interest because individuals serving on Expert Panels commonly are compensated for their services. The report said that Expert Panel member findings may be influenced by virtue of the compensation to yield safety conclusions that are inappropriately favorable to the sponsoring firm or organization. In short, GAO proclaimed that FDA should seek to minimize conflicts of interest by individuals undertaking GRAS evaluations and that FDA should provide guidance on avoiding conflicts of interest to members of Expert Panels who make GRAS determinations.
Criticisms over GRAS procedures did not end there. In the aftermath of the final GAO report, the PEW Charitable Trusts echoed the GAO’s position that changes are needed in the GRAS practices, prominently citing both FDA’s lack of awareness of large numbers of self-determined GRAS findings and the associated lack of transparency linked to such GRAS evaluations, and the matter of potential for conflicts of interest among Expert Panel members. PEW compiled materials that it maintained further supported the need for modified procedures.4
The PEW challenges to the GRAS practices were subsequently transitioned to the National Resources Defense Council (NRDC) where it was reported that an “advocacy campaign” was to be developed. It was reported in early 2014 that this could possibly include a legislative initiative to more definitively improve the oversight capability of FDA for all GRAS determinations, while correcting the deficiencies in GRAS operations as established in the 1958 amendment. It appears that the consumer activist efforts subsequently underwent further transitioning to the Center for Science in the Public Interest (CSPI).
Another significant challenge to GRAS practices surfaced in February 2014 when the Center for Food Safety filed a lawsuit against FDA.5 FDA defended its actions and practices stemming from the publication of the 1997 proposal while agreeing in October 2014 to finalize its GRAS procedures rule by August 2016.6 Interestingly, unconfirmed reports emerged prior to the negotiated settlement that possible legislative changes were under consideration by parties, including FDA, as a means of rectifying the alleged weaknesses of the GRAS practices outlined in the 1997 proposal.
Defense of 1997 Proposed GRAS Procedures
The regulated industry remained publicly rather quiet in the immediate aftermath of the issuance of the GAO report. As the challenges and criticisms of the GRAS practices intensified with the intervention of PEW and NRDC, industry expressed its support of the GRAS operations that had been implemented with the 1997 proposal. Through trade associations such as the Grocery Manufacturers Association (GMA), the Flavor and Extract Manufacturers of America, the Calorie Control Council and International Food Additives Council, and Biotechnology Industry Organization, the following comments were offered in support of GRAS practices:
In expressing satisfaction with the GRAS notification program presented in 1997, industry members noted that the public health was historically very effectively protected. Existing GRAS practices enable FDA to take actions to remove unsafe substances if scientific documentation supports such actions. Two examples associated with GRAS substances and potential public health concerns surfaced in the past few years, and in each case FDA took steps to address the concerns: 1) the use of caffeine in alcoholic beverages was deemed to not meet the GRAS safety criteria, thereby disallowing the direct use of caffeine in alcoholic beverages,7 and 2) FDA initiated regulatory proceedings in November 2013 to remove GRAS status for partially hydrogenated oils when added to foods because the reported safety was not generally recognized.8 Thus, current law provides FDA with ample authority to challenge the status of substances that have been designated as GRAS if inadequate documentation is available to support such a finding.
Industry Initiative to Bolster Existing GRAS Practices
The challenges with existing GRAS practices expressed by GAO and consumer activist groups did effectively get the attention of the food industry, however. In August 2014, the Grocery Manufacturers Association announced an industry initiative (the “GMA initiative”) directed toward increased self-regulation of ingredients used in food products. GMA proclaimed the launching of “a modernization initiative that will improve the process and increase transparency for making Generally Recognized As Safe (GRAS) determinations of ingredients added to food.”9
The GMA initiative consists of five parts, including:
The GMA initiative is indeed ambitious and appears to be well-conceived in concept. Important operational details are currently under development. As part of the Code of Practice and the associated Publicly Available Standard, GMA will convene a steering committee of qualified parties to oversee the establishment of procedures for the development of rigorous GRAS evaluations. GMA’s efforts are focused on the objective that will intimately impact self-determined GRAS assessments. Furthermore, it is encouraging to note that GMA has been and remains in communication with FDA on efforts that are underway. Nonetheless, consumer activists such as CSPI and the Center for Food Safety have denounced such industry efforts as being inadequate.10
Does Need Exist for Legislative Changes?
Clearly, the GRAS concept was established as a direct consequence of legislative actions in 1958. The debate over the merits and deficiencies of current practices includes the question as to whether or not new legislation addressing GRAS practices with an eye toward resolving the stated problems would be the required or preferred approach. Proper legislative modification would be required to substantively abolish practices such as self-determined GRAS evaluations, while compelling companies to notify FDA that such independent GRAS determinations have been made.
Does the history of GRAS practices justify the need for legislative changes? Has the objective of protecting the public health been compromised with GRAS determinations made to date? With his foresight and vision, Thomas Jefferson acknowledged the need for legislative changes when circumstances warrant. He declared:11
I am not an advocate for frequent changes in laws and constitutions, but laws and institutions must go hand in hand with the progress of the human mind as that becomes more developed, more enlightened, as new discoveries are made, new truths discovered, and manners and opinions change, with the change of circumstances. Institutions must advance also to keep pace with the times. We might as well require a man to wear still the coat which fitted him when a boy as civilized society to remain ever under the regimen of their barbarous ancestors.
In effect, Jefferson counseled that changes in laws may be warranted as circumstances and needs surface, but making changes in laws must occur when legitimate need exists, suggesting that such changes should not be done casually.
Reflecting on the 56-plus-year history with GRAS practices reveals that the potential public health risks are quite low-albeit they are not zero. Are there new discoveries and new truths-according to Jefferson-or public health problems that exist to justify modifying the law? Are there deficiencies in current practices that justify legislative changes?
Because some parties have expressed the desire for a change in the law regarding GRAS practices, it remains to be seen whether or not legislative initiatives that impact GRAS procedures will be offered by those who oppose the current GRAS operations. Certainly it has proven to be difficult to get many reforms through Congress without a critical mass of support for issues that do not routinely make headlines.
FDA Actions Regarding Current GRAS Procedures
FDA was granted the opportunity to review the GAO report in draft form. FDA articulated its position in response to each of the six recommendations contained in the GAO analysis, and the FDA response was incorporated in the final report issued by GAO.12
On December 28, 2010, FDA reopened the comment period for the 1997 GRAS proposal and requested public input on the content of the proposed GRAS procedures, while specifically identifying aspects raised within the GAO report. FDA has been engaged in its review and assessment of the composite feedback that it received in response to the original proposal as published in 1997 and feedback that the agency received after reopening the comment period in late 2010. FDA maintains that it remains in the process of finalizing the GRAS operating procedures. Based on the court-mediated resolution of the lawsuit filed by the Center for Food Safety as noted earlier, FDA agreed to finalize the subject rule by August 2016.
Considering the concerns over conflicts of interest among individuals making GRAS determinations, FDA committed to developing its guidance on this specific issue as a priority objective by the end of calendar year 2014. Hopefully, FDA’s conflict-of-interest guidance-when it is released-will provide meaningful resolution while avoiding the elimination of services of those individuals most qualified to make food ingredient safety determinations.
The GMA initiative to improve the transparency of the GRAS process is advancing with the help of dialogue that has included FDA officials. FDA has remained open to communications on procedural refinements that are permitted by existing law.
And what of those self-determined GRAS evaluations that are not shared with FDA or do not otherwise become public and some of which may be of questionable quality and rigor? FDA has consistently stated that GRAS self-determinations are permitted by law, and FDA cannot require companies to submit their GRAS notices to FDA since mandatory notification would require legislative change.
In addition to the anticipated finalizing of the regulation governing current GRAS practices and the issuance of guidance on conflict-of-interest concerns affecting GRAS Expert Panels, FDA appears to be receptive to suggestions, ideas, and refinements in operations that preserve or enhance public health objectives and that remain compatible with prevailing law.
Meanwhile, FDA says it is committed to increasing transparency in its programs while ensuring the application of high-quality and up-to-date science in the administration of the GRAS program. FDA is actively developing its Chemical Evaluation and Risk Estimation System (CERES), a cutting-edge system that will help FDA evaluate and estimate risks in pre- and post-market review of food ingredients. The system will enable FDA to fully leverage available data through modern computational and predictive methods for pre-market review as well as post-market monitoring of food ingredients and packaging materials.
FDA has also launched a review of its toxicological guidance contained in the Redbook.13 FDA has implemented a series of public meetings to discuss the science of safety assessment. FDA recently extended the deadline for submission of written public comments on the Redbook until May 2015.14 As part of this effort, FDA should define the role of scientific judgment in GRAS assessments based on over 17 years’ experience with the GRAS notification program. The Redbook identifies many tests that may be needed to assess the safety of a food additive; however, most new food ingredients that have successfully emerged from GRAS notifications do not have the full complement of tests presently prescribed by the Redbook. Most notified ingredients are supported by other information, such as presence in or compositional similarity to common foods, studies which show protective effects to various toxicants including carcinogens, and clinical studies in human volunteers.
Related scientific issues that are in play with FDA as a result of the first public Redbook meeting include new testing models-both animal and non-animal-and FDA will likely be encouraged to expand its guidance on clinical testing as well. Hopefully, FDA will clearly differentiate guidance for safety testing for food ingredients from expected revised guidance for New Dietary Ingredients (NDIs) in a manner that reflects the statutory language and intent of the respective safety standards for food ingredients and supplements. Clarity is overdue. For more on the issue of GRAS and FDA’s NDI draft guidance, read our 2011 Nutritional Outlook article, “Two Paths Converging."
The topic of GRAS practices has experienced a resurgence of interest following the issuance of the GAO report in 2010. Specific aspects have been identified as warranting modification, while some seek to eliminate the self-determined GRAS option. Others see required notification of FDA for all GRAS evaluations as the preferred approach, and still others have called for legislative changes to correct the perceived problems.
In response to this increased public dialogue, the regulated food industry recognized that selected improvements could be made, while noting that the overall program was quite effective in protecting the public health. The fruits of the industry initiative will be apparent in the coming months that will presumably improve the transparency of the GRAS process. Furthermore, FDA is actively engaged in dialogue and its own internal processes to strengthen the administration of the GRAS program, which includes finalizing the GRAS procedures.
In assessing the bigger GRAS picture dating to 1958, the GRAS program is working rather effectively in protecting the public health and facilitating food product innovation with limited FDA intervention. This finding of and by itself casts doubt as to the need for legislative changes. Refinements and incremental improvements in the GRAS program and the associated operating procedures should be expected as we advance further into 2015 and beyond.
GRAS Associates, LLC (Bonita Springs, FL), a Nutrasource company, is a technical regulatory consulting firm that assists clients in fulfilling FDA food ingredient regulatory requirements by conducting GRAS assessments and by preparing food contact notifications, new dietary ingredient notifications, and color additive petitions. Visit www.gras-associates.com and www.nutrasource.ca.
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