Public interest groups challenge FDA’s “Generally Recognized as Safe” Rule as failing to ensure food ingredients are safe for consumers.

In a recently filed lawsuit (Center for Food Safety v. Price), several public interest groups challenged the US Food and Drug Administration (FDA or Agency) final rule^[1] that outlines how food manufacturers can establish food substances as “generally recognized as safe” for their intended use (GRAS Rule).^[2]

The lawsuit, filed in the US District Court for the Southern District of New York on May 22, 2017, disputes FDA’s long-held position that it lacks the legal authority to require manufacturers to notify FDA of independent GRAS conclusions. Separate and distinct from the mandatory food additive premarket review requirements, the GRAS Rule sets forth a voluntary notification process for GRAS conclusions. The plaintiffs seek a court order vacating the GRAS Rule based on alleged violations of the US Constitution, the Federal Food, Drug, and Cosmetic Act (FFDCA), and the Administrative Procedure Act (APA). FDA has 60 days to submit its answer to this lawsuit.

The plaintiffs assert improper delegation of statutory authority to “private persons” to make GRAS conclusions in the absence of FDA review in violation of the constitutional doctrine against sub-delegation, which further forecloses judicial review in violation of the constitutional separation of powers principle. Plaintiffs further assert that the GRAS Rule exceeds FDA authority in violation of the APA because FDA does not retain necessary authority to manage GRAS conclusions in violation of the FFDCA. Finally, plaintiffs claim that the GRAS Rule is arbitrary and capricious in violation of the APA as a result of FDA’s position that the statutory GRAS exclusion precludes industry-determined GRAS conclusions from FDA notification and review.

Due to the exclusion of GRAS substances from the FFDCA’s mandatory premarket review process for food additives, it seems unlikely that the plaintiffs will be granted the requested relief. However, while it is being litigated, the lawsuit could have an impact on FDA’s management of the GRAS program. Among other things, we may see increased review times and additional information requests for submitted GRAS notifications and, if FDA resources allow, increased FDA auditing of GRAS conclusions—whether they are submitted through the GRAS notification process or not.

If the court grants the plaintiffs’ requested relief, the impact on the food industry could be significant—potentially leaving manufacturers with no mechanism to voluntarily request FDA review of their independent GRAS conclusions.

Food Additives and the GRAS Exclusion

In the 1958 amendments to the FFDCA, the US Congress excluded from the food additive premarket review process substances deemed GRAS for their intended use in food.^[3] Since that time, FDA has asserted that it has no legal authority under the FFDCA to require any type of premarket review or notification of GRAS substances. Nonetheless, since the very beginning, manufacturers of food substances voluntarily have sought FDA confirmation of their own GRAS conclusions, and FDA has attempted over time to provide some level of review—first through the issuance of a GRAS list,^[4] followed by the use of FDA Opinion Letters delivered to requestors, then through the adoption of a GRAS affirmation rulemaking process to amend the regulatory GRAS lists, and most recently through the adoption of the current GRAS notification process.

Manufacturers have never been required to participate in any of the above voluntary programs.

The GRAS Rule

The GRAS Rule amended FDA’s regulatory review process for voluntary GRAS submissions by replacing the voluntary GRAS affirmation petition process with a voluntary notification procedure. The notification process did away with a resource-intensive rulemaking process. On average, it took FDA approximately six years to complete the rulemaking process for each GRAS affirmation petition,^[5] and in some cases FDA had not completed its review after more than 20 years. Indeed, FDA believed that this resource-intensive process deterred persons from petitioning the Agency to confirm their independent GRAS conclusions.^[6]

One of FDA’s primary motivations in issuing the GRAS Rule was to streamline evaluation of manufacturers’ conclusions of GRAS status in order to enable FDA to evaluate more, and higher priority, substances and to incentivize industry participation.^[7] The new notification process—in a pilot phase from 1997 until the GRAS Rule issued in August 2016—allows for a more nimble approach to FDA review, resulting in FDA review and response to the GRAS notification submitter within 180 days of filing.

FDA response falls into one of three categories:

1. No questions letter

2. Insufficient basis letter

3. Cease to evaluate letter

Both the filed notice and FDA’s response is published to a public database for purposes of transparency. According to data provided from the pilot program, the average time for FDA to respond to a GRAS notification is less than six months—five times faster than FDA reviews under the withdrawn GRAS affirmation process. Since the pilot was initiated in 1997 through the issuance of the GRAS Rule, 600 GRAS notices have been filed, which seems to validate FDA’s expectation and hope that the new process would incentivize higher participation in the voluntary program.^[8]

FDA also amended the criteria it deems necessary to determine whether a substance is GRAS for its intended use. Specifically, the GRAS Rule

• clarified that the safety standard for GRAS substances is identical to the standard for food additives;

• clarified the necessary technical safety evidence and the role of publication in establishing general recognition of safety; and

• modified requirements as they concern substances claimed to be GRAS through experience based upon common use in food.

Further, FDA made clear in the preamble to the GRAS Rule that the same standards apply to all GRAS conclusions regardless of whether they are submitted to FDA in a GRAS notice.^[9]

Center for Food Safety v. Price

The plaintiffs in the complaint against the Department of Health and Human Services and FDA (Complaint) include the Center for Food Safety, Breast Cancer Prevention Partners, Center for Science in the Public Interest, Environmental Defense Fund, and Environmental Working Group.

Voluntary Nature of GRAS Notification Process

The central focus of the Complaint concerns what the plaintiffs refer to as the “Secret GRAS process,” i.e., those independent GRAS conclusions that are not submitted to FDA through the notification process.^[10] Because the GRAS Rule is voluntary, the harm claimed by the plaintiff organizations is that they do not have access to information about independent GRAS conclusions that are not submitted to FDA—information to which they claim they are legally entitled. Plaintiffs state that they would use such information to more effectively advocate for public health, food safety, and consumer rights and that, absent the information, they are deprived of participating in the public process associated with food additive petition approval/denial. Further, they claim that because their members lack information about GRAS substances that have not been reviewed by FDA, their members’ ability to make informed food choices and to notify FDA of potential problems is hindered. In addition, they claim that the new GRAS notification system weakened the prior regulatory scheme by repealing the notice and comment–based GRAS affirmation petition process.

The remedy sought, however, would not appear to address the plaintiffs’ asserted concerns; the relief requested is to vacate the GRAS Rule with court direction to FDA to correct the rule’s alleged legal deficiencies.

Due to FDA’s position that it lacks the legal authority to require notification of GRAS conclusions, a decision to vacate the order would result in either (1) not having any process for voluntary notice to FDA or (2) a throwback to the antiquated and inefficient voluntary GRAS affirmation petition process described above. In either case, the likely outcome would be that FDA would receive less information on GRAS substances; in the former, there would be no mechanism for manufacturers to submit information on GRAS conclusions, and in the latter, the length of time required by the notice and comment rulemaking process would reduce manufacturer interest in participation. Thus, unless the court determines that federal law requires FDA to review GRAS conclusions and orders FDA to do so (where there is no statutory basis to so rule), plaintiffs’ goal of increasing available information from FDA on GRAS substances is unlikely to be realized—even if the lawsuit is successful.

The GRAS Criteria

The Complaint also takes issue with some of the GRAS criteria in the GRAS Rule, stating, among other things, that including unpublished scientific data, information, and methods within the definition of “scientific procedures” is contrary to the statutory meaning of this term. Plaintiffs assert that the GRAS Rule would allow GRAS conclusions based on “unpublished information corroborated by unpublished information.”^[11]

While not entirely clear in the Complaint, the plaintiffs’ position appears to be that “unpublished” also means not publicly available. A review of FDA statements in the preamble to the GRAS Rule confirms that FDA does not believe such an outcome is likely under its GRAS Rule: “[A] GRAS conclusion must be based on data and information that are generally available and accepted, and as such, are publicly available.”^[12]

FDA further appears to draw a distinction between the meaning of “published” and “publicly available,” stating that information available through mechanisms other than publication in a peer-reviewed journal—such as publication in a textbook and other sources of technical literature—can help support a GRAS determination.^[13] Thus, FDA appears to interpret “published” to mean published in a peer-reviewed journal and “unpublished” as material that is otherwise publicly available to support a GRAS conclusion.

Finally, of note, the acceptance of unpublished but publicly available data as support for a GRAS conclusion is unchanged from the prior requirements under FDA’s GRAS affirmation process.^[14]

Novel Ingredients

The plaintiffs assert that there are thousands of substances used in food that have never been reviewed by FDA as a result of the voluntary GRAS process and that FDA has no means to prevent novel ingredients (such as those that use engineered nanomaterials) from being determined to be GRAS by the manufacturer. While FDA did not include language in the GRAS Rule prohibiting a GRAS conclusion for an ingredient that is new or novel, the Agency noted in the rule’s preamble that a substance cannot be considered GRAS when its characteristics are known by only a few experts.^[15] FDA also issued guidance setting forth its position that questions related to technical safety and general recognition for engineered nanomaterials are likely sufficient to warrant formal premarket review, as opposed to a GRAS conclusion.^[16] The guidance is nonbinding, but it presents FDA’s position on this type of substance and thus should be considered as a potential basis for FDA action.

GRAS Panels

The plaintiffs reference a prior Government Accountability Office report and a Journal of the American Medical Association article taking issue with the common use of expert panels to support GRAS conclusions, stating that there is no assurance that these panelists are independent and free of conflicts.^[17] Under the GRAS Rule, expert panels are not required in order to support a GRAS conclusion. However, in the preamble to the GRAS Rule, FDA acknowledges that such panels can be useful in providing evidence that generally available data and information are generally accepted by the expert community. As a result, FDA has committed to issuing a Level 1 guidance on the subject of potential conflicts of interest and GRAS panel members.^[18]

Voluntary Notification Process Results in Data Challenges for FDA

The Complaint states that because FDA is not receiving safety data on GRAS conclusions that are not submitted to the Agency, FDA is deprived of the ability to verify that the use of a substance that is the subject of a GRAS notification is truly GRAS. Specifically, the interest groups argue that it is impossible for FDA, the public, and other food chemical manufacturers to consider the probable consumption and cumulative effect of any new chemical substance on human health in the absence of data on all GRAS substances.^[19] In the preamble to the GRAS Rule, FDA acknowledges that there are challenges to understanding consumption patterns and intake levels when manufacturers do not participate in the GRAS notification process. Accordingly, FDA has reached out to interested stakeholders—including trade associations, industry representatives, and the National Academy of Sciences—to assist in acquiring such information.^[20]

Conclusion

Center for Food Safety v. Price is the first significant challenge to the recently finalized GRAS Rule. While resolution of this litigation may take years, industry should closely monitor this evolving situation, as it may impact FDA’s ongoing management of the GRAS notification program, which is already potentially challenged due to budget constraints.

This lawsuit may hasten FDA’s pace in issuing additional guidance (e.g., the promised guidance on GRAS panels and conflict of interest considerations)^[21] and in revising certain existing guidance documents directed to safety evaluation of food additives to reflect FDA’s position that the guidance documents equally apply to both food additives and GRAS substances.^[22] FDA also may consider issuing other guidance such as one further clarifying the scope, quality, and role of unpublished material in support of a GRAS conclusion.

Further, it is possible that FDA review times for voluntary GRAS notifications could increase in response to increased external scrutiny of the process triggered by the litigation, with FDA raising additional questions regarding GRAS notifications.

Finally, FDA may use additional resources to audit both GRAS notifications and independent GRAS conclusions that have not been submitted to the Agency.

Of course, in all cases, FDA’s ability to undertake these efforts will depend on the resources available to support the GRAS notification program.

_{[1] US Food & Drug Admin., Substances Generally Recognized as Safe (81 Fed. Reg. 54960 (Aug. 17, 2016)).}

_{[2] Compl. Center for Food Safety v. Price, No. 1:17-cv-03833 (S.D.N.Y. May 22, 2017).}

_{[3] FFDCA §§ 201(s) and 409 [21 U.S.C. §§ 321(s), 348]}

_{[4] 21 C.F.R. Parts 182 and 582}

_{[5] US Food & Drug Admin., FDA's Approach to the GRAS Provision: A History of Processes, FDA.gov (July 29, 2015) https://www.fda.gov/food/ingredientspackaginglabeling/gras/ucm094040.htm.}

_{[6] 62 Fed. Reg. 18939 (Apr. 17, 1997).}

_{[7] 81 Fed. Reg. 54961.}

_{[8] Id. at 54980.}

_{[9] Id. at 54964.}

_{[10] The plaintiffs make clear that they are not challenging GRAS conclusions based on common use of the substance in food prior to 1958 (Compl. at 18).}

_{[11] Compl. at 20.}

_{[12] 81 Fed. Reg. 54973.}

_{[13] Id.}

_{[14] Id.}

_{[15] Id. at 54976.}

_{[16] US Food & Drug Admin., Guidance for Industry: Assessing the Effects of Significant Manufacturing Process Changes, Including Emerging Technologies, on the Safety and Regulatory Status of Food Ingredients and Food Contact Substances, Including Food Ingredients that Are Color Additives, 15-16 (June 2014), available at https://www.fda.gov/downloads/Cosmetics/GuidanceRegulation/GuidanceDocuments/UCM300927.pdf.}

_{[17] Compl. at 20-21.}

_{[18] 81 Fed. Reg. 55026.}

_{[19] Compl. at 29.}

_{[20] 81 Fed. Reg. at 54965.}

_{[21] Id. at 55026.}

_{[22] Id. at 55028.}