Court: Court of Appeals for the D.C. Circuit; September 24, 1985; Federal Appellate Court
The consolidated cases focus on the FDA's approval of the artificial sweetener aspartame for use in liquids without a public hearing. Aspartame, known as Nutra-Sweet in food products and Equal as a tabletop sweetener, was developed by G.D. Searle Co. in the early 1970s and is significantly sweeter than sugar. Case No. 84-5253 appeals a District Court's dismissal of a claim to compel the FDA to hold a hearing on aspartame, stating lack of jurisdiction. Case No. 84-1153 reviews the FDA's regulation approving aspartame in liquids. The court affirms both the District Court's and FDA's decisions.
Background details reveal that aspartame was previously approved for dry use in 1974, with required warnings about phenylalanine due to potential health risks for certain individuals. Objections to its dry use were raised by Dr. John Olney, who cited risks of brain lesions, and James F. Turner, who expressed concerns about phenylalanine's effects on mental health. The FDA agreed to a hearing process, substituting a Public Board of Inquiry for the traditional hearing, but before it commenced, safety concerns regarding aspartame and its testing methods were reported.
In 1974, Searle reported to the FDA that rats fed diketopiperazine (DKP), a degradation product of aspartame, developed uterine polyps. This prompted investigations by four pathology teams, including one from the FDA, to assess potential safety hazards related to aspartame consumption. An FDA inspector raised concerns about Searle's lab practices, leading to an FDA task force uncovering significant flaws in Searle's research quality and reliability, which deemed the test results unreliable. Consequently, in December 1975, the FDA stayed aspartame's approval for dry use, pending an audit of Searle's safety studies.
Fifteen Searle studies were selected for audit, focusing on the authenticity of test results rather than their planning or conclusions. Twelve studies were audited by Universities Associated for Research and Education in Pathology (UAREP), which confirmed that the experiments were conducted according to protocols and reported accurately. The FDA verified the authenticity of the remaining three studies and reviewed UAREP's findings.
In January 1980, a Board convened to address concerns about aspartame's potential risks, including mental retardation, brain damage, and tumor induction in rats. The Board recommended withdrawing aspartame's approval until further studies clarified any association with brain tumors but agreed with the FDA that it posed no risk of brain damage or endocrine dysfunction. Following exceptions filed by all parties, the FDA issued a final decision on July 24, 1981, supporting the Board's findings on brain damage but overruling its tumor-related conclusion, thereby reinstating aspartame's approval for dry use. No parties appealed the FDA's decision to the Court of Appeals.
In October 1982, Searle submitted a petition to amend the aspartame food additive regulation for wet use, referencing scientific data from a previous petition for dry use. By July 1984, the FDA approved aspartame for use in carbonated beverages, amending the relevant regulation. In response, the Community Nutrition Institute, Woodrow C. Monte, Ph.D., and other parties (collectively referred to as "Appellants") filed objections and sought a stay and public hearing, which the FDA denied, stating the objections did not raise substantial issues. On December 9, 1983, additional organizations joined the objections, and Monte supplemented his claims. The FDA ultimately denied the objections and hearing requests in February 1984, citing a lack of substantial factual issues.
Subsequently, the Appellants filed a suit in District Court for a hearing and stay on the regulation, supported by consumer complaints about adverse health effects from aspartame. The District Court denied their motion for a stay, deeming the evidence anecdotal and unsubstantiated. A second motion for a temporary restraining order was filed with further supporting evidence, but the FDA moved to dismiss, arguing lack of jurisdiction as review should occur only in the Court of Appeals. The District Court ruled against the Appellants, concluding it lacked jurisdiction since the FDA had issued a final ruling on their hearing request, thus reserving jurisdiction exclusively for the Court of Appeals. The key issue in Case No. 84-5253 is whether the District Court erred in determining it lacked jurisdiction after the FDA denied the Appellants' hearing request, despite the Food, Drug, and Cosmetic Act's provision for exclusive appellate review of final agency orders.
Appellants argue that a contrary ruling would allow an agency to prolong review by delaying final action until just before a district court hearing, effectively extending the review period. They contend that, in the absence of a record, the district court should initially review to develop the record. However, it is determined that the district court lacked jurisdiction to review what had become a final order, as jurisdiction lies exclusively with the Court of Appeals. The district court also erred in claiming jurisdiction before the FDA issued a final order, as the FDA's inaction did not affect jurisdiction. Past cases indicate inconsistencies in jurisdiction over agency inaction, highlighting the need for clarity on this issue. The court cites the Telecommunications Research and Action Center (TRAC) case, which established that the Court of Appeals has the authority to review claims of unreasonable delay to maintain its jurisdiction. The dismissal of the request for a hearing by the district court is affirmed, as such matters fall under the exclusive jurisdiction of the Court of Appeals. While this court recognizes its jurisdiction over agency inaction, it does so cautiously and only in extraordinary circumstances. In evaluating agency delays, a "rule of reason" applies, indicating that reasonable delays can extend to months or a few years, but not to extreme lengths. The delay in this case of five months is not deemed unreasonable, especially considering the FDA's thorough procedures that necessitate close examination of records before granting hearings.
The FDA is required to carefully consider objections to its actions as outlined in 21 C.F.R. 12.24(b)(1), and while the denial of a hearing negates the need to apply the mandamus standard, a five-month period for fulfilling statutory requirements is not deemed excessive. Appellants sought a stay on the effective date of aspartame regulations pending a hearing, arguing that the District Court retained jurisdiction despite the FDA's denial of the hearing request. However, it was determined that the District Court lacked jurisdiction over the stay request, which must be sought via a writ of mandamus in the Court of Appeals, leading to the affirmation of the District Court's dismissal of the stay request.
In Case No. 84-1153, the core issue is whether the FDA acted within its authority under the Food, Drug, and Cosmetic Act when it denied Appellants a hearing regarding the safety of aspartame in carbonated beverages. Following the FDA's denial on February 22, 1984, Appellants filed a timely petition for review on April 17, 1984. They argue that the Act requires a hearing upon any objection to food additive safety, or at least when a material issue of fact is raised. The Court found that the FDA did not exceed its discretion in denying the hearing since the Appellants did not present material objections to aspartame’s safety. The review focused on whether the FDA adequately considered relevant evidence, concluding that no material issues regarding the safety of aspartame’s wet use were raised by the Appellants. The Court emphasized that objections already evaluated by the FDA during the approval for dry use cannot be revisited, limiting the review specifically to the concerns about aspartame's wet applications.
The agency's prior conclusions regarding the safety of dry aspartame use may not be re-litigated in this case, except where new evidence impacts the FDA's assessment of wet use, to promote administrative finality and judicial efficiency. The EPA can require interested parties to identify disputed factual issues before granting an adjudicatory hearing. Consequently, issues related to dry use safety are distinct from those concerning wet use safety, and appellants cannot present dry use arguments to necessitate a hearing before the FDA. The standard for reviewing the FDA's denial of a hearing emphasizes judicial deference to agency expertise; courts will not intervene unless material factual issues are evident. The agency's findings can only be overturned if the record indicates clear material disputes. Differences in the evaluation of scientific studies or aspartame intake estimates do not constitute sufficient grounds for judicial intervention. The FDA's food additive approval process, under Section 409 of the Federal Food, Drug, and Cosmetic Act, requires a "fair evaluation" of safety data, defined as a reasonable certainty of non-harmfulness under intended use. Appellants' claim for a mandatory hearing is unsupported by the statute, which only allows hearings if material issues are raised.
Any individual adversely affected by a food additive petition's approval or rejection has thirty days to file objections and request a hearing under 21 U.S.C. 348(f)(1). Objections must clearly specify the problematic provisions of the order and provide reasonable grounds. The Secretary is required to hold a hearing for relevant evidence unless deemed unnecessary, in which case the order becomes final. A hearing request must raise a material issue of fact pertinent to the legality of the agency's order, as established in case law. If objections lack sufficient legal foundation, they are considered null. The FDA's regulations stipulate that a hearing request must demonstrate: 1) a genuine and substantial factual issue; 2) availability of reliable evidence to resolve that issue; 3) the objector’s data could impact the factual resolution; and 4) such resolution would justify the relief sought. Failure to meet these criteria results in denial of the hearing request.
In examining objections regarding aspartame's approval for wet use, Appellants must present new evidence challenging past tests related to its safety in dry use. They claim to have introduced new evidence regarding: 1) aspartame’s effects on brain lesions and cognitive function; 2) advanced testing for toxic chemicals resulting from aspartame; 3) increased daily aspartame consumption through carbonated beverages; 4) its carcinogenicity; and 5) labeling requirements. However, the review indicates that Appellants have not provided new evidence sufficient to demonstrate that the FDA's approval for wet use was an abuse of discretion. One specific contention involves whether aspartame increases phenylalanine levels in blood plasma, potentially affecting neurotransmitter production and behavior, supported by correspondence from Dr. Richard Wurtman to FDA officials.
Dr. Wurtman's research suggested that high doses of aspartame increased levels of phenylalanine and tyrosine, amino acids that influence neurotransmitters norepinephrine and dopamine in both humans and rats. However, he did not establish a link between these biochemical changes and behavioral alterations. Additionally, another study referenced by the FDA indicated that high aspartame doses did not significantly affect neurotransmitter levels in the brain. Dr. Wurtman also expressed concerns that aspartame could disrupt serotonin production when consumed with carbohydrates, suggesting that the sweetener's effects might be enhanced in typical consumption scenarios. Nevertheless, he did not provide empirical evidence to support this claim.
The FDA reviewed these concerns and found that it had adequately assessed aspartame's safety in carbonated beverages. Dr. Paul LeChance raised concerns about the potential narrowing of the safety margin for amino acid levels due to increased aspartame consumption, but the FDA determined that a sufficient safety margin existed between harmful levels of phenylalanine and those resulting from high aspartame exposure.
Regarding nitrosamines, which are potentially carcinogenic compounds that may form from aspartame breakdown, the FDA concluded that stable nitrosamines are challenging to form and unlikely to exist in significant amounts in the gastrointestinal system. The Appellants argued for a reevaluation of nitrosamine risks based on newer detection methods, but the FDA maintained that there was no evidence linking nitrosamine formation in malt beverages to aspartame-containing soft drinks.
Lastly, the Appellants contended that the FDA did not adequately consider the implications of increased aspartame consumption from liquid use compared to dry use. However, the review indicated that the FDA had properly evaluated this aspect and concluded that the public's safety was not compromised by the increased consumption of aspartame in liquid form.
The Public Board of Inquiry estimated a 99th percentile daily consumption of aspartame at 34 mg/kg of body weight, indicating that only 1% of consumers exceed this level. This estimate was based on the assumption that aspartame would be the sole sweetener in carbonated beverages and used in various other foods. The FDA deemed an average daily intake of 50 mg/kg safe, supported by a "no effect" dose observed in animal studies ranging from 2000 to 4000 mg/kg, allowing for a conservative safety margin. The FDA acknowledged that certain consumption patterns, like drinking multiple cans of soda in hot weather, might lead some, especially children, to exceed 34 mg/kg, but cited studies showing no acute toxicity at levels up to 200 mg/kg. The FDA concluded that total daily intake, rather than consumption patterns, was critical for safety.
Appellants sought to challenge the carcinogenicity of aspartame, but failed to provide new evidence or identify deficiencies in the supporting studies that had not already been addressed during the dry use proceeding, leading to the conclusion that the carcinogenicity claims were unsubstantiated. Additionally, the Board and FDA previously evaluated labeling requirements, including warnings for those with phenylketonuria due to phenylalanine content and a caution against using aspartame in cooking when sold as a tabletop sweetener.
Appellants' objections lack new evidence or any significant factual issues regarding the need for additional warnings or labeling for aspartame. They assert that wet use of aspartame is uniquely hazardous due to potential embryotoxicity and increased decomposition risks compared to dry use. Specifically, they claim that aspartame's degradation product, diketopiperazine (DKP), is harmful to human embryos and that aspartame decomposes more dangerously in carbonated beverages under high temperatures. However, the FDA found no evidence to support these claims, referencing studies where DKP did not cause fetal damage and determining that aspartame's instability at elevated temperatures did not present safety issues warranting a hearing. Consequently, the FDA's decision to deny a hearing on the wet use of aspartame is affirmed, along with the District Court's dismissal of the Appellants' request for a stay pending a hearing due to lack of jurisdiction.
