As avowed dog-lovers and FDA law enthusiasts, a recent Complaint filed in the District Court of D.C. caught our attention. Vanda Pharmaceuticals filed a Complaint on February 6, 2019 alleging that FDA’s insistence that Vanda perform a 9-month dog study with its drug candidate tradipitant before extending human trials beyond 90 days violates the Administrative Procedures Act (“APA”). Vanda, it seems, may be on a mission to shake up FDA’s long-standing policies with respect to animal testing.
As described in the Complaint, Vanda is developing tradipitant, a neurokinin 1 receptor (NK1R) antagonist, for the treatment of several human diseases including gastroparesis. In Spring 2018, Vanda sought to extend an 8-week open-label extension Phase II study with tradipitant by adding a 52-week open-label extension period. However, FDA repeatedly asserted that Vanda was required to conduct a 9-month non-rodent toxicity study with tradipitant before performing any studies in humans lasting longer than 90 days. After some back and forth and procedural maneuvering, including Vanda’s proposal of a different 52-week tradipitant open-label extension study, FDA eventually imposed a partial clinical hold on Vanda’s two 52-week studies until a 9-month non-rodent toxicity study is performed.
Unable to convince FDA that the 9-month non-rodent toxicity study is unnecessary, Vanda sued FDA for violation of the APA. Vanda alleges that imposing a clinical hold without a demonstration of unreasonable risk to the safety of subjects and imposing “requirements” without engaging in notice-and-comment rulemaking were arbitrary and capricious in violation of the APA. Vanda argues that the nonclinical animal studies already performed included multiple 3-month chronic toxicity studies in dogs, and multiple acute and chronic rodent toxicity studies, including 3 and 6-month studies, none of which identified clinically relevant safety signals for use of tradipitant in humans.
Vanda cites FDA’s reliance on the non-binding policy document, Guidance for Industry, M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (Jan. 2010) (referred to as the “ICH Guidance” because the document was created by the International Conference for Harmonization and subsequently adopted by FDA as a non-binding guidance document), addressing nonclinical safety studies to support the conduct of human clinical trials and marketing authorization for pharmaceuticals, as the source of the additional study requirement. The Complaint alleges that FDA did not perform an “Unreasonable Risk Determination” relating to tradipitant, as required under 21 U.S.C. §§ 355(i)(3)(B)(i), (ii). These statutory provisions require FDA to demonstrate that “the drug involved represents an unreasonable risk to the safety of the persons who are the subjects of the clinical investigation” or that a clinical hold should be issued for another reason. Vanda argues that this provision requires FDA to determine that a large animal study beyond three months was necessary to prevent an unreasonable risk to the safety of the clinical subjects in Vanda’s human trials. Indeed, Vanda argues that:
- the 9-month canine study was not scientifically justified in light of the extensive nonclinical safety testing that had already been done of tradipitant, as well as other related compounds;
- scientific research and regulatory developments subsequent to the ICH Guidance support the view that such a study in canines is unlikely to identify additional toxicities that would be clinically relevant to humans and materially relevant to FDA’s decision-making; and
- requiring such an additional study, which would result in the death of every canine participant, is inhumane and unethical in the absence of any expectation that it would lead to any clinically relevant findings.
Further, Vanda alleges that FDA’s regulations do not specify that chronic toxicity studies must be conducted in non-rodent species; that such studies must be conducted in particular non-rodent species; or, that such studies must have a specified duration. Instead, Vanda argues, FDA’s regulations call for appropriate toxicity studies based on the drug and clinical development program at hand under 21 C.F.R. § 312.23(a)(8)(ii) (stating that “[d]epending on the nature of the drug and the phase of the investigation, the description [of toxicological effects of the drug in humans and animals] is to include the results of acute, subacute, and chronic toxicity tests . . . .”). But the only alternative to the 9-month dog studies that FDA offered would still eventually require Vanda to conduct the 9-month study and would therefore require the sacrifice of even more dogs.
The Complaint touches on a lot of criticisms commonly lobbed at the agency – blind enforcement of certain requirements, regulating by guidance document, outdated policies. They are indeed common critiques of the Agency. But litigating this particular application of FDA policy seems drastic.
Of note, in our experience, FDA generally requires a nine-month toxicity study in large animals prior to late-phase clinical trials or marketing. We note that while testing in beagles is expensive, it’s likely less expensive than prolonged litigation. And, given the clinical hold on the study, the clinical development of tradipitant is stalled while Vanda pursues this litigation.
Given that the issues raised by Vanda are essentially questions of scientific judgment and statutory interpretation, a court seems likely to defer to FDA discretion in accordance with Chevron. See Chevron U.S.A., Inc. v. Natural Resources Defense Council, Inc., 467 U.S. 837 (1984). And if Vanda does win this lawsuit, the court is likely to remand the issue back to FDA for further consideration and justification. See Prevor v. FDA, No. 1:11-cv-01187-RMC (U.S. Dist. Ct., D.D.C., decided September 25, 2012). Vanda would then be left in the same place it is now but after several years of litigation. And, in the end, Vanda may still need to complete at least one dog study to get approval of tradipitant. The delay during the pendency of litigation risks a competitor coming to market first, which would mean Vanda losing any NCE exclusivity that may have attached to the active moiety.
While we do not have insight into Vanda’s motivation for this lawsuit, the company appears to be using this issue to launch a springboard for reform of animal testing in the pharmaceutical industry. Given that litigation seems to be one of the only ways to get FDA’s attention (waiting years for a response to a Citizen Petition isn’t exactly efficient), maybe this will bring some change to FDA requirements. Indeed, Vanda published an Open Letter to the FDA on February 5, 2019 stating that these longer-term studies resulting in the deaths of young beagles, pigs, monkeys, or other animals are unnecessary, unethical, and inhumane. Vanda argues that these types of studies should be the exception rather than the rule and reserved for instances with a strong, science-based rationale for conducting them. Vanda points to a large body of published scientific evidence concluding that 9-month dog studies rarely identify toxicities that were not already identified in 3-month studies or other information that is important to understanding a drug’s impact on humans. In its letter, Vanda asks for other companies to stand with Vanda in lobbying FDA to abolish its “one-size-fits-all approach to animal research, including nine-month, non-rodent toxicity studies, which results in the unnecessary sacrifice of too many dogs and other animals.”
Vanda does note that it understands the necessity of animal testing but is simply trying to limit the unnecessary testing. Indeed, this could be an effective animal advocacy strategy. And the Open Letter seems to reflect genuine concern about animal welfare and animal testing. The likelihood of not doing those dog studies, at least in this specific instance given the discretion afforded to FDA for scientific determinations, may be low, but Vanda appears to be committed to the cause. The beagles thank you, Vanda.