Paw Shucks: Court Defers to FDA’s Request for Additional Animal Studies

February 18, 2020By Sara W. Koblitz

Animals, shmanimals.  Or so says FDA.  Well, FDA didn’t actually say that, but that’s the effect of the District Court of D.C.’s recent ruling in Vanda Pharmaceuticals v. FDA.  In a case we have been following for the last year or so, the District Court deferred entirely to FDA’s decision to place a clinical hold on Vanda’s human studies until studies in dogs were completed.  Vanda argued that FDA’s decision to place its trial on clinical hold lacked an articulated scientific basis and treated a guidance as binding.  In its initial Complaint, Vanda also argued that the mandated testing needlessly wastes dogs’ lives.  As such, Vanda alleged that FDA’s imposition of a clinical hold was arbitrary and capricious in violation of the Administrative Procedure Act (“APA”).  FDA asked to remand the issue to the Agency, the Court granted the request and stayed the litigation, but the Agency went back and made the same decision – this time providing significantly more explanation.  In response, Vanda revived its litigation.

In its second round of briefing, Vanda alleged procedural violations of the APA, as well as substantive violations of the Food, Drug, and Cosmetic Act with respect to FDA’s interpretation of the studies.  Vanda argued that FDA’s remand response is “impermissible post hoc rationalization” including new reasons for the imposition of the hold.  The Court rejected these arguments, noting that the justifications provided in the Remand Response were merely “amplified articulation” rather than post hoc rationalization.  Vanda also argued that the “proper decisionmakers” (the Medical Policy and Program Review Council or “MPPRC”) had not been responsible for the remand response and that the remand response amounted to the review division (Office of Drug Evaluation III) impermissibly “overruling” the MPRCC’s previous findings.  The Court quickly dismissed this argument noting that it had no support in statute or regulation, and, in any event, the remand response was issued by FDA.

Additionally, Vanda argued that FDA “skewed the administrative record on remand” by selectively opening the record and adding new studies supporting its position while ignoring studies Vanda and the Humane Society of the U.S. pointed out.  (Of note, the Humane Society tried to file an amicus brief in this case, but the Court rejected it, saying that all of the arguments it made had already been made by Vanda or were not adequately in front of the Agency prior to its decision.)  Explaining that FDA was required only to examine the record before it at the time the decision was made, the Court held that FDA was not required to consider any additional evidence in support of Vanda’s position.  The Court explained that “no provision in the APA requires FDA to give Vanda an ‘opportunity to offer contrary evidence’ on remand” and a “fundamental fairness” requirement would impose additional procedures on FDA without statutory basis.  Further, the Court noted that Vanda could have introduced its evidence into the administrative record through a “written request” containing “sufficient information” to support the removal of a clinical hold but chose not to do so.  As such, the Court rejected all of Vanda’s procedural arguments.  Finally, the Court noted that Vanda had not availed itself of the administrative pathway of dispute resolution once the clinical hold was imposed.

The Court divided Vanda’s substantive claims into two main arguments: FDA improperly used guidance as a binding legislative rule, and FDA relied on flawed scientific judgment.  Specifically,  Vanda objected to 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).  This guidance, referred to as the “ICH Guidance” because it was created by the International Conference for Harmonization, addresses the use of nonclinical safety studies to support the conduct of human clinical trials and marketing authorization for pharmaceuticals.  FDA has adopted this policy and relied on it as justification for requiring Vanda to conduct additional animal studies.  The Court concluded that the “the Remand Response makes clear that the ICH Guidance is a policy statement exempt from the notice-and-comment process, and that FDA did not rely upon it as a binding rule in imposing the clinical hold.”  As a general statement of policy (rather than a legislative rule), the Court explained that the guidance was not subject to notice and comment requirements.  Contrary to Vanda’s allegations, the true legal authority for the hold was FDA’s clinical hold regulations – not the guidance, which had no actual legal effect.

Finally, as is the norm, the Court largely deferred to FDA’s scientific expertise in this case.  Absent clear error or malfeasance, it’s almost impossible to overcome deference to scientific expertise – particularly in the area of necessary clinical studies.  Vanda argued that FDA ignored or misinterpreted cited studies; failed to explain why toxicity in nonrodent studies would be predictive of human toxicities; and that the Remand Response was a litigation-driven interpretation of a study.  In response, the Court asserted that Vanda failed to show that FDA’s interpretation of its study was unreasonable.  Additionally, because the legal framework mandates animal studies, the Court explained, the legal framework presumes some connection between animal and human toxicity.  The Court added: “If Vanda has a quarrel with animal studies and their predictive power for humans in general, its fire would be more appropriately aimed at the controlling statute and regulations, not at FDA’s actions in this case.”  Finally, the Court stated that Vanda’s litigation-driven “argument is dead in the water: the administrative record makes clear that FDA had noticed and was concerned about the adverse toxicity findings in the 3-month nonrodent studies well before the lawsuit was filed in February 2019.”

The results of the case are not surprising.  Back in February 2019, we predicted both a remand and deference to the Agency, concluding that “Vanda would then be left in the same place it is now but after several years of litigation” and still required to complete a dog study.  Based on our experience, this outcome was essentially guaranteed.  Almost a year later, we are back to the same question: what was in this for Vanda?

Nonetheless, as avowed animal lovers, our interest in this case was no less due to the implications for animal studies as it was on the implications for FDA jurisprudence.  Unfortunately, the Court was silent on this aspect of the case.  Instead, the Court left the question of the necessity of animal studies to FDA, which has committed to reduce, refine, and replace.  This commitment, emphasized as recently as 2018, is intended to “potentially replace much of the need to use dogs in future trials with new informatics tools.”  FDA wants to “do one single study involving a small number of dogs—where the dogs will only be subject to minimally invasive blood sampling, and adopted as pets at the completion of the short trial—to eliminate the need for the use of dogs in certain types of future studies, some where they might have been euthanized.”  Perhaps this statement, combined with the inconsistent demand of further dog testing, is really what prompted Vanda to file this lawsuit.  We may never know.  But, given FDA’s zealous defense in this lawsuit, with allegedly questionable scientific rational, there may be some activists questioning FDA’s actual commitment to reduce, refine, and replace.