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Vanda Pharmaceuticals wants to start a year-long Phase II clinical trial of tradipitant, its drug in development for the treatment of gastroparesis. The FDA won’t allow the trial in human subjects to go forward until Vanda conducts a nine-month toxicity study in dogs. Vanda is challenging that decision in both federal court and the court of public opinion, claiming the toxicity study is unnecessary and would result in the needless deaths of dozens of animals.

Vanda filed a lawsuit against the FDA in the U.S. District Court for the District of Columbia earlier this month asking the judge to order the FDA to lift its clinical hold (the formal name for the FDA’s action). It also wrote an “Open Letter to the Food and Drug Administration,” calling on drug companies, the scientific community, and the general public to join it in asking the FDA to revisit its “one-size-fits-all” animal testing policy, which Vanda claims is outdated and not scientifically justified.

In the Open Letter, Vanda does not dispute the necessity of animal testing in drug development and approval, which can include multiple animal studies of different lengths and in different species to identify potential toxicities that might pose a risk to humans. What Vanda does dispute is the FDA’s routine requirement of a nine-month non-rodent toxicity study which, it claims, is unnecessary in most cases.

Vanda summarizes the testing already done on tradipitant to emphasize its point. The drug has been the subject of several animal studies, including rat and dog toxicity studies at up to 300 times the intended human equivalent dose without “clinically significant safety signals” (although for a shorter time than the FDA is now demanding). This lack of safety issues, the company says, is consistent with animal studies of other drug ingredients that share tradipitant’s mechanism of action. Finally, tradipitant has been the subject of 15 clinical studies for indications other than gastroparesis without incident. (It does not appear any of these got final FDA approval.)

In imposing this testing, usually conducted in young beagles, but also other animals like monkeys and minipigs, the FDA, Vanda claims, “is ignoring a large body of published scientific evidence” concluding that nine-month dog studies “rarely, if ever, identify toxicities that were not already identified in previous animal studies of a drug in development.” Nor do they “yield new information that is important for the purpose of understanding how the drug will impact humans.”

Vanda asks the FDA to review the vast record of animal research it has accumulated in the drug development and approval process over the years and identify which animal studies are genuinely scientifically useful. This review, along with existing scientific evidence on the lack of necessity for animal studies, Vanda claims, should result in a policy where animal studies are the exception rather than the rule and are required only on a case-by-case basis when scientifically justified. Vanda is confident that the FDA would conclude nine-month toxicity studies in dogs and other animals should not be routine. The review would also “shed light on the need for other types of animal testing as well.”

Vanda points to the EPA as an example of how this could work. Based on the scientific literature and the agency’s own review of toxicity study results, the EPA abolished a blanket requirement that 12-month toxicity studies of dogs be conducted in the pesticide registration process and now requires them only on a case-by-case basis.

The Open Letter is graphic in its description of what happens to the animals studied and blunt in its judgment:

For the [nine-month toxicity] study, all of the animals must be euthanized (or “sacrificed,” in the scientific jargon) at the conclusion of their study participation so that their tissues can be analyzed. In many, if not most, cases, these longer term, non-rodent toxicity studies are unnecessary. Killing animals without a scientifically justified purpose is unethical and inhumane.

Vanda chides other drug companies for conducting animal studies for decades “reflexively, without challenging the FDA.” The FDA has relied on this industry complacency, it says, but Vanda will refuse “to sacrifice young beagles or other animals in a study that serves no scientific purpose”.

Lawsuit against FDA

Oversimplifying the 56-page complaint somewhat, Vanda alleges that, to impose the clinical hold, the FDA was legally required to find that tradipitant poses an unreasonable risk to human clinical trial subjects, something the FDA failed to do. Alternatively, Vanda complains that the FDA specifically relied on one of the agency’s non-binding guidances as the source of the study requirement instead of a properly enacted regulation. (This is a common criticism of the agency: Relying on guidance documents instead of enacting regulations, which require notice to the public and an opportunity to comment.) Thus, the FDA’s clinical hold was “arbitrary and capricious”, the legal standard Vanda must meet for a court to overturn an agency’s decision.

In what Vanda sees as a “white flag,” the FDA recently asked the court to send the matter back to the agency for further consideration of Vanda’s complaints, but it wants to continue the clinical hold while it does so. Vanda replied that it is perfectly willing for the FDA to reconsider the matter, but the court should lift the clinical hold when it sends the case back to the agency. And Vanda wants a full and fair consideration of its criticisms, not just “lipstick on a pig”, with the FDA retrofitting its decision so it can reach the same result.

This is good news for Vanda because, as the FDA Law Blog points out, the suit will be difficult to win, given the courts’ typical deference to agencies in questions of statutory interpretation and scientific judgment. And, as it also points out, even if Vanda wins, the court is likely to send the matter right back to the FDA for further consideration and justification for its decision, leaving Vanda in the same position it is now, only with several years of litigation having passed and the possibility of a competitor stepping in to fill the void.

To the authors of the FDA Law Blog, the lawsuit and the Open Letter do seem to evidence a real concern about animal welfare and animal testing. As might be expected, PETA has voiced its support for Vanda’s actions. Investors, not so much. Vanda’s stock dropped nearly 20% on news of the lawsuit and one stock analyst lowered its expectations for the stock, although the gloomy outlook is not shared by everyone.

Is animal testing in drug development necessary?

A 2016 article on the Pharmaceutical Technology website featured a debate between Dr. Jarrod Bailey of Cruelty Free International, which seeks a ban on all animal testing, and Chris Magee of Understanding Animal Research, which is supported by universities, research labs, and drug companies, among others. Both organizations are based in the U.K., which is part of the European ban on animal testing when there are available alternatives is in place. (There is no such law in the U.S., although some states do have similar laws banning animal testing for cosmetic products.)

Bailey argues that inter-species genetic variability means that “meaningful inferences between animal and human reactions is not feasible”. He points to HIV/AIDS vaccine and stroke treatment research in animals that have shown efficacy but failed to yield an actual vaccine and only a “precious few” stroke treatments. On the other hand, he says, drugs that proved safe in animal testing have turned out to cause harm in humans. According to the FDA, 92% of drugs that are successful in animal testing fail in human trials, a statistic Bailey sees as indicative that the animal testing paradigm is failing.

Magee points out that all but a few Nobel Prize winners for physiology and medicine have been animal researchers. Animal testing has elucidated the role of insulin in diabetes and other biological mechanisms and successful treatments have been based on animal physiology. He rejects the 92% failure rate as indicative of the failure of animal testing, as it includes other reasons a drug does not make it to approval, such as economic viability. He says the paucity of adverse events in human clinical trials demonstrates the contribution of animal testing, which successfully screens out harmful compounds.

Magee counters Bailey’s genetic differences argument by noting the potential of genetic manipulation to “humanize” test animals. In addition to drug trials, which make up only around 15% of animal testing, the contribution of animal research to basic knowledge underlying the development of new treatments is of vital importance, although the time between discovery and medical innovation can take years. As an example, he cites frog-cloning experiments in the 1960s that facilitated modern stem cell research.

Bailey and Magee agree that animal research is replaceable with other technologies, although they disagree on the degree to which that is currently possible. These technologies include stem cell platforms, 3D tissue and organ cultures, and computer simulation.

The author of the article featuring the debate believes

there may well come a time when technological advances turn animal research into a relic of the past, but the current best practice employed in Europe seems a sensible compromise until that time comes, and other regions would do well to follow suit.

I can see how having to determine whether alternatives are available and implementing them might be a burden and added expense in a climate where research dollars are a zero-sum game. But it is also difficult to defend the routine use of animals without giving some thought to whether the particular research is really necessary, the point Vanda makes. Then again, I am not a researcher and have no first-hand experience in dealing with these issues. I know I would like to see a cure for cancer(s) (and many other diseases) and that this is likely impossible without animal testing. On the other hand, it is hard not to think about the beagles.

Photo by Grant Durr on Unsplash.