Response to FDA statement on termination of a primate nicotine research study

The US Food and Drug Administration (FDA)  announced yesterday that it terminated a study investigating the effects of nicotine in monkeys.  This announcement, which was accompanied by the release of many records and documents related to the animals’ care, is troubling for many reasons.  Among them, it again raises questions about oversight and decision-making.

Nicotine addiction remains a major health problem that is being tackled by research funded by multiple agencies, including FDA, but also the National Institutes of Health (NIH). As reported by the New York Times:

“The suspended study, begun in 2014, was designed to inform agency officials who have expanded oversight of tobacco products, regulation of e-cigarettes and alternative nicotine delivery devices.”

While the health risks associated with combustible tobacco are well-known, there are urgent questions that remain regarding the safety and effects of nicotine delivered in other ways, such as by vaping or with e-cigarettes—particularly for children and adolescents.

In yesterday’s FDA announcement, however, the agency did not address the need for the scientific study. Nor did the FDA’s statement include any evidence that the scientific team or justification for the research was at issue. Rather, the statement focused on the results of an internal investigation of the animal’s veterinary care.  The agency released 41 documents that include clinical records and emails, and those related to the deaths of four monkeys, including one due to bloat (pages 14-16) and one following a dental procedure (pages 23-28) — neither of which were related to the experimental procedures.  The FDA’s major conclusion was that there were problems in oversight and veterinary care provided by a third-party contractor.

“While the study animals are safe and being well cared for, the team’s initial review of the NCTR study raised several concerns, including a generalized lack of adequate oversight that could lead to similar issues for other protocols and procedures, as well as several repeated reported deficiencies that occurred under the third-party animal welfare contractor [our emphasis] used during the study. Information relevant to their review can be viewed here.”

Squirrel monkey. Source: Wikipedia Commons.

According to a source familiar with the research, the records and account of events provided by the FDA leave out important information, including correspondence and records that show that the scientific team leading the study halted the work in July – months before the FDA Commissioner’s problematic public “halt” of the study that followed an equally problematic letter from Jane Goodall.  The reason for the halt in July, by the study team, was to address and resolve potential issues with anesthesia procedures, all of which were undertaken with veterinary oversight. When reading the lay summary of this research provided in the released documents, we see a more nuanced perspective from the PI, that is not captured by Goodall, and again exemplifies why Goodall’s perceived expertise is clearly lacking at best or simple-minded at worst.  The PI’s lay summary (page 4, section G) reads:

“While nicotine appears to be largely responsible for mediating the reinforcing effects of tobacco products, cigarettes contain more than 4000 other constituents and very few investigations of the reinforcing effects of these chemicals have been conducted. Thus, we will also investigate the abuse liability of the non-nicotine tobacco product constituents myosmine and anatabine, both individually and in combination with nicotine. These two non-nicotine constituents were chosen in consultation with the funding source (Center for Tobacco Products; CTP) and are two of five relatively abundant alkaloids that comprise 2-4% of the total alkaloid content in tobacco products (nicotine comprises 96-98%).”

Yesterday’s statement by the FDA also announced new procedures and policy for review and oversight at the federal agency. Of note, the FDA, as a federal agency, does not have the same external oversight system as non-federal research facilities. For example, non-federal research facilities, including universities with federally-funded research programs, fall under federal oversight by the USDA and by NIH OLAW, including inspections by the USDA. The FDA apparently does not fall under USDA oversight. Further, it is not very clear from the statement how the third-party animal care contractor was monitored, although public records appear to indicate that the Virginia-based contractor may be a long-time provider of animal care for federal facilities.

The points raised in today’s report raise a number of concerns.  First, it is true that in any complex human endeavor there is potential for error—ranging from research to air traffic control to medical care in hospitals or daily human life. The fact that there were apparent errors in veterinary care at the NCTR is an issue because it suggests that the oversight system at the NCTR may stem from weak oversight systems for the federal research facility and for third-party contractual animal and veterinary care. Thus, the FDA statement points to a broader issue that merits broader consideration.

Second, the opaque process by which FDA suspended, reviewed, and—ultimately—ended the research should be of high concern to the public, which has a stake in scientific investigations of high human health relevance. In this case, there appears to be no question about why the research is important. This point is made by the nation’s leading addiction researchers in an open letter we published previously at SR, and again today in the NYT.

Jack Henningfield, professor of behavioral biology at Johns Hopkins School of Medicine, disagreed with the decision to stop the study.

‘These studies are done to address really serious questions about the nature of tobacco addiction,” Dr. Henningfield said. ‘‘This is research in serious service to humanity. If there was an accident leading to the death of someone working in global warming research, you’d correct that situation, not stop doing global warming research. You’d say, ‘We are going to do it better, with more safety and even more care.’

Third, the FDA process also raises questions about how federal science agencies communicate transparently to the public about the role that animal research plays to inform public health. The FDA – foremost among our federal agencies — should know that nonhuman animal research and testing are a crucial part of producing basic knowledge relevant to ensuring human health and the safety of drugs and devices that they oversee. The FDA announcement and release of documents without any explanatory context is a failure of good public communication. The 41 pdfs of emails and records do little to provide an accessible account of the agency’s work, the animals’care, or the research.

Furthermore, indications are that the FDA will, as soon as next week, release videos from the NCTR monkey research in response to a FOIA request.  Sources indicate that those videos are from behavioral observations of the animals temporarily separated from their social partners, as described in the approved research protocol. The behavioral observations were made to evaluate the effect of nicotine on behavior. The goal of the research was to better understand how nicotine in conjunction with the most common constituents found in tobacco affects the likelihood that abuse and addiction occur. This research was longitudinal in nature, meaning that it studied these effects across time, beginning in the monkeys’ adolescence. This research was both highly applicable to humans in terms of the species used (primates) and needed as adolescents represent an at-risk population. These conclusions are transparent in the approved protocol prior to study initiation.

It seems reasonable, however, to imagine that the anti-animal research groups who receive the videos will convey to the public a much different picture, as we have seen previously in campaigns against research. We call on the FDA to provide an accurate explanation of what is occurring in the videos when they are released. Any less is a disservice to the public. Those who made the videos can provide the best explanation. But that will depend upon the federal agency allowing its scientists to speak to the public.

Finally, all of this raises questions about politics, science, and public health. The FDA has issued statements and is engaged in public campaigns that surround promotion of non-tobacco forms of nicotine to assist in the alleviation of abuse and addiction with respect to the burning of tobacco products. However, supplanting the consumption of nicotine via the burning or heating of tobacco by other means, such as e-cigarettes and vaping, does not reduce the importance of understanding how these products contribute to abuse and addiction by at-risk populations. For example, the replacement of tobacco with vaping, has expanded the market for tobacco products, to now include previously low risk (for use and abuse) children. Also, there is some evidence to suggest that vaping serves as a gateway to the use of traditional cigarettes. All of these public health issues warrant critical consideration and also requires that we have the effective tools – animal models – as well as the relevant infrastructure to support this emerging health concern.

Speaking of Research