Between 2000 and 2020, an estimated 482,000 primates were imported into the U.S. to be experimented on in testing laboratories. All the while, pharmaceutical drug development has been mired in serious challenges, particularly during the animal-heavy research stages known as preclinical phases. Now, a series of supply chain disruptions have created a shortage of primates for laboratory testing use. Rather than expanding the breeding of primates for cruel and scientifically unjustifiable use, this debacle should be seen as an opportunity to replace primate testing and improve medical research once and for all.
Two critical challenges are especially daunting for drug development — one, the use of animals to predict the safety (e.g. toxicity) of drugs in humans, and two, the extrapolation of the efficacy of those experimental drugs from animals to humans. Using such approach, the failure rate has been stupefying, reaching according to the National Institutes of Health (NIH) as high as 95 percent.
In essence, the widely publicized shortage in non-human primates (NHPs), as they are referred to in scientific literature, is due to an interruption in the global supply chain. The issue started during the COVID-19 pandemic, mainly after the stoppage of China’s exports of monkeys. (Further reflections on the shortage were made in a commentary from the biotech company, Emulate, and a testimonial letter concerning related legislations, such as Oregon State House Bill 2904.)
China is the major worldwide supplier of research primates, and around 70,000 are used annually for laboratory experimentation in the U.S. alone, a several fold increase since the early 2000s. The supply chain of live monkeys for experimental use was also stressed and exacerbated by recent criminal activities — namely the smuggling of Cambodian monkeys. Imports from Cambodia had somewhat compensated for the shortage of China’s laboratory monkeys, but their import to the U.S. was halted by the U.S. Fish and Wildlife Service shortly after criminal indictments were handed in November 2022.
As a response to the shortage, whispers about expanding U.S.-based breeding programs for NPHs are getting louder. These plans, promoted by animal research enthusiasts, are attractive to many groups from a financial standpoint, including commercial breeding suppliers and NHPs Contract Research Organizations (CRO). Experiments on just a handful of monkeys are invoiced at a rate of millions of dollars. This business is supremely lucrative with marked federal funding through the NIH, including a permanent networking consortium. NHPs research enthusiasts and interest groups have long desired an expansion of the U.S.-based NHPs breeding programs.
Case in point, a two-part report released by the NIH Office of Research Infrastructure Programs (ORIP) in September and December 2018 — i.e. prior to the COVID-19 pandemic and the existing NHPs logistical issues — advocated for an increase in U.S.-based colonies for NHPs.
Notably, imported primates are not the only source for laboratory animals in the U.S. The most recent ORIP Nonhuman Primate Resources Fact Sheet, published in 2023, lists an expanded network of 14 large centers across the U.S. and its territories, all funded by the NIH. Between 2020 and 2021, the NIH has invested an additional $29 million in emergency spending building outdoor enclosures and making other infrastructure improvements at seven U.S. National Primate Research Centers (NPRCs) in preparation for what appeared to be an imminent expansion of U.S.-based breeding programs, with more funding promised on the way.
On May 4, 2023, a new report by the National Academies of Sciences, Engineering, and Medicine (NAS) concluded that supply of monkeys for research is “at a crisis point.” The report, entitled, “State of the Science and Future Needs for Nonhuman Primate Model Systems,” was also commissioned by the NIH in response to a congressional inquiry and calls from animal research enthusiast groups. The NAS report lists five key multipart conclusions. Considerable effort by experts, typically volunteering their time, is needed to produce such reports. That said, these types of sanctioned documents inform health policies and therefore must be scrutinized with utmost rigor.
In a particularly alarming section, the report expressly states that:
Biomedical and public health research in the United States is threatened by dependence on imported nonhuman primates (NHPs). This reliance on external resources is unsustainable and undermines the security of the U.S. biomedical research enterprise. To ensure that NHP resources are available to respond to public health threats, the United States needs to prioritize expansion of domestic NHP breeding programs.
Given the recommendation of the 2018 NIH-OIRP report advocating for expansion of U.S.-based colonies of NHPs, the NAS report echoed, with discipline, the stance of the NHPs user industry and stakeholders on the issue. In most relevant parts, the recommendations of the NSA report are almost identical to those listed in the 2018 OIRP report, especially concerning the quest for expanding U.S.-based breeding programs. Such juxtaposition of the two reports, almost five years apart and regardless of the current import saga, suggests a dogmatic, persistent view by the establishment on the issue of NHPs in medical testing.
Instead of some innovative, out-of-the-box solutions expected from the NSA report, the same age-old refrain advocating for more federal support to fund program enlargement seems to be the fix here. This markedly detracts from the originality of the report in proposing real, unrecycled solutions to the abuse and also unreliability issues of NHPs in medical research and testing. In fairness, a commissioned committee must not deviate from the charge given to it at the outset and its overall mandate. As such, a framing bias could have been at play from the get-go.
To this end, expanding U.S. breeding programs represents a serious problem, including several ethical, scientific and safety woes. Let us set aside for a moment the conspicuous ethical argument related to subjecting animals to unspeakable physical, behavioral and emotional cruelty in exchange for unreliable data. According to the Centers for Disease Control and Prevention (CDC), three out of four novel infectious diseases are rooted in zoonotic transmissions, i.e. transmissions from animals to humans. Expansion of U.S.-based primate breeding programs will surely, at a minimum, heighten that risk.
The main challenge in drug development is the reliance on a misguided paradigm for modeling human diseases — a paradigm centered around artificial animal models that are neither predictive nor relevant. A close second is the inability to reproduce biomedical research data, dubbed in the field as the “reproducibility crisis,” which is attributed in large parts to, ironically, the use of animals in research. In 2014, Francis S. Collins, then the National Institutes of Health (NIH) director, stated in a candid reflection in the journal Nature coauthored with Lawrence A. Tabak, acting NIH director since December 2021, that “preclinical research, especially work that uses animal models, seems to be the area that is currently most susceptible to reproducibility issues.”
Despite being considered closer to humans than other species, NHPs often do not reliably predict human disease responses. As an example, NHPs showed very mild clinical symptoms in response to SARS-CoV-2, rendering them unreliable as research models for COVID-19. No fatalities from disease burden were registered in SARS-CoV-2 infected NHPs, making them also inappropriate for modeling COVID-19-induced multisystem organ failure, a hallmark of COVID-19-related deaths. The lucrative primate research business must not cloud our judgment regarding their fitness for use. We must move towards future innovations and technologies — not backwards, recycling the same unreliable models used centuries ago.
The paradigm shift can start now. What is required is a deviation from the policy of kicking the medical-research-and-testing-methods can down the road and getting serious about investing in 21st-century solutions. These solutions are made possible by the advancement of technology and innovation and are broadly referred to as alternatives methods to animal research and testing, or simply alternatives. Promising solutions include platforms using artificial intelligence (AI), Organoids and Organ-Chip technologies, to name a few. (We recently published an opinion article in Frontiers in Medical Technology containing an expanded analysis of the advantages of these alternatives and areas under development.)
In retrospect, much of the animal data generated during the pandemic produced more questions than answers. Had it not been for the world’s full attention on developing vaccines, relying only on artificial animal models could have been catastrophic from the standpoint of saving time or generating actionable information. For instance, studying COVID-19 in mice, the most widespread model in the world, is misleading. Mice — unlike humans — are not naturally susceptible to COVID-19 due to a key structural difference between the two species in their host-pathogen interaction. NHPs, like other animal models, are subjected to a range of genetic, behavioral and physiological manipulations during laboratory experimentation and testing. They were the wrong models then and are the wrong models now to study human diseases.
The bizarre reliance on animals to model human pathologies is the real crisis. Animals are widely used in preclinical testing stages of drug development. But once they reach the clinical stage, up to 95 percent of experimental drugs fail to prove safe and effective in humans, despite having acceptable safe and effective endpoints in animals. On the other hand, scores of potentially life-saving drugs are prematurely discarded based on animal data. This leads to significant productivity loss, delays in producing vital pharmaceuticals and exorbitant costs that are ultimately passed onto consumers.
Such failures can be attributed, in part, to the dearth of “human relevance” among the experimental models used in drug screening and the modeling of human pathologies — challenges that have burdened the pharmaceutical industry for decades and contributed to its “productivity crisis.” An objective examination of the many artificial animal models used in preclinical research, including NHPs, reveals radical structural, physiological, anatomic, digestive, genomic, metabolic, and behavioral differences among species.
At this juncture, it is worth highlighting one of the landmark policy decisions made at the March 2020 meeting of the International Coalition of Medicines Regulatory Authorities (ICMRA) — more specifically during the global regulatory workshop on COVID-19 vaccine development. There, global regulators stipulated that, “it is not required to demonstrate the efficacy of the SARS-CoV-2 vaccine candidate in animal challenge models prior to proceeding to FIH clinical trials.” That important policy decision was a vital step to accelerate the development of successful vaccines in a record time, with no risk to safety. In fact, such accelerated process disrupted the entire industry, launching what is now commonly known as mRNA vaccines to the forefront of therapeutic development of safe and effective vaccines.
The passage of the momentous FDA Modernization Act 2.0 (FDAMA) in December 2022 created momentum for reform. It was the extraordinary effort of the Modernize Testing campaign of the Center for a Humane Economy and its coalition partners — working alongside U.S. congressional leaders from both parties — that made FDAMA the law of the land. The new law amended the outmoded regulatory guidance at the FDA — broadening the options for drug developers seeking regulatory approvals to include new technologies and human-relevant testing methods in lieu of animal experimentation. But more progress must be made. Serious investments in alternatives are needed — not to complement an expanded U.S.-based breeding program of captive animals as conceived in the NAS report, but to use human relevant models as the basis of our paradigm for studying serious diseases.
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