Abstract
Non-human primates (NHP), particularly macaques, are commonly used in studies conducted to assess toxicity of new pharmaceutical entities. NHP harbor a variety of pathogenic and potentially opportunistic infectious organisms, which may result in overt infectious disease during the course of a study, complicating interpretation of study findings, particularly when the pharmaceutical entity under evaluation is intended to be immunomodulatory. Clinical infection occurring on a toxicology study may be useful in identifying an effect on host resistance; however, the spontaneous occurrence of infection may inappropriately suggest a test article effect. In addition, background infection may present an animal welfare or zoonotic concern. Researchers and suppliers of NHP utilize a wide variety of screening and preventive care measures as well as approaches to overt infections seen during the course of a study. A Workshop was held to bring together key stakeholders for a discussion of these issues and the various practices employed to address them. The Workshop was sponsored by the Immunotoxicology Technical Committee (ITC) of the Health and Environmental Sciences Institute (HESI) of the International Life Sciences Institute (ILSI).
There is an increasing concern that naturally occurring infectious disease in non-human primates (NHP) may complicate interpretation of study findings in toxicology assessments, particularly when evaluating potential therapeutics designed to be immunomodulatory. To minimize these complications, suppliers of NHP, contract research organizations (CRO), and pharmaceutical/biotechnology companies utilize a variety of screening and preventive care measures including vaccinations and quarantine procedures. The extent of such measures varies across facilities. If an infection is observed on a toxicology study, the animal may be treated for the infection while on the study, the dose of the test drug may be reduced, the animals may be taken off the test drug for a period of time (drug holiday) or removed from the study. Like the screening and preventive measures, approaches to dealing with NHP infections which occur during toxicology studies are also quite diverse. Some also view the development of opportunistic infections as an approach to identifying overt immunosuppression, particularly for those compounds specifically intended to modulate immune or inflammatory responses.
Given the wide variety of viewpoints and approaches, a Workshop was held on October 22, 2008 to bring together key stakeholders (experts in NHP infectious disease and pathology, laboratory animal veterinarians, anatomic and clinical veterinary pathologists, toxicologists, and regulatory scientists) to discuss these issues and different practices. The Workshop was sponsored by the Immunotoxicology Technical Committee (ITC) of the Health and Environmental Sciences Institute (HESI) of the International Life Sciences Institute (ILSI). There were 63 registered attendees, which included scientists from HESI, the Food and Drug Administration (FDA), a number of pharmaceutical industry entities, and academic institutions. The goal of the Workshop was to discuss potential types of infections seen in NHP, share information about the characteristics and ways to test for specific infections, and consider how the presence or recrudescence of naturally occurring infections may impact interpretation of toxicology studies. The potential use of infection and immune responses to infection for assessing immunosuppression potential was also a key discussion point of the Workshop.
After a brief introduction of the topic and agenda by Ellen Evans of Schering-Plough Research Institute, Carmen Booker of the FDA provided an introduction from her perspective. The remainder of the morning was devoted to presentations of experts in the field of NHP medicine, as well as several case studies.
While there are numerous species of primates used in pharmaceutical research, the typical species used in toxicology studies are rhesus and, more commonly, cynomolgus macaques. Therefore, most of the morning’s discussion focused on macaque diseases and husbandry. Vito Sasseville, a veterinary pathologist from Bristol-Myers Squibb, provided an overview of known infectious organisms seen in monkeys used for toxicity testing. His presentation included common pathogenic as well as opportunistic viruses, bacteria, parasites, and fungi. Nick Lerche, a veterinarian at the California National Primate Research Center, shared his expertise in the complex of potentially immunosuppressive retroviruses; dealing with these viruses in a toxicity setting can be particularly challenging, in that their long incubation/sero-conversion periods and high degree of latency may cause challenges in ante-mortem diagnosis, and they can cause immunosuppression in the absence of an immunomodulatory drug. Joe Simmons, a laboratory animal veterinarian associated with Charles River Laboratories, discussed latent viruses, the potential for use in monitoring immunosuppression, and Specific Pathogen-Free (SPF) colony status. Katrina Taylor of Bristol-Myers Squibb provided a clinical veterinarian’s perspective. She discussed challenges with sources of NHP, quarantine and husbandry considerations, treatment modalities that do not interfere with study endpoints, and ethical considerations for monkeys on studies. The morning concluded with presentations of cases where immunomodulation resulted in the appearance of latent viruses or clinical disease caused by opportunistic organisms. David Hutto, a pathologist at Biogen Idec, presented a case of virally-induced lymphoma, as well as sub-clinical Plasmodium infection becoming clinical malaria and a measles outbreak in primates. Karen Price, from Brisol Myers Squibb, presented a case study of opportunistic bacterial infection. The papers that follow in this issue—describing these morning presentations—are representative of the individual speakers’ perspectives and not necessarily views of HESI or the Immunotoxicology Technical Committee.
The afternoon was devoted to three sessions in which experts facilitated discussions on specific topics, with participation from the attendees. The first session was managed by Joe Simmons, Ken Olivier of Merrimack Pharmaceuticals, Keith Mansfield from the New England Primate Research Center/Harvard Medical School, and Nicholas Lerche. This session covered the infectious disease status of monkeys used for toxicology studies and the potential for complicating or compromising studies, the need for and means of screening for infection, advantages and disadvantages of using “cleaner” monkeys, and the meaning of the term “Specific Pathogen-Free” as it pertains to macaque husbandry. The second session was chaired by Karen Price, Katrina Taylor, and Joel Beren and L. Peyton Myers of the FDA, and focused on treatment of monkeys for infection while on study. There is concern that immunosuppression or the extent and severity of an infection may be masked if monkeys are treated with antibiotics or other anti-infectives. However, there are also ethical considerations which dictate treatment or removal from study if the animal’s welfare is compromised by infection. The consequences of treatment versus removal from study were discussed from the perspectives of data integrity and regulators, and there was also some dialogue regarding regulatory consequences of infection occurring in studies of compounds with known immunomodulatory potential. The third discussion session was facilitated by David Hutto, Jeanine Bussiere from Amgen, and Yanli Ouyang of the FDA. This discussion covered the use of latent virus recrudescence as a means of identifying immunosuppression, and the practicalities of doing so, as well as potential translation of findings to human risk potential and starting dose selection. Other methods for assessing infection risk potential that could be incorporated into NHP studies were also discussed.
Declaration of interest
Ellen Evans is an employee of Merck & Co. and Thomas Kawabata is an employee of Pfizer, Inc.