ATLA 37, 427–435, 2009 427 Comment

The SCHER Report on Non-human Primate Research — Biased and Deeply Flawed

Jarrod Bailey and Katy Taylor

British Union for the Abolition of , , UK

Summary — The European Commission’s Scientific Committee on Health and Environmental Risks (SCHER) recently issued an Opinion on the need for non-human primate (NHP) use in biomedical research, and the possibilities of replacing NHP use with alternatives, as part of the Directive 86/609/EEC revision process. Here, we summarise our recent complaint to the European Ombudsman about SCHER’s Opinion and the entire consultation process. It is our opinion that the Working Group almost entirely failed to address its remit, and that the Group was unbalanced and contained insufficient expertise. The Opinion presumed the validity of NHP research with inadequate supporting evidence, and ignored substantial evidence against the need for NHP research and examples of valid alternatives that could replace the use of NHPs. Because the European Commission and others might base their approach to NHP research directly on the inquiry’s find- ings during the revision of Directive 86/609/EEC, the implications of a flawed analysis of the efficacy of NHP research are extremely serious, both for and for human health and safety. The conduct of the SCHER inquiry, and its published Opinion, should therefore be of major and widespread concern, and should not be given any political, scientific or legislative credibility.

Key words: alternatives, non-human primates, SCHER.

Address for correspondence: J. Bailey, British Union for the Abolition of Vivisection, 16a Crane Grove, London N7 8NN, UK. E-mail: [email protected]

Introduction In May 2008, building on this public and political concern, the European Commission (EC) mandated European Union (EU) Directive 86/609/EEC, the Scientific Committee on Health and intended to ensure the protection of animals used Environmental Risks (SCHER) to issue an Opinion in scientific research and testing, is currently on the need for non-human primates in biomedical undergoing a much-needed revision, more than 20 research, and the possibilities of replacing NHP use years after its adoption (1). with alternatives, as part of the Directive 86/609/ Of particular concern to many stakeholders is EEC revision process. Following the submission of the fact that experiments which use non-human written evidence from stakeholders, followed by a primates (NHPs), which have become especially meeting of interested parties at which the draft controversial in recent years, are not afforded any Opinion was discussed, the SCHER’s final Opinion specific attention under the current EU legislation. was published and adopted in January 2009 (6). Polls consistently show that a majority of the However, it is a widely-shared view that the British population oppose invasive and/or pain- final report produced by the Committee is far from causing procedures on NHPs, whatever the pro- the ‘balanced, independent and scientific’ opinion posed benefit to humans (2, 3) — an opinion that is it was purported (as well as expected and required) reflected across Europe, where, most recently, 81% to be. There are serious deficiencies in three key of the public were reported to agree that experi- areas of the report and in how it was produced. In ments causing pain or suffering to NHPs should be our view: banned (4). In 2007, the European Parliament 1. The Working Group (WG) did not adequately adopted a declaration that urged an end to experi- address the remit requested. mentation on great apes and wild-caught monkeys, and a commitment to phasing out NHP research 2. The balance of individuals within the working altogether, after the declaration was supported by group was heavily skewed toward those individu- a majority of the MEPs (5). als with expertise in animal-based research, with 428 Comment

a serious absence of expertise in either specifi- tion and refinement of their use in areas where no cally NHP research or the use of alternatives to replacement can be foreseen in the medium term, NHP research. i.e. areas deserving Three Rs investment; and implications for biomedical research, should NHP 3. The Opinion document itself is seriously flawed, use be banned in the EU. Demonstrably, the because: SCHER Opinion fails to consider all of these points a) It presumes that non-human primate (NHP) with any degree of significance, with the exception research is scientifically valid, relevant to, of the first — areas in which NHP are currently and predictive for, humans. This default used. While 14 of the 25 pages of text are devoted position of validity is held with no support- to this first topic, scant attention is given to the ing evidence other than anecdote, rhetoric others and, most critically, the implications of a and opinion, with a lack of systematic and ban on NHP use are not addressed at all. comprehensive evidence borne of compre- hensive, robust and critical scientific evalua- Current possibilities for replacement tion. Crucially, in our opinion, before any assessment of the validity, scientific per- formance and human relevance of alterna- The vast subject of alternatives to NHP research is tives can be made, the imperative first step tackled in just 3.5 pages of the Opinion, with the must be to ascertain the validity, scientific first half-page constituting a position statement in performance and human relevance of the support of animal models. There is no evidence of a NHP models currently being used in literature review regarding the status of alterna- research and testing, that those alternatives tive methods, nor of any consultation with the EC’s are intended to replace. own experts via the European Centre for the Validation of Alternative Methods (ECVAM). b) It contains very little of the substantial amount of evidence against the requirement for NHPs in research that was provided by Consideration of the concept of ‘replacement’ animal-protection stakeholders, and is therefore unbalanced. Even if the Crucially, the WG has neither defined ‘replace- Committee disagreed with this evidence, it ment’, nor examined in any detail what is actually should have been included and rebutted. required of a replacement method. It clearly c) It clearly seeks reasons to support the use of expects any alternative to wholly and directly sub- NHPs, and reasons against adopting alterna- stitute for the use of NHPs — an approach that is tives. Due to the inescapable and high ethical not only naïve, but is out of touch with how those cost of using NHPs in research and testing, that research and promote alternative methods the onus should instead have been on the view their purpose or utility. Committee to do the opposite, namely, to A broader approach recognises that alternatives explore reasons for not using NHPs and to can allow scientific objectives to be met without actively encourage the use of alternatives. direct ‘like-for-like’ replacement. For example, alternative strategies can increase the availability In this commentary, we present our views on the of human organs for transplantation, obviating the SCHER Opinion. We outline the basis of the above use of animal organs in . This objections, present examples of the many unsub- broader approach requires researchers to ask, stantiated statements made by the SCHER in its “What information do I need to solve this problem?” Opinion in support of NHP research, and provide rather than “How do I do what I want to do with- examples of serious omissions of alternative meth- out using NHPs?” It is clear that the former ques- ods and evidence against NHP research that were tion is more conducive to identifying methods that supplied to the Committee. We believe the entire would avoid NHP use. Indeed, this approach is process was unsound from its inception to its com- reflected in the wording of Directive 86/609/EEC pletion, and that the resulting Opinion document itself, in Article 7(2): “An experiment shall not be should not be given any political, scientific or leg- performed if another scientifically satisfactory islative credibility. method of obtaining the result sought, not entail- ing the use of an animal, is reasonably and practi- cably available.” (1). Concerns Regarding the Remit This concept appears not to be recognised by the WG, and this is reflected in its inadequate analysis The EC requested the SCHER to issue an Opinion of the current and future situation with regard to on: current areas of NHP research; current possi- replacement. Actual opportunities for replacement bilities for replacement; scientific timetable for a are rapidly dismissed in the Opinion with no sub- phase-out of NHP use; opportunities for the reduc- stantiation; for example, “The total replacement of Comment 429 animals, including NHPs in testing for safety, is 2. In the field of Infectious Disease Research: not possible based on present knowledge” (p. 22). a) Culture systems for infectious hepatitis C virus (HCV) in vitro now exist, enabling human-specific research, but the extent to Examples of promising alternatives disregarded which this obviates the need to infect NHPs by the WG (22) is entirely overlooked in the Opinion (p. 24). Many papers detailing work that can replace NHPs in a multitude of different fields were sup- b) Alternatives in malaria research are dis- plied to the Committee, but were disregarded. For missed, because they may not mimic the example, in the SCHER Opinion: entire ‘whole body system’, despite providing equivalent information. For example: imag- 1. In the field of Safety Testing: ing technologies which permit the visualisa- tion of individual malarial parasite-derived a) Microdosing (7, 8) is misrepresented as a molecules in living cells (23); human liver- complete replacement (p. 22), and therefore cell cultures which permit the study of inter- its use in detailing the pharmacokinetic (PK) actions between the human immune system profile of a drug (replacing the use of NHPs and the malarial parasite (24); and genetic for this role) is completely dismissed. studies with human volunteers, which have b) Similarly, the US National Academy of identified a novel P. falciparum gene Sciences (NAS) report Toxicity Testing in the (MB2I), the product of which could be 21st Century (9) is dismissed entirely, as this exploited as a vaccine target, and which focused on chemicals rather than drugs. have helped our understanding of how gene Although there are many key aspects within expression in the parasite influences para- the report that can apply to pharmaceuti- sitic survival and pathogenesis (25, 26). cals, these were not investigated. c) Genetic screens that can replace NHPs for c) The use of in vitro human-based cell culture vaccine testing, but have inexplicably failed systems for ADME/Tox screening is barely to be fully implemented, such as the mentioned, despite the fact that the Com - MAPREC system for polio vaccine consis- mittee was provided with papers detailing the tency batch testing (27, 28), are not even predictivity of such systems (e.g. 10–12), as mentioned. well as on methods for further improving them (for example, by the use of three-dimen- 3. In the field of Neuroscience Research: sional cultures [13, 14] and microfluidic chips a) Alternatives to NHP use, such as human- [15–17]). based studies, are barely discussed, despite d) Similarly, no mention is made of the promise the provision to the Committee of papers of functional human tissue assays that demonstrating that epidemiological studies, measure physiological effects at the level of imaging techniques and the use of human the organ, cell, or even the gene. Such post-mortem brain tissue have impacted approaches “are often superior to extrapola- greatly on our knowledge of causative fac- tion from animal data” (10, 18) and could tors, and our understanding of brain func- have detected the adverse reactions caused tion and regeneration in Parkinson’s Disease by Cox-2 inhibitor drugs such as Vioxx, patients (29–31). which caused over 320,000 heart attacks and b) Similar papers related to the relative value strokes, killing 140,000 people, despite the of human-based research for stroke are also cardioprotective results obtained in pre-clin- not discussed. Imaging techniques can mon- ical NHP tests (e.g. 19). itor changes in the human brain following e) Progress that has been made in constructing stroke and after treatment for the condition, the human immune system is also not men- and cultured human blood vessels and tioned, e.g. the presence of a fully-human human brain slices are being used to study modular immune in vitro construct contributory factors to stroke, as well as (MIMIC®) for the efficacy testing of potential repair mechanisms and treatments (32–34). vaccines, developed “in response to the c) Papers demonstrating that comparison of recurrent failure of animal vaccine protec- brain activity or behaviour between healthy tion studies to accurately predict human and impaired volunteers can give equivalent trial results.” It measures vaccine immuno- information to primate brain-damaging genicity via induction of the memory B-cell studies, such as hippocampus damage and response — traditionally an area of high memory impairment (35, 36), are also not demand for NHPs (20, 21). considered. 430 Comment

d) Similarly, the use of implanted eye coils (37) ple cut their intake of saturated fat by just or eye tracking devices (38) in healthy 1–3% (46). human volunteers, obviating the need for non-invasive primate vision research, are A scientific timetable for a phase-out of NHP disregarded. use e) Opportunities for replacement in neuro- science research, with imaging technologies This important section is discussed in just half a such as Magnetic Resonance Imaging (MRI) page of the Opinion, covering four research areas. and Functional Magnetic Resonance No time-scale for replacement, in the short, Imaging (fMRI), Positron Emission medium or long term, is provided. Genuine efforts Tomography (PET), Transcranial Magnetic should have been made to evaluate the use of Stimulation (TMS), are dismissed in the NHPs by subject area, and to provide such time- Opinion with no substantiation or justifica- scales, which could have been derived according to tion: “…fMRI studies cannot replace studies the current status of, and investment rates in, collected with invasive microelectrode tech- alternative methods. niques; these are much more precise anatom- ically and temporally” (p. 24). Opportunities for reduction and refinement f) The use of invasive single-cell recording in the meantime techniques in humans undergoing surgery is briefly mentioned (p. 18), but not with Reduction and refinement methods are arguably reference to replacement. Single-neuron more researched and implemented than replace- recordings have been used several times in ment methods. Nonetheless, this section of the conscious epileptic patients (e.g. 39), and Opinion is restricted to just two pages. Though a another study demonstrated that neural number of refinement and reduction opportunities responses to visual objects within the hip- are mentioned, little detail and discussion is pro- pocampus proper are directly linked to vided, and in most cases, no reference is made to visual memory performance (40). The fact scientific papers. that such studies are possible should seri- ously call into question the need, on a case- by-case basis, for invasive NHP research. Areas of the Three Rs which deserve investment 4. In the field of Xenotransplanation Research: a) There is no discussion on obviating the Given the conservative conclusions reached by the need for xenotransplantation research by WG regarding the Three Rs in NHP use, this sec- increasing the availability of human organs tion should have been much more extensive than for donation and reducing the incidence of the half-page of very broad recommendations for heart disease through dietary education. ‘more research’. To be useful to policy makers and funding bodies, detailed and clear scientific and b) Evidence was provided to suggest that a com- regulatory requirements should have been sup- bination of approaches could obviate the need plied, by research area, for the replacement of for animal organs: i) The instigation of an opt- NHPs — as opposed to a brief list of generic sug- out ‘presumed consent’ organ donor system gestions such as, “Further research in the use of has seen huge increases in organ donation genetically altered animal models or other suitable and transplantation rates in countries which mammalian species in testing of vaccines and have adopted it (41, 42). A similar system of pharmaceuticals.” mandated choice has produced hundreds of thousands of new donors in Sweden, the impact of which is further amplified, because Implications of a ban on NHP use for each donor can potentially provide several biomedical research organs (43). In addition, the use of kidneys from ‘living donors’ has greatly increased There is no specific section dealing with this cru- transplant rates in the USA and Norway, for cial question. While the opinion of the WG on the example (44); ii) Just under half of all heart implications for biomedical research may be transplants are for cardiomyopathy, some of inferred from their detailed coverage of the first which are preventable. Just under half again issues considered (areas of NHP experimentation), are for coronary heart disease, of which the this is no substitute for a thorough analysis of the vast majority (if not all) are preventable (45). implications, in real scientific, medical and finan- Around 100,000 first-time heart attacks could cial terms, of an immediate ban (or even a phased- be avoided each year in the USA alone, if peo- in ban) on NHP research. Comment 431

Such an analysis is imperative, specifically in comprises: a) unsubstantiated statements made by terms of the number of research projects affected, the SCHER in support of NHP research; and b) any reduction in the production of drugs, and so on. substantial evidence against NHP experimenta- All claims and caveats should be substantiated. A tion that the SCHER overlooked. Salient examples vital part of this would be to analyse the evidence for of unsubstantiated statements from the Opinion the utility and validity of NHP research, which the (in italics), and relevant referenced evidence that WG completely fails to address. Examples of was disregarded, include: research that would have provided information on the likely implications of a ban, but that were over- 1. In the field of Safety Testing: looked in the Opinion, are discussed below. “NHPs may be more predictive for human toxic- ity [in reproductive toxicology].” (p. 13). No evi- dence whatsoever is provided in the Opinion, of Concerns Regarding the Working the predictive nature of NHPs for human phar- Group macokinetics/pharmacodynamics/safety, or for the superiority of NHPs over non-primate The balance of individuals within the working species. On the contrary, there is ample evi- group was heavily skewed toward those with dence to the contrary, which was supplied to the expertise in general animal based research, with a SCHER. perturbing absence of expertise in NHP research For example: 34% of NHPs in regulatory and in the use of alternative methods. Nine of the safety tests are subjected to single-dose toxicity 11 members were animal researchers, of which tests that have been discredited (47); an just five were experts in primate use — the focus of International Conference on Harmonisation the SCHER Opinion. Neither of the SCHER com- (ICH) guideline admits that primate toxicology mittee members who were also members of the data “can differ from humans as much as other WG, were experts in NHP use, and only four of 11 species” (48); NHP developmental toxicity data members were experts in alternative methods. correlate with human data just 50% of the time, Just one was an expert specifically in the use of less even than results from more evolutionarily- alternative methods to NHP use, though this distant species such as rats, hamsters and expertise is in the refinement of animal experi- ferrets (49); there remains “no statistically- ments in general. credible evidence” that NHP toxicology data Alternatives for chemical toxicology were sum- “contribute any predictive value, either sepa- marily dismissed (p. 23) as not being relevant to rately or in combination” (for example, with dog the use of NHPs, yet the Chair of the WG was an data; 50); and, for the prediction of drug- induced liver injury, NHPs are less predictive expert in this field. Absent from the WG were than rodents — which failed to predict up to experts from ECVAM and other Three Rs insti- 51% of effects in humans (51). tutes within the EU, such as the UK NC3Rs or the Netherlands Centre for Alternatives to Animal 2. In the field of Infectious Disease Research: Use. Indeed, we are not aware that consultation with these expert bodies was sought, or whether “Several vaccines currently used to protect specific comments were received from them. Also humans against fatal infectious diseases have absent from the WG were external experts in alter- been developed through studies in NHPs.” (p. natives such as neuroimaging and refinement, and 15). Not only is this claim unsubstantiated, but other experts from many Three Rs organisations also the WG confuses the use of NHPs with crit- worldwide. Similarly, the make-up of its WG did ical evidence of their necessity, validity and not benefit from the European Commission’s own reliability as part of the vaccine development partnership with industry in the form of the process. A great deal of evidence was provided European Partnership for Alternative Approaches to the WG, which illustrated critical species dif- to (EPAA, which has the remit to ferences affecting vaccine research and develop- help accelerate the development and acceptance of ment, and even outright failures of NHP new Three Rs methods in regulatory toxicology). models. HIV, hepatitis C and malaria were specifically mentioned. Given that no effective AIDS vaccine exists, Omission of Crucial Evidence Against despite a quarter of a century of testing in NHPs, the claims of NHPs “playing a key role in the Efficacy and Necessity of NHP AIDS vaccine development” (p. 15) are falla- Research cious. Claims that SIV-infected macaques are an important tool, ignore the lack of correlation In addition to the examples of disregarded alterna- between pre-clinical and clinical data, as well as tives to NHP research detailed above, further evi- evidence outlining important differences dence that the SCHER Opinion is seriously flawed between HIV-infected humans and SIV-infected 432 Comment

macaques, including differences in virulence, drug candidates have been tested in animals — virus genetics and biochemistry, and pathology with no success in humans (67). NHPs have (52–59) — as summarised by Bailey (60). been widely used, and it has not been estab- Protective and/or therapeutic vaccine responses lished that they are superior to non-primate have been elicited in chimpanzees via many species in terms of human relevance. Experts vaccination methods. Despite the fact that more have concluded: “Ischaemic stroke is a case than 85 different vaccines have been tested in study in failed translation” (41), and “the stroke around 200 clinical trials, protection and/or sig- community needs to think long and hard about nificant therapeutic effects have not been whether these animal models are financially demonstrated by any vaccine to date in and ethically viable.” (68). humans, despite decades of effort and extensive “Their use is considered essential in several research funding (60). research programs such as on immune based dis- Nor are there human vaccines for hepatitis C eases (e.g. multiple sclerosis), neurodegenerative or malaria, despite years of intense NHP disorders (Parkinson’s, Alzheimer’s, etc), infec- research. There are critical differences between tious diseases (HIV, Malaria, TB, Hepatitis, HCV infection in chimpanzees and humans that SARS, etc.) and other serious diseases.” (p. 6). Our are not noted in the Opinion, including different original submissions of evidence to the SCHER rates of chronic infection and viral clearance, contain detailed rebuttals of this claim and its and differences in pathology, such as the inci- association with all of these diseases. Some dis- dence of liver fibrosis, cirrhosis, and hepatocel- ease-specific information is discussed earlier in lular carcinoma, mother-to-infant transmission, this commentary. Further examples include: a) and immune response (summarised in 61). an argument that animal models of Alzheimer’s Recently, the ability to culture infectious HCV disease have been a failure, due to significant in vitro has been achieved and improved, open- confounding species differences, with very little ing new doors for human-specific research (62). progress made in understanding the various Similar differences confound malaria pathologies associated with the disease (69); and research. Although chimpanzees are suscepti- b) evidence that schizophrenia has not been ble to the main human malaria parasite, P. fal- reproduced experimentally in NHPs, nor have ciparum, it causes only brief and moderate preventive measures, diagnostic tools or treat- parasitisation and no severe infection, and ments been developed through them (70). other species differences in susceptibility to the parasite exist, due to receptor variability (63). 4. In the field of Xenotransplanation Research: There are also serious questions as to whether “However, they [in vitro and rodent models] can- the New World monkey challenge model not replace long term studies of function in ani- (NWMCM) is sufficiently relevant for humans, mals including NHPs.” (p. 25). The section on as it consists of an unnatural host, challenged the ‘Use of NHPs in Xenotransplantation’ pro- by an unnatural route of administration of an vides no evidence to support the need for NHPs unnatural inoculum, which can result in vari- in xenotransplantation research, nor any evi- able infection rates and little correlation with dence to indicate that xenotransplantation results in human trials (64). itself is likely to ever be clinically useful. Although several formidable obstacles to xeno- 3. In the field of Neuroscience Research: transplantation exist, the greatest is the rejec- “This knowledge [from basic neuroscience tion of transplanted organs. A 2005 review research in NHPs] is useful… to understand concluded that no durable mechanism for the effects and consequences of brain and spinal control of hyperacute rejection has emerged, cord damage in humans and to devise thera- despite enormous effort, that additional com- pies.” (p. 17). NHPs differ from humans in the plexities relating to immune response will spatial arrangements of their spinal cord tracts, undoubtedly face researchers in the future and corticospinal termination patterns within the any progress will be slow at best, and that lack ventral horn differ between primates, and dif- of host survival and potential for infection ferences exist in the function of central pattern would preclude clinical trials for the foreseeable generators — an important area of concern future (71). It is therefore disappointing that when attempting to translate research results the WG was not more critical of the need for from NHPs to humans (65). NHP-based xenotransplantation research. “Stroke research does not use large numbers of NHPs, but the importance of their availability as a research tool is significant.” (p. 19). There Discussion are significant species-specific and even strain- specific differences in response to ischaemic An investigation of such gravity, with serious con- injury (66). Greater than 1,000 putative stroke sequences for human health as well as the welfare Comment 433 of NHPs, should not have been so fundamentally Pursuant to Rule 116 of the Rules of Procedure by and seriously flawed as the SCHER inquiry. The Jens Holm, Rebecca Harms, John Bowis, Martine remit given to the SCHER was scarcely addressed; Roure and Mojca Drčar Murko on Primates in the Working Group (WG) had a paucity of expert- Scientific Experiments (0040/2007), 2pp. Brussels, Belgium: European Parliament. Available at: http:// ise in NHP research and alternative methods; and ec.europa.eu/environment/chemicals/lab_animals/ voluminous and crucial evidence illustrating the pdf/declaration_nhp_en.pdf (Accessed 24.08.09). inefficacy of NHP research and indicative of the 6. SCHER (2009). 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