Open access Original research BMJ Open Science: first published as 10.1136/bmjos-2019-100039 on 20 October 2020. Downloaded from Clinical impact of high-­profile animal-­ based research reported in the UK national press

Jarrod Bailey ‍ ‍ ,1 Michael Balls2

This article has received OSF ABSTRACT Strengths and limitations of this study badges for Open data. Objectives We evaluated animal-­based biomedical ‘breakthroughs’ reported in the UK national press in 1995 To cite: Bailey J, Balls M. ►This study investigates exaggeration in the media (25 years prior to the conclusion of this study). Based ► Clinical impact of high-­profile of the significance and human relevance of animal on evidence of overspeculative reporting of biomedical animal-based­ research research. reported in the UK national research in other areas (eg, press releases and scientific ►►The study focuses on articles in the UK national press. BMJ Open Science papers), we specifically examined animal research in press in a particular year, and specifically follows up 2020;4:e100039. doi:10.1136/ the media, asking, ‘In a given year, what proportion of the fate of forecasted ‘breakthroughs’, to see if they bmjos-2019-100039 animal research “breakthroughs”’ published in the UK had resulted in human benefit >20 years later. national press had translated, more than 20 years later, to ►► Prepublication history for ►►This study was comprehensive, objective and approved interventions?’ this paper is available online. To detailed. view these files, please visit the Methods We searched the Nexis media database (​ ►►Significant research was conducted for each media-­ journal online (http://dx.​ ​doi.org/​ ​ LexisNexis.​com) for animal-­based biomedical reports in reported breakthrough, and all its findings have 10.1136/​ ​bmjos-2019-​ ​100039). the UK national press. The only restrictions were that the been made available in this report. intervention should be specific, such as a named drug, Received 24 July 2019 ►►One limitation is that the focus was on one calendar gene, biomedical pathway, to facilitate follow-­up, and that Revised 21 July 2020 year (1995). there should be claims of some clinical promise. copyright. Accepted 17 August 2020 ►►However, there is no reason to believe that analyses Main outcome measures Were any interventions of other years would lead to significantly different approved for human use? If so, when and by which conclusions, with regard to the overspeculation and agency? If not, why, and how far did development overstatement of potential human benefits from proceed? Were any other, directly related interventions animal-­based research in the media. approved? Did any of the reports overstate human relevance? Results Overspeculation and exaggeration of human relevance was evident in all the articles examined. Of 27 uncertain relevance to human health and http://openscience.bmj.com/ unique published ‘breakthroughs’, only one had clearly do not provide key facts or acknowledge resulted in human benefit. Twenty were classified as important limitations’. Of these, 90% lacked failures, three were inconclusive and three were partially caveats about extrapolating animal/labora- successful. tory studies to people, while explicitly making Conclusions The results of animal-­based preclinical claims about relevance to human health, and research studies are commonly overstated in media 29% exaggerated the importance of the find- reports, to prematurely imply often-­imminent ings they described. Notably, this was much ‘breakthroughs’ relevant to human medicine. more common for animal studies: 41% were

exaggerated in this way, compared with 18% on September 25, 2021 by guest. Protected INTRODUCTION of human studies. Sumner et al7 examined 462 Animal experiments remain controver- press releases produced by the UK’s leading © Author(s) (or their sial, with issues including the welfare of 20 (Russell Group) universities, along with employer(s)) 2020. Re-­use the animals involved, and the question- the associated scientific papers and print/ permitted under CC BY. able human relevance of animal data.1–4 online news stories, and concluded that 36% Published by BMJ. 1 Despite increasing evidence of the latter (see ‘contained exaggerated inference to humans Cruelty Free International, 5 London, UK Bailey for a review), overstatement of the from animal research’. 2University of Nottingham human benefits of animal research is wide- Exaggeration of animal-based­ findings has Faculty of Medicine and Health spread, and occurs throughout the whole also been noted in online and other media. Sciences, Nottingham, UK research process, from institutional press Haneef et al8 examined the health section of releases through to reports in the media. For Google News for ‘spin’, and concluded that Correspondence to 6 Dr Jarrod Bailey; example, Woloshin et al reported that press almost half (48%) of the reports they exam- jarrod.​ ​bailey@​ releases from academic medical centres in ined that involved animal studies ‘implied contemporarysciences.org​ the USA ‘often promote research that has overgeneralization/misleading extrapolation

Bailey J, Balls M. BMJ Open Science 2020;4:e100039. doi:10.1136/bmjos-2019-100039 1 Open access BMJ Open Science: first published as 10.1136/bmjos-2019-100039 on 20 October 2020. Downloaded from from animals to humans’. The UK’s ‘Leveson Inquiry into content, provided by the international company, LexisNexis the culture, practices and ethics of the press’ concluded (​lexisnexis.​com). Media sources were selected to include that ‘overselling the results of non-human­ studies as a ‘UK national newspapers’, in the calendar year 1995. The promised cure potentially confuses readers and might search strategy involved selecting the ‘Medical research’ contribute to disillusionment with science’.9 The website ​ index term, then adding the following animal terms to HealthNewsReview.​org published an article in July 2018 identify news items based on animal research: ‘animal OR about the exaggeration of the applicability and rele- mouse OR mice OR rodent OR rat OR dog OR cat OR vance of animal data to humans, based on many of its monkey OR primate OR guinea pig OR rabbit’. Articles 6000 posts.10 ‘Vigilance’ was advised for both patients and that did not describe a clear, direct clinical promise, or that physicians when interpreting health claims that are often described a non-­clinical application (eg, agricultural or exaggerated and/or unfounded, specifically for Parkin- veterinary), or that described only mechanisms of action, son’s disease and other movement disorders, and which pathophysiology or diagnosis, or in which the intervention included ‘unfulfilled promises of animal models’.11 was not of a specific named procedure or compound, or Exaggeration is also evident in scientific publica- was not speculated to be associated with a specific gene/ tions. Contopoulos-­Ioannidis et al12 examined 101 scien- molecule/pathway, were excluded. For each report, the tific publications published in top scientific journals associated academic publication(s) were obtained, where (including, but not limited to animal research) and found available, and as much of the following data that were avail- that basic research rarely impacted clinical practice, even able were extracted: title, news media source, publishing when it was considered ‘highly promising’: 20 years later, journal, date of publication, author name(s), PubMed ID only five drugs were licensed for clinical use as a result, and links, animal species and numbers used, intervention, and only one was used extensively for the licensed indi- preventive/therapeutic in nature, expected clinical benefit cations. Lindl et al13 concluded that 17 animal research and years to expected benefit, relevant text and summary programmes licensed in Germany in the early 1990s, of findings, disease in question, institution, funding body, which promised new therapies, or at least direct clin- harms to animals, any salient quotes from authors, any ical impact, had resulted in ‘no clinical relevance’ 17 obvious related material, etc. years later.14 Hackam conducted a systematic review to To investigate whether clinical benefit transpired within see how often highly cited animal studies from the top 20-­plus years, the following websites and sources were seven science journals translated to human success, and consulted: PubMed, the European Medicines Agency, the copyright. concluded that caution should be applied when extrapo- UK Medicines and Healthcare Regulatory Agency, the lating the findings of prominent animal research to the US Food and Drug Administration (FDA), clinicaltrials.​ ​ care of human disease.15 Of 76 qualifying animal studies, gov, ​Medscape.​com, the National Institute for Health and 28 had positive outcomes in human trials; but only 8 led Care Excellence, the British National Formulary, Centers to therapies approved for clinical use.15 for Disease Control and Prevention, the WHO and the US In summary, in the past approximately 15 years, various National Library of Medicine’s TOXNET. Data obtained efforts have been made to assess the outcomes and from thorough searches of these sources were collated, http://openscience.bmj.com/ human benefits of scientific breakthroughs, and how and used to determine the outcome of each ‘break- accurately and speculatively these were reported. Over- through’ with regard to any further studies that were statement, overspeculation and exaggeration were highly conducted; whether these were human, animal or both; if prevalent. We sought to explore these issues further, and clinical trials were conducted, and what the results of these uniquely, by examining reports of animal-­based biomed- were with respect to efficacy and adverse drug reactions; ical ‘breakthroughs’ in UK national newspapers in 1995, if the drug/intervention reached the market, and if so, if 25 years prior to the conclusion of this study in 2020. Our it had been relabelled or recalled. Based on the above, a aim was to determine whether any of these biomedical decision was made, in consultation with colleagues, about

‘breakthroughs’ had resulted in clinical benefit, and whether the 1995 media report had been accurate in on September 25, 2021 by guest. Protected to what degree their clinical impact had been exagger- reporting the research as a ‘breakthrough’. For clarity: ated. This period provides ample time for the apparent if the intervention in question had not been approved at ‘breakthroughs’ to be developed, tested and ultimately the time of writing, >20 years after the media report, it translated into clinical benefit, and is a similar time span was classified as ‘failed’. Some were classified as a ‘partial to that used in a comparable study.12 We also wanted to success’, if, for example, use was restricted clinically and/ investigate whether, if any breakthrough had been real- or geographically; any use was specific to particular, rather ised, it depended on the animal studies, and if no direct than general, circumstances (ie, a narrower use than had breakthrough had resulted, any related breakthroughs been claimed); an approved therapy was of questionable could be linked to the reported animal research. efficacy; evidence from other, non-animal­ research data (including human data) suggested the animal data were not crucial to the ‘breakthrough’; there was an indirect METHODS relation between the ‘breakthrough’ and the successful The ‘Nexis’ database is an archive of more than 40 000 intervention; there was questionable clinical relevance of information sources of various types, including news the animal data and so on.

2 Bailey J, Balls M. BMJ Open Science 2020;4:e100039. doi:10.1136/bmjos-2019-100039 Open access BMJ Open Science: first published as 10.1136/bmjos-2019-100039 on 20 October 2020. Downloaded from

RESULTS reported in the 40 articles in the UK national press that The initial search produced 229 articles, and the removal met the inclusion criteria, was classified as an outright of 16 duplicates left 213 for consideration according to success. Twenty were classified as outright failures, with the selection criteria. Forty individual articles (reporting no direct clinical benefit. Of the remaining six, three were 42 animal-­based scientific ‘breakthroughs’) met these classified as inconclusive (either because clinical trials inclusion criteria. Some of these breakthroughs were were ongoing, or because the evidence was mixed), and (not surprisingly) reported in more than one article: three were classified as a ‘partial success’ (see ‘Methods’ grouping duplicates together resulted in 27 unique section for details). The overall results are summarised in ‘breakthroughs’. These involved a variety of diseases, figure 1. conditions and biomedical areas, including HIV/AIDS, malaria, allergies, Alzheimer’s disease (AD), multiple Examples of detailed discussions of each ‘breakthrough’ sclerosis, deafness, cancers, obesity, pain, organ trans- These examples—one from each of the main classifica- plantation, ageing and others. Each newspaper article tions (success, partial success and failure)—are included reporting breakthroughs in these areas contained specu- here, to illustrate the detailed and comprehensive investi- gation and follow-up­ conducted by the authors, to ensure lative claims, from scientists undertaking the research, as that the classifications are as accurate as possible. They well as from the reporters and others involved: in other were selected subjectively by the authors, as being particu- words, overstatement of the potential relevance of the larly illustrative and of interest. breakthroughs came from scientists as well as the jour- nalists involved. These are some of the more specula- Success tive examples, to illustrate what was found. With regard 11. Mending broken bones with injectable ‘Skeletal to an anti-allergy­ vaccination, ‘This is potentially one of Repair System’—Succeeded (with caveats) the biggest-selling­ drugs ever…the company estimates Cast Away Your Plaster Cast—The Times, April 25 1995 that the vaccine will be available in the UK in five years’. The Times reported the development of an inject- In cancer gene therapy, ‘It is hoped that by giving the able paste that can be introduced—‘like toothpaste’— correct version of the gene to lung cancer patients, into broken or fractured bones, or bones affected by normal apoptosis will resume and the tumours will osteoporosis. shrink. Experiments carried out on animals are encour- This bone substitute—Skeletal Repair System (SRS)— copyright. aging’. With regard to obesity treatments, ‘There seems was invented by Norian Corporation (USA). It was not the no doubt that this new technology will appear: the only first bone substitute intended to replace metal implants, question is when…within a few years a fat reducing injec- but was claimed to be a better match for real bone than tion could make liposuction a thing of the past…the fact anything that had gone before it. that it has been seen to work in several animal species The report cited a paper in Science, stating ‘Experi- shows that it is very likely to work in humans, too’, and ments with animals have given good results, and the first

‘This is a major breakthrough in obesity research…We tests on human patients…have produced good repairs of http://openscience.bmj.com/ have every reason to believe this could become a treat- broken wrists’.16 Rabbits and dogs were involved: bone ment for obesity in humans’. In organ transplantation, sections were removed from the ulnas of 12 rabbits, and ‘The first organ transplants from pigs to humans are cement injected. The rabbits were X-rayed,­ and killed ‘at expected to begin next year in a move that could signal 12 weeks’ for tissue examination. Human investigations an end to the global shortage of human donors…rejec- involved repairing the fractured distal radius of a woman tion problems involved in xenotransplantation are being aged 49 years, for whom X-­rays showed ‘stabilisation’ and solved’, and in ageing research, “Researchers have discov- ‘maintenance of correct position’ following injection of ered a natural hormone produced by the body that could SRS. delay the effects of ageing…the hormone could help to 17

A 2003 paper discussing the background to SRS on September 25, 2021 by guest. Protected defer such characteristic problems of old age as wrinkles, cited six human investigations, from 1966 to 1995, and muscle fatigue, rheumatism, bone fragility, memory loss reported human clinical investigations of SRS during the and some cancers…the results so far in animals had been 5 years after The Times report, between 1996 and 2000,18–20 “spectacular”’. as well as the authors’ own clinical research. They did, Table 1 shows a brief summary of each ‘breakthrough’, however—in common with some previous human data— with multiple reports of the same ‘breakthrough’ grouped report that ‘The risk of extrusion of the SRS cement into together. The information given includes a concise undesirable locations has been a substantial concern’, description of each discovery and its clinical promise, the leading to a higher complication rate. reporting media article, any further research and devel- More recently (2012–2013): Ozer and Chung21 cited opment and an evaluation of the final outcome. Three the papers above,17–19 as well as uncontrolled case series examples of these detailed discussions—one for each from 200322 and 200723 that showed SRS was safe and case of success, partial success/inconclusive and failure— supportive. Dorozhkin’s review24 reported problems are provided below, to illustrate the thorough nature of with SRS use, including a high rate of infectious compli- our research. Just one of the 27 unique ‘breakthroughs’ cations, which led some to discontinue SRS for some

Bailey J, Balls M. BMJ Open Science 2020;4:e100039. doi:10.1136/bmjos-2019-100039 3 Open access BMJ Open Science: first published as 10.1136/bmjos-2019-100039 on 20 October 2020. Downloaded from gy ­ based Continued aller ­ ­ based malaria inhibitor approved as ras inhibitor approved Failed . is no antisense There therapy for leishmaniasis. vaccine approved. therapy is in China. Failed . unsuccessful. Procedure Not used clinically. Failed . No plant- vaccine exists. Failed . No general anti- Failed . No attenuated live HIV/AIDS vaccine approved. Failed . No successful AD treatment this mouse model from exists. Failed . Rolipram not in clinical use due to serious adverse effects. Failed . No therapy associated with this gene/pathway exists. Failed . No anticancer treatment. Failed . GTS-21 is not used to treat dementia. Success (with caveats) . Used for specific purposes, with caution. Failed . p53 - Only approved Further animal studies conducted, but no human studies found. Further research/Status Overall outcome No further animal or clinical studies found. studies found. Clinical studies: negative outcome human efficacy outcomes (adverse reaction uncertain). No further animal or clinical studies found. Clinical studies: negative outcome; human efficacy adverse reactions Clinical studies: positive outcome; human efficacy adverse reactions Clinical studies: awaiting results Clinical studies: negative outcome; no human efficacy adverse reactions Clinical studies: negative outcome; no human efficacy adverse reactions Marketed: some adverse reactions. outcome; no human efficacy adverse reactions ­ copyright. http://openscience.bmj.com/ , 10 January 1995, Nigel Hawkes The Times ow. Daily Mail , 18 December 1995 ow. News item(s) a baboon; AIDS victim pins hopes on monkey bone- Lifeline from marr , 11 July The Times AIDS Patient to be Given Baboon Marrow. 1995, Giles Whittell shot; Innovation: British company boasts of a Ultimate allergy vaccine with huge potential. The Independent, 29 January 1995, Nuala Moran , 30 January 1995, Nigel hope for AIDS. The Times Vaccine Hawkes 1995, Nigel , 2 March The Times Drug Hope for MS Sufferers. Hawkes , 9 February The Times Alzheimer's mouse may hold clue to cure. 1995, Nigel Hawkes to Site of Child Hearing and Sight Mouse Gene Points Way 1995, Tim Radford Defect. The Guardian , 3 March 1995, Nigel , 21 March Stopping cancer in its tracks. The Times Hawkes The Observer , 9 April 1995, Nina Database—Fags for the memory. Hall , 25 April 1995, Nigel Plaster Cast. The Times Your Cast Away Hawkes on September 25, 2021 by guest. Protected ­ virus vaccine ow transplant for HIV/ essant Drug is Also marr ­ ­ HIV live- ­ DNA therapy for leishmaniasis Once Bitten. ­ Depr allergy ­ allergy vaccine eakthroughs’ listed according to results from LexisNexis database from to results listed according eakthroughs’ Baboon bone- AIDS Attenuated- (MS) for Multiple Sclerosis Treatment Anti- Disease, for better testing of Alzheimer’s new therapies childhood deafness and blindness brings hope of cure many cancers 21) ‘Skeletal Repair System’ ‘Br

Table 1 Table 2 22 5 No(s). Intervention 1 Antisense- 34 in edible plants Malaria vaccine produced , 23 January 1995, Nigel Hawkes way to health. The Times A green No further animal or clinical 6 mouse model of New improved 7 New Anti- 89 Identification of gene causing some 10 for Inhibitors of ras genes could be a cure Disease (GTS- New drug for Alzheimer’s 11 bones with injectable Mending broken 12 Curing cancer by p53 gene therapy, 1 May 1995, Nigel Hawkes Why Our Cells Must Perish. The Times Clinical studies: negative

4 Bailey J, Balls M. BMJ Open Science 2020;4:e100039. doi:10.1136/bmjos-2019-100039 Open access BMJ Open Science: first published as 10.1136/bmjos-2019-100039 on 20 October 2020. Downloaded from Continued ­ based obesity eatment approved. Failed . No antibody- tr Failed . Marimastat not in use. Inconclusive . Mixed evidence. Partial success . in some Approved countries, but questions efficacy regarding remain and safety. Partial success . Evidence supports use for but other some procedures, as (or interventions are effective. more) Failed . No antiageing therapy based on this gene approved. Failed . No human DNA vaccines approved. Further research/StatusFurther animal studies Overall outcome conducted, but no human studies found. Clinical studies: negative outcome; human efficacy adverse reactions Clinical studies: inconclusive outcomes; no efficacy human adverse reactions surrounding Controversy and safety. human efficacy Mixed outcomes/evidence base and caveats Further animal studies conducted, but no human studies found. Clinical studies: negative outcome; no human efficacy adverse reactions , 16 cise. The Times copyright. Daily Mail , 19 June 1995 http://openscience.bmj.com/ ­ obesity jab may end need to diet or exer Trials begin on pill that could control cancer. The Independent , 19 cancer. begin on pill that could control Trials May 1995, Celia Hall News item(s) May 1995, Nick Nutall Daily Mail , 23 May Can this injection get rid of your fat forever. 1995, Jane Alexander Sugar ‘Eases Pain in babies’. The Independent , 9 June 1995, Liz Hunt Clue to Long Life Unearthed. Anti- a little flower power; Long dismissed as unscientific, plants Try making a pharmaceutical comeback, says Roger Dobson. The are Independent , 23 May 1995, Roger Dobson a little flower power; Long dismissed as unscientific, plants Try making a pharmaceutical comeback, says Roger Dobson. The are Independent , 23 May 1995, Roger Dobson , 12 June 1995, Nigel Hawkes The Times Messenger. The Brain’s A Bulb Extract May Drug Hopes Rest on a Host of Daffodils; The Alleviate Alzheimer's—and Boost East Anglia Growers. Independent , 3 September 1995, Michael Leapman , 19 June 1995, Dr John The Times Made to Order. New Vaccine Turney on September 25, 2021 by guest. Protected ­ ageing elieving drugs) in young ­ r babies interventions for humans Injection to treat obesity/‘end the need to Injection to treat slim or diet’ Disease with for Alzheimer’s Treatment (Galanthamine) Extract of Daffodils place of pain- in life extension for nematode result worms, touted as a lead in anti- (eg, for influenza immunisations) Continued

Table 1 Table 14 for cancer (solid tumours) Cure No(s). Intervention 13 15 16a pain chronic Cannabis to treat 16b 19 30 18 Sugar on the tongue can ease pain (in 20 Discovery of genetic mutations that 21 vaccines based on DNA improved New,

Bailey J, Balls M. BMJ Open Science 2020;4:e100039. doi:10.1136/bmjos-2019-100039 5 Open access BMJ Open Science: first published as 10.1136/bmjos-2019-100039 on 20 October 2020. Downloaded from ­ Continued gans to humans Failed . for obesity Leptin treatment not approved. Partial success . Failed . Xenotransplantation of non- human or does not take place. Failed . use Evidence did not affect of tamoxifen. Failed . Melatonin is not approved for therapeutic purposes to ageing. related Further research/StatusClinical studies: negative Overall outcome outcome; no human efficacy adverse reactions therapy One related in the USA, with approved Further questionable efficacy. ongoing. research Further animal studies conducted, but no human studies found. Clinical studies: negative outcome; no human efficacy adverse reactions Clinical studies: negative outcome; no human efficacy adverse reactions copyright. ets of Why Diets Fail to Work. The ets of Why Diets Fail to Work. http://openscience.bmj.com/ News item(s) Brain Chemical May Hold Secr , 17 August 1995, Nigel Hawkes Times that diet: a Could these mice help women to look like this; forget daily jab may soon be enough. Daily Mail , 28 July 1995, George transplants in article (Brief mention of animal organ Gordon focusing on obesity jabs) , The Times Organs. Pig Hearts Could End Fatal Lack of Transplant Laurance 14 September 1995, Jeremy The moral implications of animal transplants will disturb many. 'Pigs will But an eminent Cambridge don says we should rejoice; for emergencies. for each of us so we have organs be tailored on a scientific their own pigs, bred may give children Godparents Kealy farm'. Daily Mail , 14 September 1995, Dr Terence Pioneer spurned by Britain. The Independent , 17 September 1995, Charles Arthur Could These Mice Help Women to Look Like This; Forget That to Look Like This; Forget Could These Mice Help Women Diet: A Daily Jab May Soon Be Enough. Mail , 28 July 1995, Gordon George on Obesity’; Steve Connor Drug Firms ‘Hyping Research for Fatness. The for an Injectable ‘Cure’ the Row Over Tests Independent , 28 July 1995, Steve Connor for Fatness has Slim Chance of Success. The ‘Miracle’ Cure Independent , 30 July 1995, Steve Connor Diet Hormone Makes Mice Thin, but Not Humans; Research The Premature. Were Suggests Hopes of Obesity Cure Independent , 1 August 1995, Steve Connor , 29 August 1995, The Mouse That Could Make Us Thin. Times Kate Muir The Independent , 19 Without Trying. How to Lose Weight September 1995, Sarah Edghill The Guardian , 13 cancer. with Breast on Women Drug Test October 1995, Chris Mihill Drug that can Cure Melatonin; It Has Been Hailed as a Wonder Insomnia and Reverse Ageing. So Why is it Being Banned? Daily Mail , 17 October 1995, Jemima Lewis on September 25, 2021 by guest. Protected gans will ­ loss drug development modified pig or ­ ­ modified mice suggests new get for weight- tar the shortage of successfully address for human transplant organs Daily injections of the hormone leptin for obesity could be a cure genetically- Genetically- survival; cancer patients could increase but would liver cancer be an issue, as studies? suggested by rodent the hormone melatonin could reverse rejuvenation and promote ageing process, and extend healthspan, also in humans Continued

Table 1 Table No(s). Intervention 23a 25 26 27 29 34 28 on dieting people and Research 23b 31 32 33 35 for breast Extending tamoxifen prescribing 36 Mouse experiments suggested the natural

6 Bailey J, Balls M. BMJ Open Science 2020;4:e100039. doi:10.1136/bmjos-2019-100039 Open access BMJ Open Science: first published as 10.1136/bmjos-2019-100039 on 20 October 2020. Downloaded from Partial success . not realised; Main promises ongoing. research Failed . to this No drugs related in use for organ finding are transplantation. Failed . for DHEA not approved ageing therapy. eakthroughs: due to multiple reports, due to multiple reports, eakthroughs: ­ based br Further research/StatusClinical studies: mixed Overall outcome outcomes, depending on specific tissue type/ application. conducted, but no human studies found. Mixed evidence—still unknown.

Figure 1 ‘Breakthroughs’: proportion of successes, failures, partial successes and inconclusive outcomes. Only one of the 27 unique animal-­based ‘breakthroughs’ could be considered successful (#11, the Norian Skeletal Repair System). Twenty of the 27 were outright failures, with no direct human clinical benefit. Of the remaining six: three were Shelf Skin Cloned ­ inconclusive, and three ‘partially successful, with caveats’. the- ­ These results indicate a failure rate of 26 out of 27, and an copyright. outright success rate of only 1 out of 27.

specific uses.25 SRS had shown high infection rates in other human studies,26–28 as well as cement fragmenta- tion27 and wound dehiscence.28

A 2010 meta-­analysis noted bone cements were first http://openscience.bmj.com/ introduced in ceramic form in 199229—3 years prior to The Times article and the associated paper.16 The ‘paste form’ became available in the ‘early 1990s’, again before these publications. It also noted caveats regarding long-­ 30 31

om the Human Body? The Guardian , 28 October 1995, Tim term results, and complication rates of 13%–31%. fr Radford Genetic Engineering: Tinkering with the Destinies of Mice and Men. The Observer , 29 October 1995, Judy Jones Daily Mail , 30 October S & N's $ 1bn Science Fiction Adventure. 1995, Michael Walters , 9 November 1995 The Sunday Times Gender Transplants. Further animal studies News item(s) , 9 Natural Hormone May Soften the Blows of Age. The Times January 1995, Nigel Hawkes Is This a Breakthrough to Benefit Mankind … or Science Running Is This a Breakthrough Harrison Amok? Daily Mail , 24 October 1995, Tracey Medicine; Off- Of Mice, Men and Wacky Overall, reported complication rates were up to 62%, and were often serious and extended for many years after surgery.29 Norian was bought by Synthes in 1999, when SRS on September 25, 2021 by guest. Protected had been approved for use in the arm, and another version,Craniofacial Repair System (CRS), for use in the skull. Ten years later, Synthes was accused of ‘running illegal clinical trials—essentially, experimenting on humans’. They had mixed SRS with barium sulphate, in ed antigens impact a new formulation known as XR, to facilitate visualisation

­ occurring hormone on X-rays.­ Although XR had been approved by the US ­ discover FDA in 2002, it had expressly not been approved for use in certain spinal surgeries, such as the treatment of vertebral success of organ transplants between success of organ them will help sexes: new drugs targeting dehydroepiandrosterone (DHEA) promises (DHEA) promises dehydroepiandrosterone of ageing the adverse effects to reverse Growing tissues in the laboratory for Growing transplantation: the famous/infamous ‘mouse with an ear on its back’ experiment Naturally- compression fractures—a common consequence of oste- Continued

oporosis. This was due to concerns over Norian cement leaking into blood vessels—numerous in the spine— which, it was known, could cause blood clotting, with Table 1 Table the number of unique breakthroughs was 27. For each of them, the table shows: article identification number; brief description intervention/discovery; title, publishing the number of unique breakthroughs and final evaluation of the outcome. of intervention/discovery; further research date and author; clinical promise newspaper, No(s). Intervention 42 animal- shown. Forty media articles reported Brief summaries are together. grouped are of the same ‘breakthrough’ Multiple reports 37 38 39 40 41 Newly- 44 severe or lethal consequences.

Bailey J, Balls M. BMJ Open Science 2020;4:e100039. doi:10.1136/bmjos-2019-100039 7 Open access BMJ Open Science: first published as 10.1136/bmjos-2019-100039 on 20 October 2020. Downloaded from

In 2009, Norian wanted to begin using a new formu- into their brains, and 4 weeks later were killed for analysis lation—XR—in spinal surgeries, as they considered it by decapitation. The need for this harmful study is open would be lucrative, but the US FDA ordered them to to question, given the weight of evidence implicating the conduct lengthy and expensive clinical trials. Instead, cholinergic system in memory and learning. The authors they persuaded ‘a few sites’ to perform 60–80 human themselves cited previous research that did this, including procedures and publish the results—quicker and both rat experiments and human research.33–35 The cheaper, but at least five people died. This had taken stated value of their study was that it ‘had not been proved place despite data highlighting its risk: small amounts of that regional ACh is causally required for learning and XR had caused human blood to form clots in test tubes, memory’. Furthermore, drugs to address this issue were suggesting blood vessels in patients’ hearts or lungs could already in use and in clinical development, so in no way also be blocked. In addition, the injection of XR into a could have depended on these particular animal experi- pig’s vein had caused clots in its lungs that killed it within ments. This was tacitly acknowledged by the authors. seconds. The company pleaded guilty to dozens of felo- It is worth examining the path of galanthamine to clin- nies and misdemeanours, was fined US$23 million, and ical trials, particularly for the contribution (or lack of) four of its executives were imprisoned. of animal experiments. It was discovered accidentally in It must be concluded, therefore, that even though the early 1950s, and used for various purposes since then, SRS was approved for human use, the animal data did including nerve pain, polio and in anaesthesiology.36 It not predict many of the major complications of SRS has been extensively investigated in humans, showing use that were revealed by research with humans. While memory enhancement properties, although with some SRS remains in use, it is used with caution and only for adverse effects; and derivatives have been sought and particular purposes, and certain caveats must be borne in tested to overcome these effects. mind—all as a result of human studies. There was extensive, promising, human research preceding the 1995 ‘breakthrough’, in both patients with Partial success AD and healthy volunteers.37–40 A 2004 review showed 16b, 19 and 30. Treatment for Alzheimer’s Disease galanthamine had been used for many years in Eastern with Extract of Daffodils (Galanthamine)—Partly Europe, prior to its preclinical testing in Western Europe successful, with caveats in the 1980s.41 In the 1950s, it was used to ease nerve pain,

Try a little flower power; Long dismissed as and to treat polio; preclinical experiments continued copyright. unscientific, plants are making a pharmaceutical throughout the 1980s, and some salient research involved comeback, says Roger Dobson—The Independent, May ex vivo muscles from frogs, leeches and rabbits, rather 23 1995 than experiments involving live animals, to investigate its The Brain’s Messenger—The Times, June 12 1995 inhibitory properties for acetylcholinesterase. Drug Hopes Rest on a Host of Daffodils; A Bulb Clinical development progressed throughout the Extract May Alleviate Alzheimer's - and Boost East 1990s; and it was first licensed for AD treatment in 2000

Anglia Growers—The Independent, September 3 1995 in Iceland, Ireland, Sweden and the UK, followed by http://openscience.bmj.com/ An extract of daffodil and snowdrop bulbs was proposed the USA and other countries in the early 2000s. There to slow the progress of AD. Brain-­damaged rats, deficient have been significant issues, however. While some trials in the neurotransmitter acetylcholine (ACh), showed a showed it to be well tolerated and to improve cognitive slower rate of learning to navigate through water mazes. function in patients with AD,42 43 two large trials did This is consistent with poorer memory in patients with not show a significant difference from the effects of the AD, whose brains show a deficiency in ACh, although placebo, with regard to rate of progression of AD.44 One there remains controversy over whether this is cause or 2018 review noted that clinical trials were ‘still ongoing’.45 effect. Rats genetically modified (GM) with cells that Other major caveats, including with other cholinesterase

replaced the lost ACh could navigate mazes better than inhibitors, donepezil and rivastigmine, included that they on September 25, 2021 by guest. Protected those who had not: ACh replacement appeared to restore are effective for a maximum of about 3 years, and also that memory function and learning deficits. It was hoped that they treated only AD symptoms, not the disease itself.46 this would lead to drugs designed to halt the decline of Other caveats are still being reported: galanthamine ACh associated with AD. However, a drug to do this was treatment is ‘still saddled with numerous side effects’.47 already in clinical trials (galanthamine, extracted from In summary, there was substantial, significant weight of daffodil bulbs), and another—Tacrine—had already evidence of the role and ACh in AD prior to the 1995 rat been licensed in some countries. A subsequent article in experiments; much of this was human specific and much The Independent briefly discussed the progression of galan- of this was acknowledged by the authors themselves. thamine into clinical trials, which had reached phase III, Drugs targeting this pathway were already in clinical involving 560 patients across Europe. development, and so it cannot be claimed that galanth- The paper described how rats had their brains damaged amine development depended on animal research—and via direct injections of ibotenic acid, causing ‘perma- certainly not on this particular research—due to the exten- nently and selectively damaged learning and memory’.32 sive human data relating to it, which go back hundreds of The ‘ACh-replaced’­ rats had GM cells grafted/infused years, and which include detailed pharmacodynamic and

8 Bailey J, Balls M. BMJ Open Science 2020;4:e100039. doi:10.1136/bmjos-2019-100039 Open access BMJ Open Science: first published as 10.1136/bmjos-2019-100039 on 20 October 2020. Downloaded from pharmacokinetic data preceding 1995. Human trials are rejection of an organ following transplantation, which still ongoing, and it is they that will clarify issues regarding can occur within minutes. There are other types of rejec- safety and efficacy. tion that may occur subsequently: acute/acute vascular rejection, which can take several days, and chronic rejec- Failure tion, which can take years. However, White was dismis- 23b, 31, 32, 33. Genetically modified pig organs will sive of concerns about such levels of confidence being successfully address the shortage of organs for human premature, and about assertions that much more under- transplant—Failed standing of the mechanisms of transplant rejection was Could these mice help women to look like this; forget needed, stating, “As far as we can see, the other hurdles that diet: a daily jab may soon be enough—Daily have not raised their head of (sic) the timeframe of our Mail, July 28 1995 (Brief mention of animal organ experiments”. transplants in article focusing on obesity jabs) Building on this: GM pigs were created, with genes for Pig Hearts Could End Fatal Lack of Transplant two regulators of complement activity.49 The following Organs—The Times, September 14 1995 year did not see any human trials commence, however, The moral implications of animal transplants will and transplantations were not taking place within 5 years, disturb many. But an eminent Cambridge don says as promised. In fact, while research has progressed, the we should rejoice; ‘Pigs will be tailored for each of intervening quarter of a century has revealed numerous us so we have organs for emergencies. Godparents and unforeseen challenges, and human trials still seem may give children their own pigs, bred on a scientific distant. First, Imutran and associated companies closed farm’—Daily Mail, September 14 1995 down. Other companies and researchers pressed ahead, Pioneer spurned by Britain—The Independent, and failed to deliver on earlier promises, with failure after September 17 1995 failure. Major immunological barriers have manifested, In the main article, The Times reported the expected with recent publications confirming that organ rejection commencement of clinical trials of pig-to-­ ­human organ is still a major issue. For example, although one author transplants—xenotransplantation (XTP). considered survival times of 90 days in their research These trials would be based on experiments in which ‘impressive’,50 orthotopic heart transplants from pigs to hearts from GM pigs survived for up to 60 days in monkeys baboons were associated with a maximum survival of 195 who had received transplants, supported by immunosup- days, though this particular animal had to be killed due copyright. pressive drugs to help prevent rejection—a perennial to signs of heart and liver dysfunction.51 The Interna- issue with organ transplantation, but particularly with tional Society of Heart Lung Transplantation suggested transplantation between different species. The article that clinical trials of heart XTP should be considered was optimistic: the director of the company directing when pig hearts could be transplanted into non-­human the experiments, Imutran, claimed ‘a big hurdle in the primates (NHPs), with predefined immunosuppression, development of transplants between species known as with ‘60% survival at 3 months and a minimum of 10 xenotransplantation had been overcome’; ‘the rejec- animals surviving for this period’,52 53 but this has still not http://openscience.bmj.com/ tion problems involved in xenotransplantation are being happened, even though some claim that this goal may solved’ and that they had ‘found a way to trick the immune be attainable.53 Furthermore, most experiments have system of a primate into accepting a pig organ’, while involved heterotopic, rather than orthotopic, transplants, the director of transplant services at Papworth Hospital in which the transplanted organ is placed away from its stated, “If progress continues the way it is, we intend to normal site in the abdomen, which is non-­life supporting; start human clinical trials in 1996”', and that it would be orthotopic transplantation, where the organ is placed in at least 5 years before animal transplants were generally its usual site, in order to support life, will be required by available. At the same time, the article noted the urgent the regulatory authorities.54

need for organs for transplantation, stating that ‘The first Additionally, issues with the transfer of pathogenic on September 25, 2021 by guest. Protected organ transplants from pigs to humans are expected to microorganisms from the donor pigs to organ recip- begin next year in a move that could signal an end to the ients continue, despite significant efforts to combat global shortage of human donors’, and ‘If successful, the them. Other variables affecting survival include immune technique could open up the prospect of animal trans- suppression, donor genetics, recipient species (ie, plants to thousands more patients who are denied treat- humans will probably react differently to NHPs), viral ment because of a shortage of human organs’. status, the level of pre-­existing antipig antibody, prophy- A paper in Nature carried an associated report.48 The lactic antiviral and antibacterial therapy and postopera- medical director of Imutran (David White) was quoted tive care.53 A 2018 review noted that, while survival had again, reporting that 10 monkeys with pig hearts had increased over the years (decades) ‘from days to months’, survived an average of 40 days, with two surviving for >60 ‘additional barriers due to antigenic and physiologic days. The basis for this improved survival was that the differences in cross-species­ transplantation continue to new GM pigs, providing donor hearts for the monkeys, remain a challenge’.55 had been genetically engineered in an attempt to over- Ongoing work towards human trials centres around come hyperacute rejection. This is the almost immediate increasing ‘tolerance’ via multiple genetic modifications

Bailey J, Balls M. BMJ Open Science 2020;4:e100039. doi:10.1136/bmjos-2019-100039 9 Open access BMJ Open Science: first published as 10.1136/bmjos-2019-100039 on 20 October 2020. Downloaded from of pigs, targeting the many (and increasing) antigens reader wondering if the research was done in humans or involved in organ rejection. The current level of immu- animals.61 62 nosuppression required to prolong survival post-XTP­ Similar observations have also been made for publica- is still unacceptably high, and so even greater genetic tions in scientific journals (see ‘Introduction’).12–15 64 65 In modification of pig donors is necessary.56 This is already addition, for instance, Kilkenny et al highlighted serious high: multitransgenic pig kidneys containing five modi- omissions in the way that research using animals is fied genes have been tested in baboons: one combina- reported (eg, in experimental design, description and tion allowed survival of 6 months or more, while another statistical analysis), recommending that authors should still resulted in serious problems, leading to the conclu- explicitly comment on limitations of animal data and sion that ‘the exact responsible genes have yet to be their relevance to humans.66 ter Riet et al examined publi- identified’.55 cation bias in animal research, revealing that ‘negative’ It therefore must be asked; how much genetic modifi- animal results were rarely published, leading to a publica- cation might permit an adequate level of survival? And, tion bias that ‘will impede the performance of valid liter- even if it were possible, could it ever be enough? This ature syntheses’, as this invariably must lead to an inflated may be illustrated by the identification of another crucial view of the success of animal studies.67 antigen involved in rejection, B4GALNT2.57 One initial We found that only one of 27 original breakthroughs ‘success’ of GM pigs was the knockout of the Gal gene— reported in the UK national press in 1995 had led unam- but while this helped resolve Gal-mediated­ rejection, biguously to clinical benefit >20 years later. This result it ‘did not eliminate antibody-­mediated rejection and carries more weight than it might have, because we made instead highlighted the importance of antibody directed attempts, where no direct breakthrough was evident, to non-­Gal pig antigens’. Many other antigens have been to determine whether any related breakthroughs had implicated, and others remain to be discovered. Reviews resulted from the animal experiments, and if so, whether from 2017 to 18 detail the complexity of XTP organ rejec- the animal research had been essential. Even if any of the tion, and the numerous genetic modifications created in six ‘breakthroughs’ currently classified as ‘inconclusive’ attempts to overcome it: 26–30 different modifications or a ‘partial success’ are reclassified as a success in the in pigs, involving genes associated with Gal, complement future, the degree of successful translation—and there- regulation, cellular immune response, anticoagulation, fore exaggeration—are still disappointing, especially anti-­inflammatory, anti-­apoptotic and other pathways, given the high ethical and economic costs of animal copyright. and noted that other, new antigens were being discovered research. that may require further genetic modifications.58 59 Classifying some of the ‘breakthroughs’, for example, Within a few days of the article in The Times, two other as ‘partial successes’ or as ‘failures’, was not straightfor- articles were printed. One in the Daily Mail was an overly ward. Some areas of research had taken a related, but speculative positive spin on results from Imutran, in which different, direction; some results effectively duplicated, quotes illustrated comprehensively the issue of exaggera- or at least were strongly underpinned by, previous human tion and embellishment. The other, in The Independent, research and/or animal research; some interventions had http://openscience.bmj.com/ focused on why British venture capitalists failed to back complex and changing nomenclatures; some were broad Imutran, and was also replete with positive spin. In it, a in nature (eg, the identification of a gene, rather than the major financial backer appreciated that ‘These things testing of a specific intervention); some had gone on to take between 6 and 10 years to mature’—but a quarter of clinical trials with unpublished results and so on. a century later, we are still waiting. In terms of limitations, our study focused on one calendar year. While there may be some degree of vari- ability from year to year with regard to the areas of animal DISCUSSION research and the degree of the translation to human

Our analysis demonstrates that the relevance and impact benefit reported in the media, we employed broad selec- on September 25, 2021 by guest. Protected of animal-­based findings to human health are frequently tion criteria, reflected in a wide variety of research topics, overstated in the UK national press—findings that are and are therefore confident that these particular aspects consistent with similar reports of exaggeration in institu- of our findings can be generalised. We accept that our tional press releases, online news, etc,6–11 and which are analyses could not include animal research that was not not limited to English-speaking­ researchers and English-­ expressly reported as animal research, that is, that was language media.60 Recent publications have accepted conveyed as if it already applied to humans. Our search and addressed this, by recommending increased accu- strategy could not identify such reports, but it was not racy and detail in academic press releases and subse- the aim of our work to do this; however, our goal was to quent media articles, which should include more explicit examine research clearly done in animals, as reported in caveats and more cautious language—and that this can the UK national media. be done without harming public interest in the news.61–63 Our findings, along with the observations of the There is some evidence of this being implemented, in other authors cited, should encourage media reports of that more media articles reporting results from animal animal research ‘breakthroughs’ that forecast benefits to experiments now do so explicitly, instead of leaving the human health to be viewed with caution. This is of crucial

10 Bailey J, Balls M. BMJ Open Science 2020;4:e100039. doi:10.1136/bmjos-2019-100039 Open access BMJ Open Science: first published as 10.1136/bmjos-2019-100039 on 20 October 2020. Downloaded from importance, as widespread and high-profile­ dissemina- eu/​public_​opinion/​archives/​ebs/​ebs_​340_​en.​pdf [Accessed 15 Jul 2020]. tion of exaggerated and overspeculative claims will lead to 2 Leaman J, Latter J, Clemence M. Attitudes to Animal Research general overconfidence among the public—as well as the in 2014. A report by Ipsos MORI for the Department for Business research community—of animal research as an approach, Innovation & Skills. Ipsos MORI Social Research Institute, 2014. Available: https://www.​ipsos.​com/​ipsos-​mori/​en-​uk/​attitudes-​animal-​ and an overly optimistic assumption of eventual clinical research-​2014 [Accessed 15 Jul 2020]. benefits.68 There are also implications for the policies 3 Gallup. Americans continue to shift left on key moral issues, 2015. Available: http://www.​gallup.​com/​poll/​183413/​americans-​continue-​ of governments, regulators and funders of biomedical shift-​left-​key-​moral-​issues.​aspx [Accessed 15 Jul 2020]. research, institutional and personal advocates and practi- 4 Cruelty Free International. Ending medical testing on animals in the tioners of animal research and other stakeholders. Ideally, USA. A nationwide Poll of 1,000 adults conducted by SurveyUSA. Available: https://www.​crue​ltyf​reei​nternational.​ ​org/​sites/​default/​ the culture ingrained in the scientific community—which files/​USA%​20Medical%​20Poll_​compressed.​pdf [Accessed 15 Jul is to some degree understandable, given the competition 2020]. 5 Bailey J. Can animal experiments be ethically acceptable when they for funds and need to justify research—of embellishment are not scientifically defensible? In: Linzey A, Linzey C, eds. The of research results in all communications, from grant ethical case against animal experiments. University of Illinois Press, applications and institutional press releases, through to 2017: 175–84. 6 Woloshin S, Schwartz LM, Casella SL, et al. Press releases by papers in scientific journals and associated media reports, academic medical centers: not so academic? Ann Intern Med must be addressed, perhaps with policy decisions. This is 2009;150:613–8. 7 Sumner P, Vivian-­Griffiths S, Boivin J, et al. The association between especially necessary for research on animals, with its asso- exaggeration in health related science news and academic press ciated welfare implications, which can be severe. releases: retrospective observational study. BMJ 2014;349:g7015. 8 Haneef R, Lazarus C, Ravaud P, et al. Interpretation of results of studies evaluating an intervention highlighted in Google health news: Acknowledgements The authors would like to thank Cruelty Free International a cross-sectional­ study of news. PLoS One 2015;10:e0140889. Trust (London, UK) for supporting this work, and all friends and colleagues who 9 Leveson BH. An inquiry into the culture, practices and ethics of the have provided the benefit of their knowledge, wisdom, brilliance and experience to press: executive summary and recommendations [Leveson report] improve the manuscript. (House of Commons Papers). London: The Stationery Office, 2012. 10 Joyce M. Of news releases and mice, 2018. Available: https://www.​ Contributors The corresponding author, JB, was responsible for the planning, healthnewsreview.​org/​2018/​07/​3-​news-​releases-​about-​3-​mouse-​ conduct and reporting of the work described in the manuscript, with support of studies-​teach-​important-​lessons-​about-​how-​extrapolating-​benefits-​ the coauthor, MB. The corresponding author accepts full responsibility for it, had to-​humans-​is-​unjustified-​and-​harmful/#.​W1BqD7lE4vo.​twitter access to all data and controlled the decision to publish. The corresponding author [Accessed 15 Jul 2020]. attests that all the listed authors meet the authorship criteria and that no others 11 Robledo I, Jankovic J. Media hype: patient and scientific meeting the criteria have been omitted. JB’s current affiliation is the Centre for perspectives on misleading medical news. Mov Disord Contemporary Sciences, MA, USA. 2017;32:1319–23. copyright. 12 Contopoulos-­Ioannidis DG, Ntzani EE, Ioannidis JPA. Translation of Funding This study was funded by Cruelty Free International Trust (London, UK). highly promising basic science research into clinical applications. Am Competing interests All the authors have completed the ICMJE uniform disclosure J Med 2003;114:477–84. 13 Lindl T, Voelkel M, Kolar R. [Animal experiments in biomedical form at www.​icmje.​oeg/​coi_​disclosure.​pdf, and declare that: the corresponding research. 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12 Bailey J, Balls M. BMJ Open Science 2020;4:e100039. doi:10.1136/bmjos-2019-100039