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Rapid Responses: Rapid Responses published:
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Similarities and differences between men and mice
- Dietmar Fuchs (24 March 2006)
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Let us make Research More Personal - A Resident's Appeal
- Suviraj James John (25 March 2006)
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TGN 1412 and Bird flu
- Evan L Lloyd (27 March 2006)
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First do no harm: How safe are our clinical trials?
- Sohil Ahmed Khan, Gabriel Rodrigues, Consultant Surgeon, Kasturba Medical College, Manipal, INDIA (27 March 2006)
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Harm Reduction in Human Experimentation – Time to Revisit Research Governance.
- Sati Ariyanayagam (27 March 2006)
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Safety testing in animals deserves scrutiny
- Kathy A Archibald (31 March 2006)
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Governance of clinical research.
- Alexander SD Spiers (3 April 2006)
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Ultimate basis of the TGN1412 disaster
- Duncan D Adams (3 April 2006)
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TGN1412 - Did the striking nutritional contrasts between the rats and men contribute to the disaster?
- Michael A. Crawford (1 August 2006)
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Of Mice and Men and Pandora: Looking Back – Moving Forwards
- Michael DE Goodyear (12 August 2006)
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Re: Of Mice and Men and Pandora: Looking Back – Moving Forwards
- Kathy A Archibald (22 August 2006)
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Of Mice and Men and Pandora: Looking Back? Moving Forwards
- Simon Festing (26 June 2007)
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Dietmar Fuchs, Innsbruck Medical University 6020 Innsbruck, Austria
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How could it happen that volunteers who received TeGenero's TGN1412, a new humanised monoclonal agonist of the CD28 T cell surface receptor, ended up in the intensive care unit at Northwick Park Hospital when all the criteria for testing such a new drug have been met? Even if these criteria are well established, one has to keep in mind that the switch from an animal model system to humans remains a critical event. In most circumstances biology of humans matches well enough with what is known from rats mice and dogs. However, this is certainly not true for all aspects of pathophysiology and unfortunately this seems especially not true for immunobiological pathways. E.g. it is well established that human and primate monocyte-derived macrophages are unique in their production of pteridine derivative neopterin upon stimulation with pro-inflammatory cytokine interferon-gamma (1). This peculiarity is due to a specific discrepancy of the enzymatic repertoire of cells from different species: relative deficiency of pyruvoyl-tetrahydropterin synthase in human and primate macrophages gives raise to the accumulation of neopterin which, however, occurs at the expense or tetrahydrobiopterin (2). As for a few other enzyme reactions, the latter is a necessary cofactor for cytokine- inducible nitric oxide synthase (iNOS). iNOS is critically involved in the host-response during infections, autoimmunity and malignancy (3), and nitric oxide, beside other roles, is an important vasodilatory compound. Although it has been demonstrated as well that the induction of high output nitric oxide in human macrophages is almost impossible (4), the development and testing of drugs to modulate nitric oxide biochemistry still is conducted almost exclusively in animal model systems with fully equipped tetrahydrobiopterin biochemistry (5). Notably, TGN1412 is designed to modulate immune response and therefore one important aspect of its clinical application will be the treatment of autoimmune and immunodeficiency disease. Adverse effects of TGN1412 were mild or non-existing in animal models and became evident first when moving to humans, and six healthy volunteers developed multisystem failure within short. Adverse effects of TGN1412 seem to relate to specific differences between humans and animal models and the discrepancy in tetrahydrobiopterin biochemistry could represent an important aspect. Dietmar Fuchs
1. Murr C, Widner B, Wirleitner B, Fuchs D. Neopterin as a marker for immune system activation. Curr Drug Metabol 2002;3:175-87. 2. Werner ER, Werner-Felmayer G, Fuchs D, et al. Tetrahydrobiopterin biosynthetic activities in human macrophages, fibroblasts, THP-1 and T 24 cells. GTP-cyclohydrolase I is stimulated by interferon-gamma, 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase are constitutively present. J Biol Chem 1990;265:3189-92. 3. Tinker AC, Wallace AV. Selective inhibitors of inducible nitric oxide synthase: potential agents for the treatment of inflammatory diseases? Curr Top Med Chem 2006;6:77-92. 4. Schneemann M, Schoedon G, Hofer S, Blau N, Guerrero L, Schaffner A. Nitric oxide synthase is not a constituent of the antimicrobial armature of human mononuclear phagocytes. J Infect Dis 1993;167:1358-63. 5. Tinkwer AC, Wallace AV. Selective inhibitors pf inducible nitric oxide synthase: potential agents for the treatment of inflammatory diseases? Curr Top Med Chem 2006;6:77-92. Competing interests: None declared |
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Suviraj James John, Fellow (Minimal Access Surgery) Department of Minimal Access Surgery & GI Surgery, GEM Hospital, Coimbatore, India 641045
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While the incident at reported in this issue of the BMJ may call into account issues relating to the differences between human and animal models (1) and protocol/policy imperatives (2), I would like to draw attention to a parallel issue which I believe in the long run will impact the health of medical research – “The state of personal research”. Let's face it, the implications of today's medical research are evident to all of us - lives saved, the personal fulfillment, scientific- medical progress, funding, professional promotions, academic prominence, opportunity to present at conferences (you can even see it on TV on ER). I can feel the pressure mount (as every resident feels) as I go through a residency and I feel this is where the incumbent-hatchling researcher tends to set-reset his/her research 'conscience-thermostat'. There is nothing like a healthy collective humane conscience in the medical community which can prevent double-harm (to both the patients and the embattled-traumatised physicians faced with an adverse/tragic outcome despite their altruistic intentions and efforts). I can remember occasions at places where I have worked, when staff have shot down an incumbent procedure/ research (often published work) because of lack of appropriateness, which at many other places would be undertaken unopposed. We can be truly thankful to those critics at this moment. Yet, we need to find a healthy balance, when dealing with a progressive science such as medicine! I strongly feel a more personal approach to research and fostering a friendly (close-knit relationship with patients) and informal scientific community (which allows checks and counter-checks) within a medical institution will also go a long way to truly establish a 'more transparent culture', as suggested by Professor Michael Goodyear (2). This feature may not be always accomplished by a very formal process. I can say this with a degree of confidence as I myself have volunteered as a subject for research (although they did not test us with new drugs) while being a medical student along with my classmates. We were comfortable as there was an atmosphere of perfect trust. My thoughts are with the young men who are ill and the physicians attending on them. Suviraj J. John Department of Minimal Access Surgery & Surgical Gastroenterology, GEM Hospital, Coimbatore, India. 1. Similarities and differences between men and mice: Dietmar Fuchs (24 March 2006): Rapid Responses published:http://bmj.bmjjournals.com/cgi/eletters/332/7543/677#130435; British Medical Journal; 2. Editorial: Learning from the TGN1412 trial: This experience should foster an open culture in medical research; British Medical Journal 2006;332:677-678 (25 March) Competing interests: None declared |
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Evan L Lloyd, Retired 72 Belgrave Rd, EH12 6NQ
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Dear Sir The effects of the TGN 1412 infusion seem to be very similar to the effects on humans of the current strain of bird flu causing so much anxiety. It also seems to mimic many of the symptoms and signs of the 1918-19 flu epidemic, which has also been traced to a bird flu origin. It would be interesting to see if the knowledge gained about the progression and subsequent management of the TGN 1412 trial could be of value in the prevention and/or managemnet of any possible flu epidemic which will occur if or when the bird virus manages to mutate to become transmissable from human to human. Sincerely Dr Evan Lloyd FRCP; FRCA. Competing interests: None declared |
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Sohil Ahmed Khan, Faculty and Research Scholar Manipal College of Pharmaceutical Sciences, Manipal, INDIA, Gabriel Rodrigues, Consultant Surgeon, Kasturba Medical College, Manipal, INDIA
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Recently the first human trial of a new humanized monoclonal superagonist TGN1412 of the CD28 T cell surface receptor [which received the EU-Orphan drug designation on March 11, 2005](1) designed to mitigate autoimmune and immunodeficiency disease has once again raise the concern of drug safety in clinical trials. The six men who received the active component rapidly developed catastrophic multisystem failure; the remaining two, who received a placebo, were unharmed. At the time of going to press, two remained in a critical condition (2). The study once again raises many potential questions against our safer clinical trials. This Phase I study involved the participation of healthy volunteers for a drug used in autoimmune condition that raises the ethical concern. The protocol for the trial also states that the dosing was staggered over a relatively short period of time. Whenever a new drug of a newer class is tested for the first time in human we should be vigilant enough to observe any adverse event in the first volunteer before proceeding to the next. Under no circumstances we should compromise over the drug safety be it with respect to time or cost incurred by the clinical research organizations. The incident is an eye opener for all those involved in clinical research. It’s always difficult to predict the drug safety of a newer class in clinical trials though the drug passes the stringent safety tests in pre-clinical studies. Safety of drugs in animals can never guarantee the same for humans. What we need to practice is the strict vigilant approach whenever the study involves such type of drugs. The hospitals conducting such clinical trials needs to facilitate utmost care for the volunteers that includes adjacent intensive care units to a clinical trial center in case of life threatening conditions. When the drug enters the Phase IV studies, due to limited experience, conservative estimates of the overall merit seem preferable so that the prescriber will use the drug critically. Subsequently, re-evaluation of the risk-to-benefit balance is necessary as greater knowledge of efficacy and adverse effects is acquired. It is possible to provide a general ‘principle of threes’(3) structure for a merit assessment of drug safety based upon the concepts of seriousness, duration and incidences as related to disease indication, disease amelioration by a drug, and the adverse effects ascribed to the medicine. This allows a rapid first comparison of medicines for a given indication. . On 16th March 2006, The Food and Drug Administration (FDA) and The Critical Path Institute (C-Path) announced the formation of the Predictive Safety Testing Consortium between C-Path and five of America’s largest pharmaceutical companies to share internally developed laboratory methods to predict the safety of new treatments before they are tested in humans (4). The goal of the Predictive Safety Testing Consortium is to enable pharmaceutical companies to share knowledge and resources. This will allow the pharmaceutical companies to determine which of the lab tests that they have developed individually should be recommended by the FDA to screen drugs and better understand the potential side effects before the drugs enter clinical testing in humans. Companies will share the details of the methods that each has developed for specific kinds of tests and then agrees to test another’s method to determine if it is reproducible. The results of the comparison will be collected and summarized by C-Path for submission to the FDA. Those methods that the FDA finds to be reliable and reproducible will form the basis for agency-issued guidelines about which safety tests should be used in the drug development process. An initiative like this by FDA is needed for ensuring the pre clinical safety of drugs. We need to re-consider the basic fact that: First and foremost DO NO HARM, which should be the basis of clinical research. References: 1. TeGenero AG receives EU-orphan drug designation for Humanized Agonistic Anti-CD28 Monoclonal Antibody TGN1412 for the treatment of B- CLL. http://www.tegenero.com/documents/pr_tegenero_march_11_2005.pdf (Accessed: 26th March 2006) 2. Learning from the TGN1412 trial (Editorial). BMJ 2006;332:677-678 . 3. Ralph Edwards, Bengt-Erick Wiholm, Carlos Martinez. Concepts in Risk-Benefit Assessment. In : Drug Safety. Ralph Edwards, Marie Lindquist, Ronald Meyboom, Sten Olsson Eds. Adis International, Auckland 2001;543. 4. FDA and the Critical Path Institute Announce Predictive Safety Testing Consortium Consortium Will Share Tests to Understand Safety of Potential New Drugs Earlier. http://www.fda.gov/bbs/topics/news/2006/NEW01337.html (Accessed: 26th March 2006) Competing interests: None declared |
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Sati Ariyanayagam, Deputy Vice Chair, Eastern Region Multi Centre Research Ethics Committee Oldchurch Hospital , Romford, Essex RM70BE,UK
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1. Among the questions that arise from the human tragedy at Northwick Park Hospital (1) are the following: 1 Is the design of the trial well thought through?
With the benefit of hindsight it is easy to cast doubts on the credibility of the researchers and those who form part of the research regulatory system but the general consensus within the medical community is that at a time of much distress to the casualties and their next of kin, it would be inappropriate to be judgmental prior to the conclusions of the investigations in to this unfortunate incident. History reveals that contemporary society continues to benefit from ethically sound and medically safe human experimentation. Against this background, the Northwick Park tragedy offers an opportunity for reflection for the scientific community. Such reflection should not be directed towards apportioning blame but rather on harm reduction to volunteers in the future unless of course negligence can be proven. Questions around ‘staggered dosing’’ and other issues such as the manner of recruitment are certainly the right ones to be raised but there is a need for a detailed stock take, looking at the bigger picture at the conduct of phase I trials as a whole with closer scrutiny (2,3). Commercial sensitivity and the rules around intellectual property rights however place limits on the extent to which the trials can be subjected to ‘public’ scrutiny, although such right to confidentiality have been called in to question already (4). Clinical trials are designed to prevent harm, if not reduce harm but never to cause harm or fatalities! The reality though is that any cautionary approach involving the administration of a phase I trial drug can only be aimed at harm minimization. It will be unrealistic to expect zero health risk in these circumstances. Good research is essential in the public interest but the incentive offered to the volunteers to participate does pose an ethical question that requires a debate, particularly in the light of the adverse events at Northwick Park. Could it be argued that the financial incentives offered and not altruism that motivate those volunteers? If so, could such offer have clouded their judgment that led to participate? Do such financial rewards render the volunteers vulnerable? In the event would such financial incentives be considered ethical? Payments to medical workforce for undertaking, recruiting and or administering research at public organizations also raise ethical questions (5). Research Governance Systems require an urgent revisit if the public confidence in the medical establishment, namely the research community is to be restored. Dr Sati Ariyanayagam
References: 1 Goodyear M, Learning from TGN 1412 trial, BMJ 2006; 332: 677 –678 2 Stewart PM, Improving Clinical Research, BMJ 2003; 327:999-1000 3 Bell J, Resuscitating Clinical Research in the United Kingdom, BMJ, 2003; 327:1041 - 1043 4 Ashcroft R, Pfeffer N, Ethics behind closed doors: do research ethics committees need secrecy? BMJ 2001; 322:1294 -1296 5 Rao JN, Sant Cassia LJ, Ethics of undisclosed payments to doctors recruiting patients in clinical trials, BMJ, 2002; 325:36 - 37 Competing interests: None declared |
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Kathy A Archibald, Director, Europeans for Medical Progress PO Box 38604, London W13 0YR
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Michael Goodyear comments that the tragic TGN1412 trial will probably change the face of drug testing and that an independent inquiry is needed. Patient safety group Europeans for Medical Progress agrees. We believe a vital part of any inquiry should be a comparison of animal tests with microdosing, human tissue tests and other state-of-the-art methods of predicting human metabolism. 83% of GPs and over 200 MPs support such a scientific evaluation of the best means to protect public health and safety: see www.curedisease.net Michael Goodyear is right that relative lack of severe toxicity in animal models should never be construed as a guarantee of safety in man, as the story of thalidomide should have taught us. TeGenero insists monkeys and rabbits showed TGN1412 was safe. Monkeys and mice even showed that Vioxx was cardioprotective. When will we learn? Kathy Archibald Director, Europeans for Medical Progress PO Box 38604 London W13 0YR info@curedisease.net Competing interests: None declared |
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Alexander SD Spiers, Professor of Medicine (Retired) n/a
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The tragic outcome of a Phase I clinical trial of TGN1412 at Northwick Park Hospital raises many very important questions about the conduct and governance of clinical trials in general and Phase I drug studies in particular. Was the hospital negligent in permitting this trial, which was flawed in its design and had obvious risks? Was the Human Subjects Committee failing in its duty when it approved the study? Should a commercial company, in this case the US firm Parexel, be permitted to run a clinical pharmacology research unit in a public hospital? Did the mechanism for recruiting volunteers undergo adequate ethical scrutiny? Was the Informed Consent form subjected to rigorous evaluation, in particular its statement of potential risks and adverse effects? Was the financial reward offered to the volunteers too great, and therefore likely to impair their judgement regarding participation in the study? Were the investigators properly trained in the conduct of Phase I studies? Were they adequately supervised? These are extremely grave issues. A poorly designed clinical trial is intrinsically unethical, because it is unlikely to provide valid scientific information, thus making the risk/benefit ratio unacceptably high. The most effective defence against such trials is not bureaucratic decrees but an expert and fearless Human Subjects Committee that includes scientists, ethicists, clinicians, statisticians, lay persons, and coopted members appointed when special expertise is required to evaluate a particular study proposal. Such committees are vital not only for the protection of human subjects, but for the status and reputation of science itself. Competing interests: None declared |
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Duncan D Adams, Honorary Research Fellow Faculty of Medicine, University of Otago, Dunedin, New Zealand
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Dear Madam, Apart from its reckless design1, the TeGenero company's drug trial disaster ultimately stems from a huge ignorance of the basic principles of the pathogenesis of autoimmune diseases.2 A crucial fault in current research is the loss of Burnet's forbidden clone theory of autoimmune disease,3 which was proved for Graves' disease in my laboratory by demonstration that the causative thyroid-stimulating autoantobodies in individual patients contain only one of two possible light chain types and therefore originate from a single lymphocyte by somatic V gene mutation.4 The clear objective in seeking curative therapy for autoimmune diseases is to discover the pathogenic forbidden clone and selectively destroy it, leaving the rest of the immunity system intact. The way to do this has been pioneered in Belgium, in Dumont and Vassart's laboratory, by cloning the autoantigen for Graves' disease.5 Attachment of a cytotoxic element, such as 131I, could enable the forbidden clone to be selectively destroyed. This is not necessary for Graves' disease where excellent therapy is already available, but it shows a research pathway towards specific immunotherapy for other autoimmune disease, such as rheumatoid arthritis and the psychoses. LATS protector6, the human-specific version of the thyroid- stimulating autoantibodies is not active in guinea pigs and mice, illustrating how a very small change in amino-acid sequence can hugely change reactivity between man and laboratory animals. Incidently, the infusion of LATS protector into humans, with the very slight risk of transferring a latent noxious virus, was exemplary in using Otago Medical School professors as subjects, rather than impecunious people. TeGenero's attempt to develop treatment for autoimmune diseases by trying to multiply mythical "regulatory T cells" with a monoclonal antibody, should never have passed a competent scientific assessing committee. Perhaps TGN1412 accidentally enabled T cells to attack host histocompatibility antigens, for which they are very close to having specificity. DD Adams MD DSc FRACP
References 1 Goodyear M. Learning from the TGN1412 trial. BMJ 2006; 332: 677- 678. 2. Adams DD, Knight JG. Principles of autoimmune disease: pathogenesis, genetics and specific immunotherapy. J Clin Lab Immunol 2003; 52: 1-22. 3 Burnet FM. Autoimmune disease. BMJ 1959; 2: 645-640 and 720-725. 4 Knight JG, Laing P, Knight A, et al. Thyroid-stimulating autoantibodies usually contain only Ć light chains: evidence for the forbidden clone theory. J Clin Endocrinol Metab 1986; 39: 826-832. 5 Costagliola S, Morganthaler N, Hoemann K, et al. Second generation assay for TSH receptor antibodies has superior diagnostic sensitivity for Graves' disease. J Clin Endocrinol Metab 1999; 84: 90-97 6 Adams DD, Fastier FN, Howie JB, Kennedy TH, Kilpatrick JA, Stewart RDH. Stimulation of the human thyroid by infusions of plasma containing LATS protector J Clin. Endocrinol Metab 1974; 39: 826-832. Competing interests: None declared |
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Michael A. Crawford, Research Director Institute of Brain Chemistry and Human Nutrition, , N7 8DB
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It is claimed that TGN1412 is a humanised monoclonal antibody that binds, and is superagonistic to the CD28 receptor of the immune system's T cells (1). "The superagonistic properties of this agent means it fully activates T-cells without the need for additional antigen-receptor stimulation. Superagonism of these antibodies was found to be dependent on binding to a specific part of the CD28 molecule. Once the investigators found antibodies with these properties they wondered if they could be therapeutically useful in stimulating the immune system in immunosuppressed patients as these antibodies would be expected to crudely activate all T-cells simultaneously" (2). It is important to know exactly what tests were carried out in animals as there has been little detail given by Goodyear, the manufacturer, nor the MHRA who only say no adverse reactions were observed.(3). The Te Genero Web Site states that “It has shown unique ex vivo and in vivo T lymphocyte stimulatory capacity and therapeutic potential for a number of autoimmune/inflammatory as well as oncological diseases” It also states that “Multiple preclinical results indicate that CD28-SuperMA® are capable of inhibiting clinical signs, surrogate parameters and pathophysiological characteristics of autoimmune/inflammatory diseases in a well-tolerated fashion. ‘ Thus, TGN1412 is a novel approach to addressing the medical need in chronic autoimmune/inflammatory diseases.” The immune system is highly complex. Nutritional factors play a significant part in the genesis of several chronic diseases, including auto-immune disease and cancer .Diet also affects immunomodulatory activities with different dietary lipids having quite opposite effects (4). The diet of laboratory animals is low in fat. However fed a high fat diet, marginal vascular dysfunction due to diabetes was found be greatly exaggerated (5). Whilst it is plausible that the development of a humanised monoclonal antibody might not be recognised in lower animals, no stone should be left unturned in the search for the cause of the alleged cytokine storm at Northwick Park. Apart from the species difference between humans and the animals used for testing TGN1412, there would also have been a huge difference in the background diets between the humans and the test animals, and hence immune behaviour which should not be overlooked in the search for answers. Indeed from what we know about the cell membrane and the lipid domains for the receptors, the binding of these antibodies to a specific part of the CD28 or indeed to other molecules would be expected to be influenced by the membrane lipid domain which will be very different in a human and a rat. The misinterpretation of the use of COX2 inhibitors, associated with several deaths, also came about because of a poor understanding of the dietary links to cell behaviour. Michael A Crawford. 1. Chia-Huey Lin, Thomas Kerkau, Christine Guntermann, Martin Trischler, Niklas Beyersdorf, Yvonne Scheuring, Hans-Peter Tony, Christian Kneitz, Martin Wilhelm, Peter Mueller, Thomas Huenig, Thomas Hanke (2004- 11-16). "Superagonistic Anti-CD28 Antibody TGN1412 as a Potential Immunotherapeutic for the Treatment of B Cell Chronic Lymphocytic Leukemia". Blood (ASH Annual Meeting Abstracts) 104 (11): Abstract 2519. 2. Wikipedia, the free encyclopedia, http://en.wikipedia.org 3. Michael Goodyear Learning from the TGN1412 trial, BMJ 2006; 332: 677-678. 4. Lee JY, Hwang DH. The modulation of inflammatory gene expression by lipids: mediation through Toll-like receptors. Mol Cells. 2006; 21(2):174-85. 5. Holemans K, Gerber R, O'Brien-Coker I, Mallet A, van Bree R, van Assche FA, Poston L.. Raised saturated-fat intake worsens vascular function in virgin and pregnant offspring of streptozotocin-diabetic rats., Br J Nutr. 2000;84(3):285-96 Competing interests: None declared |
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Michael DE Goodyear, Assistant Professor Department of Medicine, Dalhousie University, 1278 Tower Road, Halifax, Nova Scotia Canada B3H 2Y9
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As Crawford (1) points out, due to a problematic habit of pharmaceutical companies not publishing details of their preclinical data, at the time of the unfolding of this tragedy there was very little information available in the public domain. Some months later, we are now in a better position (2) to reassess this and address the questions raised by Crawford and many others. Further correspondence is perhaps best directed there. The main sources of information are the release of the MHRA documents and the interim report of the Expert Scientific Group (ESG). In addition a large number of immunologists have since commented on the underlying biology and pathology. I agree that the immune system is a highly complex system, that may, like Pandora’s Box, react in unpredictable ways. Furthermore there is a need to study it in the intact organism, rather than isolated components, if we wish to reliably predict the effects of interventions. With reference to Crawford’s specific questions about the validity of murine models, we can now say that they were of limited relevance, the primary data for the extrapolation to man being based on non-human primates. However these also failed to reliably predict the effects in man, as did ex-vivo experiments on human blood. For now, the full explanation of the pathogenesis of the massive cytokine release syndrome, or at least why it was confined to the experimental human subjects remains a mystery. Ultimately new drugs need to be tested in man, a critical event, as Fuchs (3) points out, and whether we have placed an unjustified reliance on animal testing, as Archibald implies, (4) and need to consider a parallel process, using human tissues, needs careful consideration. Adams’ (5) intriguing suggestion that new drugs should first be tested on medical school professors (Otago or otherwise) raises important issues as to whether the scientific and ethical review (which he suggests was far from optimal) would be raised to a higher level under these circumstances. One would like to think that those responsible for human subject protection would use a similar standard to that which they would demand for themselves. Speirs (6) asks many relevant questions, which the ESG must address if we wish to prevent a repetition of these events. Perhaps the most important issue he raises is the interface of ethical and scientific review. It is easy to believe (although we have no direct evidence to date, and this must also be addressed) that the Human Subjects Committee simply accepted on face value the review and assessment of risks presented to them by the MHRA and the investigators. Unfortunately many now consider that review inadequate, chiefly because of the lack of independent expert assessment. This interface remains one hotly debated in the overall governance of research ethics. It would be a mistake to see these as separate processes, although no universally agreed model for their integration has been adopted. Golec (7) argues that both processes should be an integral part of protocol design well before the issues come before a Human Subjects Committee. Ariyanayagam (8) is right to question the current balance of proprietary information over public interest and safety, to point out the crisis in public confidence and the need for a more careful examination of the potential risks and benefits to both individuals and society in testing new drugs, issues also addressed by Khan (8). Khan also emphasises the need for an open and collaborative approach to drug development, both between companies and between companies and regulators, which is congruent with the thrust of the World Health Organization’s Clinical Trials Platform. (10) This is a theme that the ESG have also chosen to emphasise. John (11) reminds us of the need to consider personal factors, especially the pressures on clinicians and researchers to advance the agenda, and the need to constantly keep the welfare of the patient or subject paramount. References 1. Crawford MA. TGN1412 - Did the striking nutritional contrasts between the rats and men contribute to the disaster? 1 August 2006 2. Goodyear MD. Further lessons from the TGN1412 tragedy. BMJ. 2006 Aug 5;333(7562):270-1. 3. Fuchs D. Similarities and differences between men and mice 24 March 2006 4. Archibald KA. Safety testing in animals deserves scrutiny 31 March 2006 5. Adams DD. Ultimate basis of the TGN1412 disaster 3 April 2006 6. Speirs ASD. Governance of clinical research. 3 April 2006 7. Golec L. Integrating Scientific, Ethics and Research Process Assessment into Protocol Design. 19th Graven Conference on the Physical and Developmental Environment of the High Risk Infant: Human Factors and Research in the NICU. University of South Florida 2006. 8. Ariyanayagam S. Harm Reduction in Human Experimentation – Time to Revisit Research Governance. 27 March 2006 9. Khan SA. First do no harm: How safe are our clinical trials? 27 March 2006 10. http://www.who.int/ictrp/en/ (accessed August 11) 11. John SJ. Let us make Research More Personal - A Resident's Appeal 25 March 2006 Competing interests: None declared |
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Kathy A Archibald, Director, Europeans for Medical Progress PO Box 38604, London W13 0YR
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Michael Goodyear says that whether we need to consider a parallel drug testing process, using human tissues, needs careful consideration. Surely the case for doing so is overwhelming, particularly in view of the fact that human tissue company Asterand have a standard assay which could have predicted the TGN1412 reaction - see http://www.asterand.com/Asterand/NEWSEVENTS/2006PRESSRELEASES/4-17- 2006.aspx. The Government is making no investment into the increased application of ethically-donated human tissue testing, so it is left to small, struggling companies like Asterand to develop tests which would benefit all of humanity, let alone the pharmaceutical industry, entirely unaided. Let us not forget that 92% of drugs fail in clinical trials, having successfully passed through animal studies. Although they do not often fail in such spectacular fashion as TGN1412, trial volunteers can nevertheless be harmed or even killed by experimental drugs. Surely they deserve better protection than 'proof of safety' in animals, which - as thalidomide, eraldin, opren, clioquinol, isoprenaline, rezulin, Vioxx, etc, etc. should have taught us - means very little for humans. Competing interests: None declared |
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Simon Festing, Director Research Defence Society
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Of course Professor Goodyear was right to remind us that a lack of severe toxicity in animal models should never be construed as a guarantee of safety in man. These are inevitable limitations of animal studies. But seat belts do not guarantee safety in cars; this is not an argument against using them. The parallel process which Professor Goodyear refers to involves animals studies as well as alternative methods -- an entirely sensible approach. The conclusions of the Expert Scientific Group which looked in detail at the role of animal experiments in the TGN1412 trial could not be more clear-cut. They stated that: Animal studies taking due regard of the three ‘Rs’ remain necessary for many aspects of pre-clinical development of novel agents including testing of ‘off-target’ and ‘on-target’ toxicity and understanding the fundamental biology relevant to a new medicine and its target molecules in the human. The key point we want to make is the importance of deciding what can be learned from animal studies in the pre-clinical development of a new medicine, and what limitations there might be when it comes to predicting the response, and dose-response relationship, in humans. Competing interests: Represent almost all major research institutes in the UK to explain why well-regulated animal research is essential |
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