Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Negligence or incompetence? And whose?
- Arun S Nanivadekar (24 March 2006)
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Re: Learn lession to improve safety
- Naidu MUR (26 March 2006)
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Allocating Blame
- Michael Goodyear (27 March 2006)
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The Perils of T regulatory cell manipulation
- salman siddiqui (27 March 2006)
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Clinical Research in India
- Michael Goodyear (27 March 2006)
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Arun S Nanivadekar, Retired C-2 Flushel Apts, 21 Road, Bandra (W), Mumbai 400050
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The TGN1412 episode scares me on the background of expanding clinical trial activities in India. Was the episode due to negligence, incompetence, the limits of our current knowledge, or a combination of these? And who had the most opportunity and facility to avoid it: sponsor, regulator, investigator, or ethics committee? I think ethics committees need to have better facilities and resources to access the expertise necessary to comprehend and interpret the information provided in the investigator's brochure, and to ensure that the investigator defends the protocol both on scientific and ethical grounds. Whether an ethics committee meets these requirements needs to be appraised by a national body. Hospitals and institutions keen to attract the flow of clinical trial funds should also be committed to equip and empower their ethics committees with appropriate expertise and resources. Competing interests: None declared |
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Naidu MUR, Professor of clinical pharmacology Nizam's Institute of Medical sciences HYderabad 500082 INDIA
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The TGN1412 episode scares all of us on the background of expanding clinical trial activities in India. I agree with the statement given by Dr. Nanivadeker. Due to large ethinic variation , poor educational background and powerty ,Indian trial subjects are comparatively, more vulnerable and at higher risks of Adverse drug events, only suitably qualified and properly trained person in clinical research from recognised institutes should be allowed to conduct the trial related activities.One also take effective measures to educate our polulation on clinical trials. Every Indian clinical trial site having ethics committee ,must have a separate scientific review committee with qualified clinical pharmacologist and subject experts to review the safety data and study protocol. Only protocols approved by scintific review boards should be then consider for ethical committee evaluation. Govt. scientific organisation responsible for clinical trials must setup training facilities and accreditation system for other training institutes. This will fulfill the need of country's trained manpower and capacity building for clinical trial. Competing interests: None declared |
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Michael Goodyear, Assistant Professor Department of Medicine, Dalhousie University, Halifax, NS, Canada B3H2Y9
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In response to Arun Nanivadekar, I would state that we know very little as yet, about the events, and even less about the drug or the trial (which in itself is a major issue that must be addressed – see below). If we concentrate on allocating blame we are even less likely to obtain answers. The issue that we need to grasp is that multiple events line up to create the opportunity for unwanted and unanticipated events(1), as the UK’s Chief Medical Officer constantly reminds us. This is Reason’s ‘Swiss Cheese’ Model (2). Concentrating on a few potential causes is likely to miss the context in which they occur and which predisposes to their occurrence. Nobody would argue that ethics committees need more support and resources. Specifically, the issue here is the adequacy of ethical and scientific review. While there is general agreement that bad science is bad ethics, there is less agreement as to whose responsibility this is. It would be unusual for ethics committees to have the expert independent immunological advice that might have raised more flags in this case, and which emerged after the adverse events were reported. It would be easy but unwise for ethics committees to assume that the Medicines and Healthcare Products Regulatory Agency has ensured scientific validity, and it is unlikely the trial was subject to independent external peer review. It is for this reason that the Lancet is now asking for evidence that an adequate and systematic review of the literature has been performed to justify the study. (3) However the issues here go further. What were the flags in this case? TGN1412 is unusual amongst immunomodulatory monoclonal antibodies (MABs), in that it is an agonist not an antagonist. Secondly, as the sponsor’s refer to it, it is a Super MAB, which bypasses a crucial regulatory step in T cell activation (4). Normally antigen activation of T cells requires costimulation by both an antigen-presenting cell (APC) and CD28. TGN1412 bypasses the APC, raising the possibility of uncontrolled T cell activation. Thirdly, the first test of a new drug in man is associated with a high degree of uncertainty based on extrapolation from pre-clinical studies. All of these would identify this as a high risk study necessitating a high level of review and monitoring. This in itself mandates ensuring that subjects are aware of all of the above. A number of people have called for an independent and far reaching inquiry (5). It is unlikely that any one single simple remedy is likely to emerge from this. However we can take a bold step to reverse many of the conditions that have contributed to what happened at Northwick Park. We can reject a research culture that has become progressively more competitive and secret with one based on traditional scientific norms (Mertonian Principles) of openness and collaboration. If all governments embraced the World Health Organization’s Clinical Trials Platform (6) by incorporating registration of all clinical studies into legislation and regulation, we would be one giant leap closer to this goal. References 1. Perneger TV. A research agenda for patient safety. Int J Qual Health Care. 2006 Feb;18(1):1-3 2. Reason J. Human error: models and management. BMJ. 2000 Mar 18;320(7237):768-70. 3. Young C, Horton R. Putting clinical trials into context. Lancet. 2005 Jul 9-15;366(9480):107-8. 4. Jiang H, Chess L. Regulation of immune responses by T cells. N Engl J Med. 2006 Mar 16;354(11):1166-76 5. SuperMAB on trial. Lancet. 2006 Mar 25; 367(9515): 960 6. http://www.who.int/ictrp/en/ Competing interests: None declared |
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salman siddiqui, research SPR/Respiratory SPR Glenfield Hospital. Leicester.LE39QP
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The unfortunate incident at Northwick Park Hospital, following the use of TGN1412 a humanised monoclonal antibody to CD28 a regulatory T cell surface antigen, should prompt changes to Phase 1 studies. Manipulation of T regulatory cells without full prior understanding of the inflammatory pathways that regulate and mediate inflammation, would seem to be innapropriate. The use of humanised monoclonal antibodies in non genetically modified mice that do not express the 'human' form of the cell surface antigen (in this case CD28) is unlikley to provide evidence towards the safety of these drugs in man. Finally the case highlights the potency of the immune host response. Perhaps an independent panel of immunologists should be consulted prior to use of novel drugs that target T regulatory cells. Competing interests: None declared |
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Michael Goodyear, Assistant Professor Department of Medicine, Dalhousie University, Halifax, Nova Scotia Canada B3H 2Y9
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Arun S Nanivadekar and Naidu Mur raise timely and appropriate questions regarding both the globalisation of clinical research and the ethical challenges of trans-jurisdictional research. A recent news story highlights this even further (1). These issues are highly controversial, dealing predominantly with the ethics of distributive justice. Further discussion can be found in the Committee for International Organizations of Medical Sciences Ethical Guidelines for Biomedical Research Involving Human Subjects (2). Also UNESCO’s Universal Declaration on Bioethics and Human Rights (3). References 1. http://www.wired.com/wired/archive/14.03/indiadrug.html 2. http://www.cioms.ch/frame_guidelines_nov_2002.htm 3. http://portal.unesco.org/shs/en/ev.php- URL_ID=1883&URL_DO=DO_TOPIC&URL_SECTION=201.html Competing interests: None declared |
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