Introduction
The TeGenero tragedy refers to an unwanted biological activity resulting from biotechnological drug testing on humans. In the clinical trial, six humans received the drug TGN 1412, which resulted in health complications that lead to the people’s admission to the intensive care unit because of their life-threatening conditions. Following drug administration, the patients complained of pain, high fever and headache. The tragic trial of TGN 1412 involved four main parties in the entire drug development process. The first was the TeGenero Pharmaceutical Company and its scientists. The second party was the Parexel research organization, which was contracted to conduct the trial. The third-party was Boehringer-Ingelheim Company, which manufactured the drug for trial. The fourth was the agency under the British government that authorized the trial. The final parties were the six men on whom the researchers administered the drug.
The drug – TGN1412
The drug, TGN1412, is based on the super agonistic properties of CD28 antibodies, which have the effect of activating and proliferating T cells following any signal received from the cell receptors. CD4+CD25+ cells have regulatory functions and help in preventing autoimmunity in the body (Masteller, Warner, Tang, Tarbell, McDevitt & Bluestone 2005). Therefore, the drug is based on the in vitro capacity to stimulate T cells through antibodies combined against the receptors. Therefore, successful development of the drug intended to activate regulatory T cells as a therapeutic way of managing cancer and autoimmune diseases (Hünig 2007). This resulted in various processes, including preclinical trials, before the actual trial of the drug, which turned tragic.
Right aspects of trial
Most of the drug development process progressed according to the standard procedure. First, was the development of the TGN1412 drug. The development followed CD28 identified to have the ability to activate T cells when they receive a signal from their receptors (Hünig 2007). This resulted in research to determine the activation potential for the possible design of the drug. Second, researchers conducted a comprehensive in vitro examination of the drug in non-human and human cells (Gallin & Ognibene 2012). In the in vitro examination, scientists evaluate the drug’s specificity using bio core analysis and flow cytometry, cross-reactivity of the drug with CD28, and understanding of sequence homology (Masteller et al 2005). From the in vitro study, the outcome indicated super agonistic properties, which ushered the next stage of development. Third, the scientists conducted in vivo studies to determine the efficacy and safety of the drug after using a variety of variants of the drug in preclinical research. The studies indicated the effectiveness of the drug in managing various deficiencies of T cells (Hünig 2007). Fourth, in the clinical development of the drug, the scientists got approval from regulatory authorities to conduct phase one of the trials, which included a small number of healthy humans. Finally, the scientists did the dose calculation for humans and non-humans based on preclinical trials (Hansen & Leslie 2006).
Wrong aspects leading to the TeGenero disaster
After complying with the requirements of drug development and collection of data to justify the testing, everything went wrong on phase one trial done on six healthy men. The company contracted Paraxel to carry out the trial in Northwick hospital in the UK. A few minutes after the administration of TGN1412, all the six men developed life-threatening complications, which occasioned their admission under intensive care (Hanke 2006). Problems in the research involved five main areas of the study. First, there was a problem in interpreting the preclinical research conducted in primates (Hansen & Leslie 2006). The trials revealed low levels of cytokines released by the trial animals, which should have raised caution and further investigation. Second, there was a problem in using human cells in vitro as they were not sufficient enough to draw effective conclusions. Third, the choice of the dose to start the trial was wrong. Clear differences exist between the human and primate target ligand, which means the drug potency, differs between the two. The difference might have caused a problem in calculating the dosage based on the level of adverse effects, which may not be appropriate for human beings. Fourth, the interval of dosage for investigation subjects was wrong. Administration of the drug on the six men went on without allowing considerable time between the men. The short interval prevented researchers from observing side effects on the first subject (Gallin & Ognibene 2012). Finally, there was no adequate preparation for managing possible side effects. The cytokine storm, as was the case in the six subjects, indicated a lack of preparation to anticipate the storm, identify and provide earlier intervention.
After the first dose disaster, various authorities conducted investigations to identify various things that researchers did wrongly when developing the drug. For instance, the Medicines and Healthcare Products Regulatory Agency (MHRA) of the United Kingdom investigated the case to identify ethical and procedural problems in conducting the drug trial. The investigation by the agency failed to identify problems in the manufacturing process or trial procedure, asserting that the negative reactions resulted from unforeseeable biological implications of the drug. However, the agency noted flaws within the trial, including poorly maintained medical records, inadequate insurance cover by the sponsor, limited medical coverage in case of negative outcomes, and inappropriately qualified physicians performing the test. Furthermore, the 100% homology between human and primate cells asserted by researchers in the brochure had no adequate citation to confirm the claim (Gallin & Ognibene 2012). Indeed, further tests conducted on trial primates and humans revealed up to 4% variation between the cells of humans and primates, which might have caused the problem. This highlighted flaws in guaranteeing scientific validity before conducting phase one of clinical trials.
Citing a lack of independence in investigating the disaster, the various journals under the British Journal of Medicine conducted a further investigation of the incident to provide a critical and independent outcome. The Journals formed a group of scientists led by Professor Gordon Duff to identify the ethical and biological problems leading to the disastrous result in phase one of the clinical trial (Horvath & Milton 2009). As the group of scientists under Prof. Duff indicated, researchers in the trial were aware of inflammation resulting from the drug based on previous trials for other drugs such as muromonab-CD3, alemtuzumab and rituximab antibodies (Masteller et al 2005). Indeed, the scientists anticipated the release of cytokines from the six trial subjects. According to the group of scientists, the prior knowledge of inflammation and cytokine release should have informed the scientists to be more cautious and allow more time in the interval of administering the drugs.
Worse still, by the time of administering the drug on the sixth man, the side effects were apparent in the first person, which should have informed the physicians to stop the administration. As the group of scientists noted in their reporting, the facility for conducting the trial was not a hospital per se, it was a leased property without adequate test and treatment facilities for the people affected. In spite of anticipating allergic responses in the trial, the preclinical in vitro and in vivo tests failed to test for allergic reactions (Hansen & Leslie 2006). Clearly, the scientists must have been aware of the allergy-expressing cells, which also express CD28. Had the doctors conducted an allergy test in the trial period, they could have noticed the allergy and developed preventive measures in the drug (Horvath & Milton 2009).
Recommendations and changes following the disaster
Based on the ethical and technical problems identified by the bodies conducting research, recommendations and changes were implemented to ensure no the future occurrence of the disaster. Indeed, the trial came at a heavy cost for all parties taking part. First, the healthy human volunteers had to spend a lot of time in the hospital, as they remained in the hospital under intensive care because of life-threatening problems arising from the drug administration. Scientific research had a blow as levels of trust went down because of the apparent breach of ethical and scientific standards in conducting research (Gallin & Ognibene 2012). The sponsoring company, TeGenero suffered a major blow economically. After the tragedy, the organization became bankrupt (Hanke 2006). People raised ethical concerns about phase one of clinical trials, which involve human subjects.
The problems in the trial highlight the need of noting every slightest of effects on animals in the preclinical phase and investigate the potential impact on human beings (Hansen & Leslie 2006). In conducting in vitro research on human cells, it is important for researchers to take cells from the target tissues or from closer cells to mimic the impact of the drug in a better way. The dose and risk regimen should be widened as much as possible between animals and humans to cater to unforeseeable biological variations. Above all conducting the actual test in human bodies must be done with caution and preparation for anything, achievable through longer dosing intervals between human volunteers. Lack of preparation for adverse effects calls for adequate measures to deal with potential negative outcomes based on theoretical knowledge of such outcomes. Failure of the TGN1412 resulted in a number of changes in the drug development process (Hanke 2006). Changes included safety measures in the in vitro testing procedures and choosing the first dose for human volunteers, among other regulatory measures (Hansen & Leslie 2006; Horvath & Milton 2009).
Conclusion
From the case of TeGenero tragedy analysis, it is apparent that while a drug may indicate efficacy and safety outcomes using animal models in pre-clinical trials, the outcome may vary when used in humans because of different pharmacological properties. The TeGenero strategy highlights the need for adequate consideration of proper approaches in preclinical trials to achieve efficient and effective prediction of how the drug would behave in the human system before the actual testing. Although the company followed the procedure and right way of doing things before the actual trial, they missed on critical details, which resulted in everything going wrong. The clinical trial should include a small number of people following a comprehensive pretrial process with animals with the ability to mimic human behavior given the specific properties of the drug. Although all clinical trials are risky, scientists can minimize them by following every detail in the development process.
References
Gallin, JI, & Ognibene, FP, Eds, 2012, Principles and practice of clinical research. Academic Press, Waltham, MA.
Hanke, T, 2006, ‘Lessons from TGN1412’ The Lancet, vol. 368, no. 9547, pp. 1569-1570.
Hansen, S, & Leslie, RGQ, 2006, ‘TGN1412: scrutinizing preclinical trials of antibody-based medicines’, Nature, vol. 441, no. 7091, pp. 855-856.
Horvath, CJ, & Milton, MN, 2009, ‘The TeGenero incident and the Duff Report conclusions: a series of unfortunate events or an avoidable event?’ Toxicologic pathology, vol. 37, no. 3, pp. 372-383.
Hünig, T, 2007, ‘Manipulation of Regulatory T‐Cell Number and Function with CD28‐Specific Monoclonal Antibodies’, Advances in immunology, vol. 95, no. 2, pp. 111-148.
Masteller, EL, Warner, MR, Tang, Q, Tarbell, KV, McDevitt, H, & Bluestone, JA, 2005, ‘Expansion of functional endogenous antigen-specific CD4+ CD25+ regulatory T cells from nonobese diabetic mice’, The Journal of Immunology, vol. 175, no. 5, pp. 3053-3059.