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Brief History and Shortcomings of the TGN1412 clinical trial
In the year 2006, eight healthy male volunteers participated in a clinical trial for an experimental drug known as TGN1412 (Bhogal & Combes 2006). The drug developed to act as an anti-inflammatory monoclonal antibody was developed by Tegenero at Parexel International Corporation’s Pharmacology Research Unit. Following the need to continue with further trials the developers proceeded to phase I trial at the Northwick Park Hospital in London (Bhattacharya 2006). At the hospital it was noted that upon administration of the drug there was a rapid deterioration in of six of the volunteers (Griffin 2009).
The aim of this drug was to treat inflammatory conditions such as leukemia and rheumatoid arthritis (Bhogal & Combes 2006).Despite the surprising turn of events during the clinical trial the company had undertaken preclinical studies which indicated the drug was ready for Phase I trials. In this report the discussion will attempt to preset arguments to indicate what went wrong as identify changes that have been made in regulations following this event.
One of the potential shortcomings of the TGN1412 trial appears to be the fact that the trials were undertaken based on available data in the research file which was in adequate to allow the trials to proceed (Kenter & Cohen 2006). This is because before the trial commenced it has been noted that essential information was absent (Gad 2009). In addition to that it should have been noted that this anti body was a high risk compound and as such would be unsuitable for administration to people without additional preclinical testing (St. Clair 2008).
It has been mentioned that a prerequisite for in depth analysis of the protocol and preclinical data for any trial is that all parties involved have access to all necessary findings (Kenter & Cohen 2006). Based on this it becomes the responsibility of the sponsor to make these findings available and discuss the data available in the research file. Based on this, relevant new information discovered after submission should be added and discussed as soon as possible. It has been observed that this process is especially important in the early and rapid development of a new medicine (Kenter & Cohen 2006).
Based on the above requirement it is possible to assume that the assessors involved in the TGN1412 trial did not receive all the relevant information (Kenter & Cohen 2006). This is because even when all data is available, the different individuals who assess the risk should communicate their findings in an orderly and consistent manner. This boosts the chances that the right questions are asked. It is possible that the parties involved did not cover all relevant points in a transparent manner (Kenter & Cohen 2006).
In addition to the information available it has also been suggested that the poor performance during human trials may have been based on the drugs behavior with regard to T-cells (Bhattacharya 2006). During the early developmental stages of the drug it had been reported that high doses of the drug boosted the production f T-cells. In these reports it was noted that in healthy mice and rats it was able to boost regulatory T-cells from 5% to 20% (Bhattacharya 2006). There were similar results recorded when the drug was tested on monkeys and rabbits. However, researchers claim there was no suggestion of the violent reaction seen among humans.
According to some professionals in the field there was an increase in overall T-cell numbers when TGN1412 was administered to animals (Bhattacharya 2006). The main reason that no adverse effects were anticipated was based on the fact that there were no adverse effects reported during the animal trials. In tests on human cells outside the body there was no reported adverse effect. Some researchers have argued that instead of acting on regulatory T-cells the drug simply over stimulated all T-cells (Criado 2006). Based on this an attack was initiated on everything including the body’s vital organs (Bhattacharya 2006).
Another possible scenario that could have given rise to the reported results in the trial of TGN1412 is due to the possibility of contamination (Bhattacharya 2006). This is because contamination by fungi or bacteria is another possibility that could cause the reported symptoms. It has been reported that bacteria, especially Escherichia Coli, has the ability to cause catastrophic blood poisoning (Bhattacharya 2006). The same bacteria is also capable of causing septic shock which can prompt a reaction by the immune system causing massive inflammation and a profusion of inflammatory cytokines. These symptoms are capable of causing death rapidly due to multiple organ failure.
Another possible cause of the adverse effect noted during the TGN1412 trial is based on the effect of dosage administered (Criado 2006). It was observed that the dosage used during the trial was within the permitted range for therapeutic protocols currently applied with non binding anti CD3 antibodies (Criado 2006). It has been observed that selection of the right dosage is an art based on a science as observed in the protocols for dosage studies (Ritter 2010). The toxicity for TGN1412 was highly species specific for reasons that are yet to be completely understood. However, it has been suggested that the starting dose for first in man trials to reach the lower threshold of a dose-response curve in man (Ritter 2010). This is based on the fact that it has been admitted that the TGN1412 study had not given adequate consideration to what constitutes a safe dose for use in humans (Garrett-Mayer 2010). It should be noted that the company could not be taken to task for this owing to the fact that there was no legal requirement that suggested a need for undertaking such estimation by law (Day 2006).
Also worth noting in relation to the TGN1412 trial is the fact that the company appeared to make several administrative errors in conducting the trials (Day 2006). It has been reported that Parexel which carried out the phase I trial failed to keep adequate records and this may have contributed to the negative outcome. In addition to that it was noted in a report following the failed trail that one of the doctors involved in the trial lacked sufficient training (Day 2006).
In addition to the above it was also noted that Parexel which carried out the trials did not sufficiently check the insurance records of TeGenero, the company that developed the drug (Day 2006). In addition to that the report also mentions that there was no formal system in place within the trial unit that provided 24 hour medical cover. The agency investigating the incident also established that the volunteers who received the placebo were allowed to leave the trial before appropriate checks were carried out (Day 2006). It is normally procedure to have individuals who have the placebo administered to be checked to confirm that they have indeed been administered dummy infusions rather than the actual antibody (Day 2006).
Summary of regulatory changes: EMEA CHMO SWP 2007
In line with improving the process of regulating drugs some changes that have been observed following the TGN1412 incident are related to the added value of new drugs (Garratini 2007). It has been established that drug companies often undertake long term post marketing trials to define efficacy of new drugs in relation to drugs on the market. It has been observed that such trials often g to show equivalence or non inferiority rather than superiority to those already available (Garratini 2007). Based on this approach therefore, new regulations prefer trials aimed to show that drugs are similar to current products as opposed to showing superiority. Trials performed merely to get market authorization should be discouraged.
Another change that has been noted following the TGN1412 incident is the increased emphasis on independent research and development (Garratini 2007). In line with this it has been suggested that one phase of the trial be carried out by an independent nonprofit organization. IN such cases EMEA may commission a study by academic health structures which would later be audited by independent research organizations (Garratini 2007).
Another change that has been observed following the TGN1412 incident is in relation to information disclosure. Previously, the European agency (EMEA) kept all information secret. It has been established that although disclosure could help competitors, there is no reason to hide data on toxicology ad clinical evaluation. The approach before the incident did not allow disclosure of information on the evaluation of the marketing application. This indicates that prior to the incident the agency did not permit independent evaluation by people outside the agency (Garratini 2007).
Also changed following the incident was the agency implementation of pharmacovigilance (Garratini 2007). It has been reported that prior to the incident the agency relied on national data and spontaneous reports from patients and doctors. Such an initiative will allow for the exchange of information on suspected adverse reactions. In addition to this companies should be subjected to present data on both beneficial and adverse events in their regular safety reports.
Another regulatory change that emerged following the crisis was with regard to removal of bias (Garratini 2007). It has been established that the right of drug companies conflicts with rights of patients. The patients have a right to drugs that have been studied enough to ensure their increased safety and efficiency when compared with current treatments. This suggests that drug companies should be required to known the content of articles published as opposed to relying on the work of ghost writers. In addition to this it has been observed that much of the agency’s budget comes from fees paid by applicants. The removal of this bias may go a long way in improving the regulation of drugs in future.
In addition to the above it has been established that following the incident it has become a requirement that all data of toxicological and pharmacodynamic nature is provided (Talbot & Aronson 2011). The main objective of this is to provide the best possible translation of pharmacological and toxicological range. In addition to this requirement it has also been noted that it is required that data from other drugs is made available (Plunkett 2008). This is with reference to similar or drugs with similar mechanisms. Such data is believed to be useful in provision of data on pharmacology and toxicology (Talbot & Aronson 2011).
It has also been suggested following the incident that all pharmacokinetic data on investigational compound studies be used in estimation (Vogel, Maas & Gebauer 2010). This includes studies from animal and human models and the aim being to determine expected dose-exposure relationship in man (Talbot & Aronson 2011). In addition to that data from other drugs assumed to have similar pharmacokinetics should be used to support expected human pharmacokinetics (Vogel, Maas & Gebauer 2010). Lastly, it has been observed following the incident that the selection of a starting dose should aim for minimal pharmacological effect with no expected toxicity (Talbot & Aronson 2011).
References
Bhattacharya, S 2006, ‘One drug trial, six men, disaster…’, New Scientist, pp. 1-3.
Bhogal, N & Combes, R 2006, ‘TGN1412: Time to change the Paradigm for the Testing of New Pharmaceuticals’, ATLA, vol. 34, pp. 225-239.
Criado, G 2006, ‘TGN1412: Superagonist Dr. Jekyll and Superantigen Mr. Hyde’, Immunologia, vol. 25, no. 2, pp. 147-150.
Day, M 2006, ‘Agency criticizes drug trial’, BMJ, vol. 332, pp. 1290.
Day, M 2006, ‘Duff’s report calls for changes in way drugs are tested’, BMJ, vol. 333, pp. 1235-1240.
Gad, SC 2009, Drug Safety Evaluation, John Wiley & Sons Inc., New Jersey.
Garratini, S 2007, ‘How can we regulate medicines better’, BMJ, vol. 335, pp. 803-805.
Garrett-Mayer, E 2010, Principles of Anticancer drug development, Springer Science+Media LLC, New York.
Griffin, JP 2009, The Textbook of Pharmaceutical Medicine, Blackwell Publishing Ltd., West Sussex.
Kenter, M & Cohen, A 2006, ‘Establishing risk of human experimentation with drugs: lessons from TGN1412’, Lancet, vol. 368, pp. 1387-1391.
Plunkett. JW 2008, Plunkett’s Biotech and Genetics Industry Almanac 2009, Plunkett Research Ltd., Texas.
Ritter, JM 2010, ‘Testing new drugs in naked apes and getting the dose right in their young’, British Journal of Clinical Pharmacology, vol. 70, no. 4, pp. 467-470.
St. Clair, EW 2008, ‘The calm after the cytokine storm: lessons from the TGN1412 trial’, Journal of Clinical Investigation, vol. 118, no. 4, pp. 1344-1347.
Talbot, J & Aronson, J 2011, Stephen’s Detection and Evaluation of Adverse Drug Reactions: Principles and Practice, John Wiley & Sons Ltd., West Sussex.
Vogel, HG, Maas, J & Gebauer, A 2010, Drug Discovery and Evaluation: Methods in Clinical Pharmacology, Springer Science+Media LLC, Berlin.
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