Secondary response
2 secondary responses
1.
Specific to whether the manufacturers of TGN1412 could have done more to improve the safety profile of the product, I think it is an unfair question because all manufacturers can do an infinite amount of tests on their product. However, due to limited time and resources, manufacturers follow a set of guidelines that outline what are the critical tests that can prove safety and efficacy prior to human trials. Based on reading the article, the manufacturer has followed the general protocol of completing the necessary in vivo studies, clinical development and dose calculation studies. The in vivo studies were conducted on cynomolgus and rhesus monkeys as the non-human primate models based on their similar affinity for TGN1412. All preclinical studies showed TGN1412 to be safe and efficacious. In the table outlining the learning points, it states that more caution should have been put interpreting the preclinical studies due to crossing the species barrier and use of human material that is as close as possible to the target tissue is important in in vitro studies. However, these are constant obstacles in preclinical studies where there is not direct replica of a human. Therefore, you have to justify using something that you think is as close as possible and that obviously still leave gaps.
However, to answer whether me as a FDA regulator at the FDA would fault the manufacturer for the adverse events occurred, I believe I would. While I believe they have followed general guidance in preclinical phase, they did not have a comprehensive plan in place for the human trials, which ultimately caused harm to the patients. The article outlined a few deficiencies in the drug trial, including “inadequate maintenance medical records. physician with inappropriate qualification, inadequacy in ensuring insurance protection of the sponsor, and failure in arranging early medical coverage”. The article also pointed out how the 6th patient was still administered with the product after the 1st patient has started showing adverse events, which showed negligence on the investigator’s part. The lack of reactive measures, such as administering the product in a hospital setting, showed lack of planning and disregard of patient safety in the manufacturer’s part.
Reference:
Attarwala, H. (2010). TGN1412: From Discovery to Disaster. Journal of Young Pharmacists, 2(3), 332-336. doi:10.4103/0975-1483.66810
2.
One of the major challenges with pre-clinical testing is the shift from utilization of animal models to in vivo human use. While certain animal models have similarities with specific human biological systems, there is risk that the biologic may respond differently in the human body (or vice versa) than in the animal models used in pre-clinical testing. For this product, non-human primates were used as predictive models for pre-clinical testing. In these models, pharmacokinetics, pharmacodynamics, and repeat-dose toxicokinetics were evaluated and followed by toxicological and immunogenicity studies.
Given the challenge in using animal models to predict safety effects in humans, I would suggest diversifying the animal models used (i.e. using an additional animal model that was not a non-human primate). This may have raised a safety signal that would have informed the product development. Traditionally, both a rodent and a large, non-rodent animal model are used in pre-clinical testing. Furthermore, I would recommend in vitro human studies. Based on the article provided, this was not performed even though it may have provided insight into the toxicological effects of the biologic on human cells, tissues, or organs.
As required by regulatory authorities, the Phase 1 study design was submitted to the regulatory authority and permitted. Relevant guidelines were followed in order to set the dose. However, the subjects were dosed in parallel and with a shortened dosing interval than was mandated in the protocol. This removed the ability of the investigator(s) to respond quickly to adverse events and prevent repeating the effect in the subsequent subjects. In addition, the testing should have been performed in a location that allows for rapid medical response to unexpected adverse events. The sponsor and the investigators underestimated what they did not know about the product.
Having said this, the biologic and its mechanism of action were novel and much has been learned since this incident. It is important that we integrate the lessons from failed clinical trials. This case is a reminder that the phased approach of testing in humans is critical and that the safety of subjects must always be the priority. Safety in humans cannot be assumed on the basis of animal studies alone.
Attarwala, H. (2010). TGN1412: From discovery to disaster. Journal of Young Pharmacists, 2(3), 332-336. doi:10.4103/0975-1483.66810
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