Tegenero trial ethics

Learn More. After a drug is confirmed as safe and efficacious in preclinical studies, it is tested in healthy human volunteers for first in man trials. After very first infusion of a dose times smaller than that found safe in animal studies, all six human volunteers faced life-threatening conditions involving multiorgan failure for which they were moved to intensive care unit. After this particular incident, a lot was changed over how first in man trials are approved by regulatory authorities and the way clinical trials are conducted.

This review primarily deals with preclinical studies conducted by TeGenero, results of which encouraged them to test the antibody on human subjects, reasons why this drug failed in human trial and aftermath of this drug trial. In addition, another drug—Fialuridine which failed in phase 2 clinical trial leading to death of five human subjects is briefly reviewed.

CD28 superagonist antibodies can cause activation and proliferation of regulatory T cells regardless of signal received by T-cell receptor. Since activation of regulatory T cells can be useful for the treatment of a variety of autoimmune diseases and cancer, they were investigated for their therapeutic potential in different animal models for their superagonist activity.

TGN could cause ex vivo expansion of T cells in the absence of additional stimuli from T-cell receptor. In preclinical studies, well-tolerated expansion of T cells was observed without any measurable proinflammatory reaction.

Moreover, TGN also demonstrated its therapeutic potential for use in autoimmune disease because of its capability of activating regulatory T cells.

Thus, depending upon the condition of the immune system TGN was thought to be useful for disease related to low numbers of activated T such as B-cell lymphoma or for treatment of autoimmune diseases such as rhematoid arthritis. When this antibody was tested in humans, it was immediately withdrawn from phase 1 clinical trials and volunteers had to be taken to intensive care unit 8 h after drug infusion due to multiorgan failure. After identification of CD28 antibodies capable of activating T cells along with signal from T-cell receptors, studies were conducted to evaluate T-cell activation potential of these CD28 antibodies.

Large number of mouse hybridomas were isolated and investigated for functional activity through CD It was found that one category of these antibodies was capable of activating T cells irrespective of signal received from T-cell receptor. They were named as CD28 superagonists. These antibodies did not differ in antibody class or the binding avidity for the CD28 receptor but differed in the epitope-binding site.

From these studies, TGN, a genetically engineered humanized anti-CD28 antibody was produced by transferring complement-determining regions from variable regions of heavy and light chains of monoclonal anti-mouse CD28 antibody 5. A mouse antibody used in humans may have toxicity problems related to immunogenicity and problems related to effective functioning of antibody. To avoid these problems, the above humanized antibody TGN was constructed. These assays showed specificity of TGN for CD28 receptor and that TGN did not cross react with other closely related molecular targets such as Cytotoxic T-lymphocyte-antigen-4 and inducible co-stimulator.

In vitro studies for cross reactivity of TGN with CD28 expressed on T cells of rodents and non-human primates revealed that TGN had low-binding affinity for rodent CD 28 whereas the same was high in case of T cells from for CD 28 to T cells derived from cynomolgus monkey and rhesus monkey.

When incubated with different subsets of T cells obtained from healthy donars, only TGN but not conventional CD28 antibody was able to cause rapid proliferation of T cells in the absence of stimuli from T-cell receptor. These results showed that TGN had superagonistic activity for T cells obtained from healthy donars and that they could specifically react with CD28 receptor having sequence homology with human CD28 receptor.

Prior to use of TGN different antibody variants were used for preclinical studies. All these studies demonstrated that these superagonist are safe and efficacious Investigation brochure, These encouraging results demonstrated high possibility for the use of this superagonist for the treatment of different T-cell deficiency syndromes like auto-immune diseases and B-cell lymphoma.

To further evaluate its efficacy, humanized antibody as described above was engineered from 5. Selection of proper non-human primate model was an important issue for testing further safety and efficacy of this antibody. On the basis of this hypothesis, it was decided that results obtained from pharmacokinetic and pharmacodynamic studies in these closely related species would most closely predict fate of drug response when tested in humans.

A repeat dose study for toxicokinetic evaluation of TGN was conducted. Plasma half-life of TGN was found to be 8 h which was as expected for a large protein molecule like an antibody. Despite four increasing repeated doses of TGN resulting in four plasma peaks concentrations of TGN, only one peak for increase in T-cell number was observed. This was because extent of expansion of T cells by TGN is highly dependent on availability of T cells and saturation kinetics of CD28 co-stimulator receptor.

After these studies, toxicological studies using rhesus and cynomolgus monkeys were conducted. A repeat dose pilot study was conducted in cynomolgus and rhesus monkey.

In addition, no signs of toxicity were observed in any of the physiological systems including cardiovascular system, respiratory system, or central nervous system. In addition, there was no signal from any of the animals treated with any dose of superagonist indicating symptoms of anaphylactic shock or development of autoimmune disease, or systemic immune suppression.

In addition to these studies, tissue cross-reactivity studies were performed where distribution of lymphocytes was observed by lymphocyte staining.

These studies revealed a consistent tissue staining in lymphoid tissue as expected demonstrating target-tissue specificity of CD28 superagonist. In addition, studies for immunogenicity of TGN were performed on primate model. Anti-TGN antibody titers were observed in all animals, which were thought to be as a consequence of the humanized antibody being used in primate model. After getting approval from regulatory authorities, phase 1 trials were conducted. The main aim was to establish safe human dose which can be further be used for subsequent drug trials.

For this purpose, it was decided to conduct the trials on healthy human volunteers because disease free subjects have comparable CD28 receptors as in case of rhematioid arthritis or B-cell lymphoma. Also, immunological safety was expected to be more in healthy subjects compared to those with pre-existing disease. In the London drug trial, the dose administered to all six volunteers must have been sufficiently high to cause all of them to become critically ill.

Another factor that should have made those involved in the London trials much more cautious is that the drug tested was unusual even among monoclonal antibody drugs.

Soon after the first monoclonal antibodies were raised against the cell surface molecules of white blood cells in the later s, researchers have realised that they could be used to change immune responses, potentially for therapeutic purposes.

The majority of the antibodies block immune functions or augment them when used in conjunction with other reagents. A much smaller subset of antibodies activate white blood cells autonomously, and are defined as superagonists [14, 15].

Natural activation of T cells requires both the T cell antigen receptor TCR and T cell marker CD28 to be stimulated by specific ligands diffusible signal molecules , causing the TCR and CD28 respectively to become cross-linked and clump together on the cell membrane. What happens downstream is not well understood, but is thought to involve cross talk between the clumped TCR and CD28 patches at the cell membrane.

Researchers from TeGenero working with other laboratories showed that superagonist and conventional rat and human CDspecific MABs bind at different sites, and that the superagonist binding site is conserved across the evolutionary divide separating rodents and humans [14]. They also claimed previous research in the rat model showed that superagonist CD28 MABs were highly potent stimulators of T cell proliferation in vivo without apparent toxicity, and were ready to exploit the MABs for therapeutic purposes.

Although TeGenero claimed to have carried out extensive animal testing of TGN, it provided no scientific papers on the tests. The dust from the catastrophe has far from settled. It has left the scientific and medical community stunned, and serious soul searching began almost immediately in the aftershock. The report raised a number of key questions: Was informed consent adequate?

Were the right subjects recruited for the trial? Were the right doses given? Did the company carrying out the trial behave responsibly? Parexel International, the company contracted to do the clinical trial, operates in 39 countries.

Ethicists in the United States have called for the careful scrutiny of a newly loosened set of rules for making and testing drugs in human trials, as well as the lucrative business of contract research organizations CROs such as Paraxel. Bioethicist Art Caplan is concerned that CROs are tacitly encouraged not to focus on protecting human subjects. The London drug trial episode came in the wake of 11 otherwise healthy people who tested positive for tuberculosis in Montreal, Canada, after they were paid to volunteer for research conducted by a private company.

Writing in the Philadelphia Daily News , Caplan expressed doubt that informed consent and safety were given the priority required to protect the human volunteers taking part in such studies [17].

When subjects went public with complaints, at least three of them said they SFBC officials bullied them and threatened them with deportation.

Twenty years ago, Caplan said, most clinical research was conducted in academic medical centres, and most research was paid for with government money. A lot of this research is done using poor people or students, sometimes in the United States, but often in Europe, India and Southeast Asia. This syndrome had apparently been observed in some animal testing, although the species of primates tested did not manifest the syndrome.

TeGenero, however, felt that this reaction was "not expected," in the human trial. He believed "he was participating in a fairly standard trial of a painkiller like ibuprofen, for arthritis.

Headaches and bruising were listed as potential side effects, as well as the possibility of a severe allergy. But that risk was downplayed. Since the trial, "the companies [TeGenero and Parexel] have been unwilling to meet with the trial subjects or provide more data…. In my humble opinion, this newspaper article raises further serious questions about whether research subjects were adequately informed about the nature of the trial and its possible risks, and why the investigators continued to administer the drug after the first subjects had begun to experience adverse effects.

Hopefully, further investigations will afford more transparency, and will lead to improved conduct of trials that put the interests of patients ahead of the imperative to "speed your product through clinical development. Poses MD at AM. Such material is made available for educational purposes, to advance understanding of human rights, democracy, scientific, moral, ethical, and social justice issues, etc.