In a press release, ISIS puts the system’s failure to prevent the near fatal consequences of that catastrophic trial (TGN1412) in proper perspective:
"An unconventional member of a new class of drugs, all known to have caused serious side effects including deaths, has been approved for clinical trial based solely on unpublished animal tests." The fact that the results of TGN1412 animal tests have not even been published raises questions about those studies’ findings.
TGN1412 demonstrates that the current research approval system–with its obliging ethics committees–fails to ensure adequate precautions are taken to safeguard human subjects from harm. The emphasis is on speeding up the testing process.
"While Paraxel said it followed the rules for drug research, a former executive of the company, who asked to remain anonymous, expressed surprise that the drug was tested on so many persons at once. “It is common sense not to dose six individuals with the drug at once where there is no prior human experience,” he said .
ISIS challenges MHRA’s claim that the adverse effects were “unforeseeable.” Monoclonal antibodies are unconventional treatments of last resort because the known risks are so severe. Furthermore, "there are over 355 MAB drugs in clinical development, and the US Food and Drug Administration (FDA) has granted approval to18 so far, mainly for cancer treatment and control of immune system disorders. There is warning posted on every one of the approved drugs, as one of us has readily discovered and compiled the list (“Warning on FDA approved monoclonal antibodies”, this series). So it is difficult to believe that the problems were unanticipated as claimed."
"the problems associated with MAB drugs are widely recognized. One drug approved for treating multiple sclerosis (MS) was associated with several deaths from brain infections, probably because it blocked immune cells migrating to the brain to fight infections. That drug was voluntarily suspended pending further studies. The other MAB drugs approved are almost without exception associated with severe side effects, in many cases including death. These drugs provide, in most instances, treatment of last resort for terminal or highly debilitating disorders. For that reason, the risk of administering the treatment has been deemed acceptable provided that consent for treatment is truly informed."
The ethics committee that approved this experiment failed to regard the potentially fatal consequences for healthy volunteers. That demonstrates a blatant disregard for the ethical principles that by which permissible human research are defined. Those ethical principles are enshrined in the Nuremberg Code: http://www.ushmm.org/research/doctors/Nuremberg_Code.htm
Contact: Vera Hassner Sharav
Science Society Sustainability http://www.i-sis.org.uk
ISIS Press Release 07/04/06
London Drug Trial Catastrophe – Collapse of Science and Ethics
An unconventional member of a new class of drugs, all known to have caused serious side effects including deaths, has been approved for clinical trial based solely on unpublished animal tests.
Dr. Mae-Wan Ho <mailto:firstname.lastname@example.org> and Prof. Joe Cummins <mailto:email@example.com>
A fully referenced version <http://www.i-sis.org.uk/full/LDTCFull.php> of this article is posted on ISIS members’ website. Details here <http://www.i-sis.org.uk/membership.php>
Drug trial that went horribly wrong
On 13 March 2006, six healthy young volunteers took part in a clinical trial and became violently ill minutes after having been injected with a drug developed to fight autoimmune disease and leukaemia [1-5]. One of the two additional volunteers injected with a placebo who showed no ill effects recalled to newspaper reporters : “The men went down like dominoes. They began tearing their shirts off complaining of fever, then some screamed that their heads were going to explode. After that they started fainting, vomiting and writhing around in their beds.”
One man became especially bloated, “like the Elephant Man”. All six suffered multiple organ failure, and were admitted to intensive care. The Medicines and Healthcare products Regulatory Agency (MHRA), which gave approval for the trial, immediately withdrew authorisation; and an international warning went out to prevent the drug being tested abroad.
Two weeks later, two men remain in hospital; one still in intensive care and conscious, the other said to be making good progress . The case is under investigation by the MHRA. But serious questions should also be asked concerning the MHRA’s approval for the trial in the first place.
A new kind of drug previously untested on humans.
The drug tested, TGN1412, was developed by the company TeGenero based in Würzburg, Germany, and manufactured by Boehringer Ingelheim. But another company, Parexel International Corporation based in Lowell, Massachusetts, USA, was commissioned to carry out the clinical trial. The six young men were paid a small fee to participate in the experiment [1-5], according to one of them, £2 330 (US$4 070).
Paraxel said it followed the rules for drug research, but a former executive of the company, who asked to remain anonymous, expressed surprise that the drug was tested on so many persons at once. “It is common sense not to dose six individuals with the drug at once where there is no prior human experience,” he said .
TeGenero describes TGN1412 on its website as  “an immunomodulatory humanized agonistic anti-CD28 monoclonal antibody that is being developed for the treatment of immunological diseases with a high unmet medical need, such as multiple sclerosis, rheumatoid arthritis and certain cancers”. A monoclonal antibody (MAB) is an immunoglobulin protein made by the descendants of a single antibody-producing cell.
In a statement updated 24 March 2006 , the company disclosed that TGN1412 binds to the cell marker CD28 present on the cell surface of T lymphocytes, causing more T cells to be created. It claimed that the safety of TGN1412 was extensively tested on “rabbits and monkeys”, that “there were no drug related deaths despite administering doses up to five hundred times the dose to be used in the phase 1 clinical trial”. Nevertheless, in pre-clinical tests, 2 monkeys experienced a transient increase in the size of lymph nodes, but TeGenero considers that not a drug related side effect.
Family members of the human volunteers were told that a dog died in testing, TeGenero denied that TGN1412 was tested on dogs, but stated that academic research which led to the initial development of TGN1412 did include testing on mice and rats.
TeGenero had applied to conduct the same test and gained approval both in the UK and in Germany, though the test in Germany had not yet started and has been abandoned.
It said that the drug was given to volunteers “within a period of 2 hours”, as “approved by the MHRA and the local ethics committee”. TGN1412 was the company’s “most advanced product candidate and the first to reach human testing.”
What went wrong?
No one knows what caused the shocking reactions in the volunteers. An error in drug dosing or manufacture was suspected . Simon Gregor, spokesperson for UK’s MHRA, said managers at Northwick Park Hospital where the trial took place were so surprised that they called in the police to check for evidence of a crime. But MHRA and other investigations found no evidence of crime or technical error.
Was a contaminant in the MAB drug responsible? MAB drugs typically begins with extensive genetic engineering to produce the appropriate protein antigen, which is injected repeatedly into mice together with transgenic cells producing the protein, in order to challenge the mice to produce antibodies to the protein. The mice are then killed and the spleen cells isolated and fused with cancer (lymphoma) cells to create ‘hybridoma’ cells. Clones of single hybridoma cells are then obtained to give permanent cell lines, each of which grows and secretes a single antibody protein (monoclonal antibody) continuously. ‘Humanized’ monoclonal antibodies would have involved additional genetic engineering to alter the monoclonal antibody protein molecule so that it would not be rejected when given to human subjects. Each step in this complicated process could have introduced dangerous contaminants.
An interim report from MHRA said that the drug did not appear to have been contaminated, “or to have contained anything other than the correct ingredients”, said Professor Kent Woods, the chief executive of the MHRA, which regulated 350 Phase 1 clinical trials (first testing on humans) in the UK every year. The report also cleared Paraxel, which appeared to have run the trial according to the agreed protocol, with the correct dose given to the patients .
More and more, the suspicion has turned onto TGN1412 itself, which may have triggered the T cells to release a toxic flood of cytokines (cell signalling molecules), or the T cells may have attacked the body’s own tissues, leading to multiple organ failure [9, 11]. But MHRA, TeGenero and Paraxel all maintained that the volunteers’ reactions were “unforeseeable”. TeGenero’s chief scientific officer Thomas Hanke issued a statement on 17 March: “Extensive preclinical tests showed no sign of any risk.”
Henke told Science magazine that a rodent version of TGN1412 was tested extensively at high doses in rats and mice, with no ill effects; and TGN1412 itself was given to 20 cynomolgus monkeys in an unpublished study, after it was shown that their T cells were activated in the same way as human cells, with no significant adverse effects other than a brief increase in lymph node size. Simon Gregor of MHRA said that they have gone back to the files and there was nothing in the documentation that would cause them to think there was a concern.
We do not know what the documentation contained, but disagree that the problems were “unforeseeable”.
The problems should have been anticipated
At least one drug, CTLA4 monoclonal antibody, which binds to a different cell marker, have caused side effects in human trials, including skin rashes and gut reactions, which were controlled with steroids.
In fact, there are over 355 MAB drugs in clinical development, and the US Food and Drug Administration (FDA) has granted approval to18 so far, mainly for cancer treatment and control of immune system disorders. There is warning posted on every one of the approved drugs, as one of us has readily discovered and compiled the list (“Warning on FDA approved monoclonal antibodies”, this series). So it is difficult to believe that the problems were unanticipated as claimed.
On the contrary, the problems associated with MAB drugs are widely recognized. One drug approved for treating multiple sclerosis (MS) was associated with several deaths from brain infections, probably because it blocked immune cells migrating to the brain to fight infections. That drug was voluntarily suspended pending further studies. The other MAB drugs approved are almost without exception associated with severe side effects, in many cases including death. These drugs provide, in most instances, treatment of last resort for terminal or highly debilitating disorders. For that reason, the risk of administering the treatment has been deemed acceptable provided that consent for treatment is truly informed. I
The problems associated with up-regulating the immune system are also well known, and include inflammation of the eye, skin, gut, pituitary gland along with cases of hepatitis and loss of skin pigmentation . A humanized MAB used to treat colon cancer caused 17 percent of the cancer patients to experience adverse immune events . Initiation of such adverse events in susceptible patients could be detected by first administering a low dose of the drug, so those patients could be removed from further treatment with high doses . 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.
Superagonist monoclonal antibodies are unconventional
Soon after the first monoclonal antibodies were raised against the cell surface molecules of white blood cells in the later 1970s, 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.
In experimental systems, the natural ligands of TCR and CD28 can be replaced by specific MABs.
There are two types of MABs that bind to CD28 to stimulate T cells, conventional MABs that depend on simultaneous stimulation of TCR, and superagonist MABs that can give full activation of T cells without TCR stimulation. Researchers from TeGenero working with other laboratories showed that superagonist and conventional rat and human CD28-specific MABs bind at different sites, and that the superagonist binding site is conserved across the evolutionary divide separating rodents and humans . 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.
Animal tests consist of “unpublished data”
Although TeGenero claimed to have carried out extensive animal testing of TGN1412, it provided no scientific papers on the tests. A review published by TeGenero in 2005  referred solely to “unpublished data” as far as animal testing was concerned.
The review referred to studies in rats and mice given superagonist anti-CD28 MABs, in which a transient but significant increase in overall T cell numbers was found, without unleashing a toxic “cytokine storm”; and the researchers concluded that, “the lymphocytosis induced by CD28 superagonists appears to be benign and well tolerated.” A dose range 0.5mg/kg to 5mg/kg body weight led to a transient increase in the proportion of T regulatory cells from 5 to 20 percent, while absolute cell numbers increased up to 20 fold. Low doses of anti-CD28 MABs (0.5m/kg body weight per rat) appeared to expand T regulatory cells without inducing overall T cell increase; hence it was concluded that CD28 superagonist stimulation in vivo leads to the preferential expansion and strong activation of naturally occurring T regulatory cells over other T cells.
The review claimed that: “Efficacy of CD28 superagonist therapy has so far been evaluated in animal models of both peripheral and central nervous system inflammation as well as in a model of human rheumatoid arthritis.” These animal models showed that CD28 superangonist “prevented or at least greatly mitigated clinical symptoms when given prohylactically – that is, before the animals showed signs of clinical disease (unpublished data).” And, “even after the onset of clinical symptoms therapeutic CD28 superagonist administration rapidly stopped disease progression and induced remission.” Consequently, for “successful therapy, as for Treg cell expansion, low doses of CD28 superagonist (0.5mg/kg body weight) were sufficient (unpublished data).”
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.
UK’s top science journal Nature reported the trial under the headlines, “London’s disastrous drug trial has serious side effects for research”, predicting tighter restrictions on clinical research and closer scrutiny of the private companies that carry out the majority of clinical trials .
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? Some observers say that the company TeGenero should have been more cautious about the drug as it bypasses the immune system’s natural control mechanism; as immunologist Angus Dalgleish of St. George’s Medical School in London said, “all hell can break loose”.
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. He said CROs are often told by pharmaceutical companies to “just get us the data on the deadline”, and “don’t get asked questions on how that’s being done.” The Association of CROs boasts that CROs conduct clinical trials 30 percent more quickly than the pharmaceutical companies that hire them.
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. The volunteers apparently caught TB from an infected subject they’d been housed with as part of the study paid for by a Canadian company, but conducted by the CRO SFBC International.
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 .
“The recruitment of the participants into the British trial certainly left much to be desired ethically.” Caplan wrote. The website recruiting volunteers said almost nothing about risks, but went on and on about good pay, free medical care, free food and “plenty of time to read or study or just relax, with digital TV, pool table, video games, DVD player and free internet access.”
The other CRO, SFBC International, has problems beyond Montreal. The company’s major facility for housing subjects in long-term studies in Miami had received numerous safety and fire-code violations. 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. Now, private CROs running studies for pharmaceutical and device companies are a $14 billion industry in the United States alone. 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.
The role of the regulatory agency should also come under careful scrutiny. Why did the MHRA allow the tests to be carried out simultaneously on all six volunteers? Did it have all the information available when it approved the trial? Did it make sure that informed consent was adequate?
In Germany, the local public prosecutor in Würzburg is investigating whether any criminal wrongdoing was involved . The Paul Ehrlich Institute, which authorises human trials of biological drugs, announced it will tighten regulation of the first tests of such drugs in people. Johannes Löwer, president of the Institute based in Langen, asked why six people were treated at the same time, instead of starting with one. He said his Institute will start requiring sequential rather than simultaneous administration of ‘high risk’ monoclonal antibodies such as TGN1412, which activates the immune system.
Have the standards of science and ethics both collapsed in the new ethos of the “knowledge economy” that promotes wealth creation above all else?
This article can be found on the I-SIS website at <http://www.i-sis.org.uk/LDTC.php>
1. The voluntary consent of the human subject is absolutely essential.
This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved, as to enable him to make an understanding and enlightened decision. This latter element requires that, before the acceptance of an affirmative decision by the experimental subject, there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person, which may possibly come from his participation in the experiment.
The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.
2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.
3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study, that the anticipated results will justify the performance of the experiment.
4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.
5. No experiment should be conducted, where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.
6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.
7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.
8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.
9. During the course of the experiment, the human subject should be at liberty to bring the experiment to an end, if he has reached the physical or mental state, where continuation of the experiment seemed to him to be impossible.
10. During the course of the experiment, the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgement required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.
"Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10", Vol. 2, pp. 181-182. Washington, D.C.: U.S. Government Printing Office, 1949.]
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