In this experiment, all six previously healthy young male volunteers (aged 19 to 34) nearly died after being infused with an experimental genetically engineered antibody drug affecting the very building blocks of life. A report in The New England Journal of Medicine (September 2006) by a team of critical care doctors at Norwick (Extract below) describes the catastrophic results in detail. Each of  six volunteers who received the drug suffered “substantial renal impairment… acute lung injury… neurologic sequelae” and had to be on life-support; one had fingers and toes amputated. The long-term harm from the drug-induced “cytokine storm” leading to multi-organ failure is unknown. Only the two volunteers who were given a placebo were unharmed.

This catastrophic experiment is a prima facie example of irresponsible medical research. The experiment encapsulates multiple systemic failures—including reckless abandonment of minimal safety standards that are expected in the testing of new drugs in healthy volunteers. Those who conducted the experiment and those who approved it failed to consider the safety of the human subjects who were exposed to a class of genetically engineered drugs that had previously been found to be toxic. [3] The British Sunday Times quoted Dr. Angus Dalgleish, a world expert on immunology: “previous studies caused similar severe side effects in patients already suffering from cancer. [The researchers] should have known they would get a meltdown because this drug was hitting exactly the same immune response pathways.”[4] http://www.timesonline.co.uk/article/0,,2087-2092619,00.html

Despite evidence of severe side effects produced in prior trials testing similar monoclonal antibody drugs in cancer patients, the experiment was approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for testing in healthy volunteers. The evidence further shows that rather than minimizing risks—as was done in the TGN1412 trial involving monkeys—in humans the drug was administered simultaneously instead of sequentially, in high instead of graduated doses, in a brief instead of a prolonged infusion, all of which increased risks unnecessarily for the six volunteers. BBC has obtained documents revealing that in monkeys, the drug was administered slowly, during the span of an hour. In the six human volunteers, the drug was administered at a high dose within 3 to 6 minutes. The MHRA Expert Scientific Committee has concluded that: "The dose was undoubtedly too high which is why we saw all six recipients get ill and so severely ill. What that tells us is the methods used to calculate the dose failed to predict a safe dose." [2] http://news.bbc.co.uk/2/hi/health/5377866.stm

The most obvious way to minimize risk in phase I safety studies—particularly trials of experimental classes of drugs whose unpredictable mechanism of action pose high risk—would have been to test a miniscule dose of the drug administered slowly to one human being while monitoring all side effects for at least 24 to 48 hours. If no adverse effects occurred, an equally miniscule or somewhat higher dose might be administered to a second human subject. Responsible medical research in normal volunteers testing high risk substances mandates increasing doses slowly while monitoring and documenting all changes and side-effects at each juncture. Before increasing the dose there should be a reasonable degree of certainty that it poses no harm at low dose.

Indeed, BBC reports that in 1993, Professor Terry Hamblin, of the University of Southampton, was investigating the effects of a new cancer drug, Interleukin 2. “As the drug had never been tested on humans, he tried it on one patient first. He gave the man the drug through an infusion into his vein over a number of hours, so if anything went wrong he would be able to stop the test before the patient’s body was overwhelmed with the drug. Soon it was clear the drug was having a therapeutic effect on the cancer – but it was also causing side-effects that were the same as those of Interleukin 2 and the trial was halted.” [2] http://news.bbc.co.uk/2/hi/health/5377866.stm

There is no doubt that if this experiment had been conducted within accepted standards, with risks to subjects minimized, all six would not have been exposed to the full dose of the drug. If the experiment had been conducted responsibly, fewer persons would have been harmed: perhaps one, at most two persons would have suffered much less severe ill effects. Six human beings would not have suffered catastrophic effects—as happened. 

BBC calls the disparity between the rate at which the drug was administered in humans (3 to 6 minutes) compared to monkeys (one hour), a “reckless mistake.”  The trial protocol can only be described as reckless endangerment of human lives. Standard practice by responsible researchers follows careful dose escalation methods and sequentially testing a new drug’s safety in each volunteer before proceeding to the next.  It is reasonable, therefore, to consider this deviation from standard practice—the exposure of six volunteers at once instead of sequentially, and the rapid administration of a potentially lethal drug at a high dose—criminal negligence. Indeed, it was reported that: “Scotland Yard has assigned officers from its elite Specialist Crime Directorate to the case raising the possibility that charges may be brought for negligence or even manslaughter, if any of the men die.” [5] http://www.newsinferno.com/archives/1019 https://ahrp.org/cms/content/view/121/84/ 

The experiment was an entrepreneurial venture involving multi-national stakeholders: TeGenero Therapeutics, the developer of TGN1412; Boehringer-Ingelheim, the manufacturer; and Parexel International, the US contract research organization (CRO) that conducted the trial.  Its approval by the UK- MHRA shows a disturbing similarity to the FDA’s trumpeting “phase zero studies” [6] whose rules loosen the federal human subject protections. https://ahrp.org/cms/content/view/121/84   This trend on both sides of the Atlantic, to speed up the drug trial process at the expense of safety, illustrates the kind of protection the public is getting from our health authorities. It leads one to ask whether regulators demonstrate incompetence, lack of resources to do their job, or whether this colossal failure to protect human subjects from harm suggests a more sinister motive for rubber stamping approval—namely, to accommodate commercial interests.

The six volunteers in this experiment were enticed into a medical disaster with financial incentives and sales pitches that concealed the true risky nature of the invitation: “You’ll be paid for your time. Free food….digital TV, pool table, video games, DVD player and now FREE internet access…” [7] https://ahrp.org/cms/content/view/346/80 The approval and conduct of the experiment demonstrates how the culture that embraces utilitarian ethics—which maintains that the ends justify the means—diminishes the value of human subjects. In that culture the safety of individual subjects is subordinated to achieving an end. In such a culture, researchers are encouraged to seek maximum utility by conducting “high impact” experiments without regard for the increased risks for the subjects. Clearly, those who conducted the TGN1412 experiment failed to take reasonable precautions to minimize risks for the human subjects—in fact, they speeded up the process thereby increasing risks. The experiment confirmed that absent a culture of precautionary medicine, absent a law backed up with mandated penalties, responsible research gives way to expediency and exploitation. Not even healthy volunteers are protected from preventable medical disasters. Concerns have been raised by immunologists and oncologists as well as the press, about the ethics of testing of such drugs that stimulate the immune system posing a risk of multi-organ failure in healthy volunteers. [4] [below]

But an editorial, “Volunteers At Risk” by Dr. Jeffrey Drazen, [8] editor of the New England Journal of Medicine (NEJM, September 7), defends this catastrophic experiment as the cost of doing business: “As long as we continue to manipulate biology in new ways, we probably cannot prevent all such events from occurring. We must do what we can to minimize risk, but the future health of the world population demands that we not let adverse events put an end to medical progress….the work must go on.” https://ahrp.org/cms/content/view/347/84/

Whether or not “the work must go on” if those entrusted with conducting human experiments fail to adhere to safeguards aimed at preventing catastrophic organ failure, should not be a decision left to those with a financial and / or professional stake in the biomedical research endeavor.  The academic medical community’s failure to rein in those who exhibit a callous indifference to the value of human life has resulted in human sacrifice on the altar of Science. Dr. Drazen represents a radical utilitarian segment within the scientific community. While reiterating the ethical and regulatory requirement, “to minimize risk”  he has consistently justified unethical medical experiments [9]—no matter how many safety standards were violated, no matter how many subjects suffered preventable harm, no matter that informed consent was not obtained, and no matter that risks were not minimized. Dr. Drazen justifies the violations (or pretends they haven’t occurred) by claiming their importance for furthering science.  Oddly, however, while Dr. Drazen invokes the importance of "people who place themselves at risk to advance our knowledge," neither he nor any of the scientists who irecruit others into high risk experiments have offered to contribute themselves for the greater good. It is fair to suggest that those who hold the view that others, but not they, should willingly assume risks "to advance medical progress" should not be entrusted with research involving human beings.

Immunology experts expressed dismay that the MHRA allowed the trial to proceed exposing healthy human beings to the high risks posed by this class of monoclonal antibody drugs. There is no mention in Dr. Drazen’s editorial that data from prior monoclonal antibody trials showing harm were presented at a meeting of the American Society of Clinical Oncology in May 2005. In one study testing another monoclonal antibody drug (MDX-010) 12 of 20 subjects suffered “a severe toxic reaction.” [5] http://www.newsinferno.com/archives/1019  No mention either that those who conducted the TGN1412 experiment failed to take even elementary precautions to “minimize risk” for the subjects. [6] https://ahrp.org/cms/content/view/346/80  Dr. Drazen’s editorial understates the catastrophic consequences for the volunteers whom he brushes off—as if their suffering and shattered health were a minor event. He makes a tacit acknowledgement that no safeguards exist to protect human subjects. Dr. Drazen sees no problem that the harm magnified by researchers’ failure to follow responsible safety standards—and that they should, therefore, be held accountable. Neither does he place any responsibility on the research community: volunteers, he says, are “people who are willing to place themselves at risk to advance our knowledge.”

The editorial should to be included in and become part of every informed consent form presented to every potential human research subject together with a discussion of how risks were not minimized in this dubious experiment in normal volunteers.  When patient safety collides with the interests of commercially driven research, the editor of the NEJM has consistently endorsed the research interests at the expense of patient safety. For example, the NEJM published the Vioxx-VIGOR study whose claims were shown to be contradicted by the evidence. The editors let the false claims of “positive” safety findings stand for five years without a correction—thereby misleading clinicians into believing Vioxx safe.[9] https://ahrp.org/cms/content/view/168/55/

It is hoped that the NEJM does not represent the moral values of the entire medical research establishment.  Clearly a law is needed to protect people from researchers who have derailed medicine from its legitimate healing tradition.

In the meantime, people who are being sought as research subjects need to know that medical research is a highly risky endeavor; that human beings who serve as test subjects in medical research—as it is conducted today—have no assurance that safeguards will be followed to protect them from harm. Failure to hold those who disregard safety standards accountable has fostered indifference to the serious consequences among some powerful leaders within the research community—who shrug off the harm by invoking—“Stuff Happens.”

Unanswered questions that require straightforward answers: 

• Given the exceptional risks linked to monoclonal antibody drugs which stimulate the immune system, why was    TGN1412 injected into six healthy volunteers?
• Why were all six healthy subjects exposed simultaneously with a high dose of a drug tested for the first time in humans? 
• Why was the drug infused in humans at a rate 15 times higher than that used for monkerys?
• Since other monoclonal antibody drugs had caused severe side effects in cancer patients, shouldn’t that information have been disclosed to the subjects?

Reference:
1. BBC News. Drug ‘administered too quickly’.
 http://news.bbc.co.uk/go/pr/fr/-/1/hi/health/5377226.stm
2. BBC: The Future of Drug Trials By Helen Sharp, Producer, audible online for 7 days.
http://news.bbc.co.uk/2/hi/health/5377866.stm
3. Lois Rogers and Isabel Oakeshott. Earlier trials had shown that drug group was highly toxic The Sunday Times, March 19, 2006
http://www.timesonline.co.uk/article/0,,2087-2092619,00.html
4. Hall C. Medical Editor, Antibody ‘puts immune system in overdrive’ The Telegraph–UK, 17/03/2006 http://www.telegraph.co.uk/news/main.jhtml?xml=/news/2006/03/17/ntrial117.xml&sSheet=/news/2006/03/17/ixhome.html
5. DiJoseph S. As Investigators Seek Answers and Victims of UK Drug- Trial Disaster Recover, All Clinical Testing May Suffer a Setback, Newsinferno, March 27, 2006: http://www.newsinferno.com/archives/1019 
6. Wadman M. Drive for Drugs Leads to Baby Clinical Trials: US Regulators Are Moving Sharply to Ease the Early Stages of Drug Development, Despite Safety Concerns, Nature, March 22, 2006 at: https://ahrp.org/cms/content/view/121/84
7. Lois Rogers, Richard Woods and Brian Dee. Poison Chalice, The Sunday Times – Britain, March 19, 2006. 
http://www.timesonline.co.uk/article/0,,2087-2092527,00.html
8. Drazen, JM. Volunteers at Risk, Editorial, New England Journal of Medicine, 355; Sept. 7, 2006 https://ahrp.org/cms/content/view/347/84/
9. Drazen, JM. Controlling research trials. N Engl J Med 348;2003:1377-80.

Contact: Vera Hassner Sharav
212-595-8974
veracare@ahrp.org
~~~~~~~~~~~~~~~~~~~~~~~

1. CYTOKINE STORM in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412
Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes C, Brunner MD, Panoskaltsis N. N Engl J Med 2006;355:1018-28. 

EXCERPT from a report by the physicians who provided intensive care to the six patients whose lives they saved—although their health cannot be restored.

“All six patients who received the trial drug were male, with a median age of 29.5 years (range, 19 to 34) (Table 1). None had a notable medical history, and all were clinically well during the 2 weeks before the study; baseline laboratory values were normal (Table 2). Beginning at 8 a.m. on day 1, each volunteer received an intravenous infusion, 10 minutes apart, of either the study drug or placebo. Each infusion lasted 3 to 6 minutes. The six volunteers in the treatment group each received 0.1 mg of TGN1412 per kilogram of body weight, infused at a rate of 2 mg per minute; the remaining two volunteers received a similar volume of saline.

Initial Response after Infusion of TGN1412

A series of adverse effects began in the treatment group after infusion, starting with the onset of severe headache in five patients after a median of 60 minutes (range, 50 to 90), accompanied by lumbar myalgia in all six patients after a median of 77 minutes (range, 57 to 95) (Fig. 1). Subsequently, during this early phase, the patients were restless and had varying degrees of nausea, vomiting, bowel urgency, or diarrhea (Table 1). Five  subjects had short amnestic episodes associated with severe pyrexia, restlessness, or both. All patients had a systemic inflammatory response that included erythema and peripheral vasodilatation (the timing of which was undocumented), with recorded rigors in four patients at a median of 59 minutes (range, 58 to 120) after infusion. Hypotension (defined by a decline in systolic blood pressure of 20 mm Hg or more) developed in all patients a median of 240 minutes (range, 210 to 280) after infusion, accompanied by tachycardia, with maximal heart rates of 110 to 145 beats per minute.

All patients received intravenous lactated Ringer’s solution during this time. Body  temperatures of 39.5 to 40.0°C were recorded a median of 280 minutes (range, 240 to 390) after infusion. At 300 minutes after infusion, Patient 1 had signs of respiratory failure, with tachypnea and a partial pressure of arterial oxygen (PaO2) of 52 mm Hg while breathing ambient air; the PaO2 increased with the addition of supplemental oxygen. Chest radiography revealed pulmonary infiltrates; these findings were not consistent with the expected response of a fit young man to the infusion of less than 4 liters of fluid at this stage. There was no clinical evidence of bronchospasm or laryngeal
edema….

All patients required the replacement of blood components by means of the infusion of fresh frozen plasma and cryoprecipitate to correct co-agulopathy. Owing to their severe lymphopenia, the patients were treated according to a protocol of infusions of irradiated red cells and platelets, as required, to prevent possible graft-versus-host disease….

Between 16 and 20 hours after infusion of TGN1412, the patients had further signs of respiratory deterioration: all six had signs of tachypnea, use of accessory muscles, inability to complete spoken sentences, and bilateral pulmonary infiltrates on chest radiography (Fig. 2A and 2B), and two had symptoms of dyspnea. There was also evidence of substantial renal impairment and disseminated intravascular coagulation, as indicated by an elevated prothrombin time, low fibrinogen level, high level of D-dimers, and decreased platelet counts in all six patients (Table 2). All patients had severe lymphopenia and monocytopenia, with sparing of neutrophils. Blood smears showed toxic granulation with Döhle’s bodies and a dysplastic appearance of the neutrophils, with pseudo–Pelger–Huët anomaly (Fig. 2C and 2D)……

Over the next 30 days, all patients had generalized desquamation (most marked in Patients 5 and 6) and muscle weakness on discharge from the ICU. Five patients had late myalgia, headache after the discontinuation of corticosteroids, difficulties with concentration, and short-term difficulties in finding words (particularly names). Three patients had delayed hyperalgesia, and two had peripheral numbness.

As compared with reactions to the infusion of other immunomodulatory agents (such as  anti-CD20,15 anti-CD3,16 and anti-CD52 monoclonal antibodies17 ), the response to TGN1412 initially had similar kinetics, including the rapid increase in the levels of first TNF-α and then interferon-γ and interleukin-6, followed by cardiovascular instability, and disseminated intravascular coagulation. However, from phase 2 onward, features unique to the response to TGN1412 were apparent — including early acute lung injury, diffuse erythema with late desquamation, neurologic sequelae, and post-illness myalgias (Table 3).

These events occurred during the first dosing interval in a phase 1 drug trial of a humanized immunomodulatory monoclonal antibody involving healthy subjects. The events provide insight into an immune-mediated cytokine storm leading to multiorgan failure in the absence of infection, contamination with endotoxin, or underlying disease. The TGN1412 variant of the syndrome had some features that set it apart from a typical cytokine storm, most notably early acute lung injury and marked lymphopenia.”
Xxx cut xxxxxx

~~~~~~~~~~~~~~

http://news.bbc.co.uk/2/hi/health/5377866.stm
BBC radio: ‘We need to know about the failures’ 
By Helen Sharp, Producer, The Future of Drug Trials September 26, 2006

In 1993, Professor Terry Hamblin, of the University of Southampton, was investigating the effects of a new cancer drug.  At the time, a wonder drug was being used to treat people with serious cancer diagnoses, called Interleukin 2.  It was incredibly effective but had very toxic side-effects: drops in blood pressure, fevers and back pain.  Professor Hamblin’s new drug was being tested to see if it was any more effective but without the side-effects. "The idea was to stimulate the lymphocytes, the defence cells in the body, to attack the cancer," he said.

Slow infusion
As the drug had never been tested on humans, he tried it on one patient first.
He gave the man the drug through an infusion into his vein over a number of hours, so if anything went wrong he would be able to stop the test before the patient’s body was overwhelmed with the drug. Soon it was clear the drug was having a therapeutic effect on the cancer – but it was also causing side-effects that were the same as those of Interleukin 2 and the trial was halted.

Successful trials tend to get more attention 
Professor Hamblin said: "It stimulated many cells in the body so  patients regularly got high fevers, shivering attacks, their blood  pressures fell, they had headaches, they vomited, they had diarrhoea, they had a rash where their skin began to peel off, very similar symptoms in fact to what the patients at Northwick Park developed."                 

The scientific community should take responsibility for letting us know what’s important in a particular area Professor Deborah Saltman Professor Hamblin’s drug and TGN1412, the drug given during the drug trial, work in similar ways. They both want to stimulate part of the immune system to produce an immune response in the body.

During the trial at Northwick Park Hospital, six men were given the drug intravenously, over a period of minutes. But within an hour, side-effects much like those in Professor Hamblin’s trial were being seen.

Not published
However, TeGenero, the makers of TGN1412, did not know about Professor Hamblin’s work because, at the time, a failed trial with a drug that was less effective than one already on the market would not have been published. But his observations would have been helpful to TeGenero and possibly to other drug companies working on similar treatments.

Since the TeGenero trial, the government has set up an Expert Scientific Committee to look into how early-stage drug trials should be carried out.  They recommend that work such as Professor Hamblin’s should be published on a database, which those doing the trial and those regulating the trial have access to.  This way, those involved can see if work has been done previously that could give some indication of the outcome of the trial.  In fact scientists have been working, together with drug companies, to produce something like this for the last 20 years.

There are various places on the internet where people can publish their results – including negative and null results. Professor Deborah Saltman, editorial director of medicine for Bio Med Central, one of the largest open-access publishers on the web, says that choosing the important results to publish is key. "We have what’s called peer review: if your colleagues, scientists working in the area consider it’s important, it should be published. "The scientific community should take responsibility for letting us know what’s important in a particular area."

Rethink needed
The Expert Scientific Committee has reached various conclusions, and one is that the dose given to the men was wrong. Professor Gordon Duff, who chaired the committee highlights that the way in which drugs trials are organised needs to be looked at.  "The dose was undoubtedly too high which is why we saw all six recipients get ill and so severely ill. What that tells us is the methods used to calculate the dose failed to predict a safe dose.  Those methods were largely based on the current norms, the regulatory guidelines that were operating at the time."

* The TGN1412 trial took place at a laboratory on the Northwick Park Hospital site, but was nothing to do with the hospital.

The Future Of Drug Trials will be broadcast on Tuesday 26 September on BBC Radio 4 at 2000 BST. You can also listen online for 7 days after that at Radio 4’s Listen again <http://www.bbc.co.uk/radio4/progs/listenagain.shtml>

  © BBC MMVI
 
 
2. Celia Hall, Medical Editor. Antibody ‘puts immune system in overdrive’
The TELEGRAPH UK March 17, 2006
http://www.telegraph.co.uk/news/main.jhtml?xml=/news/2006/03/17/ntrial117.xml&sSheet=/news/2006/03/17/ixhome.html

The experimental drug that has caused the violent reaction in six healthy volunteers is an entirely new type of antibody treatment which puts the body’s immune response into overdrive rather than subduing it. That may help to explain why the reaction was so severe. The antibody also stays in circulation for a long time, making it very hard for doctors to treat the young men affected.

Prof Sir Gregory Winter, a world leader in antibody research, said that the new antibody "super-charges" the immune response in the body rather than turning it down. "Other antibody drugs like Herceptin [for breast cancer], Avastin [for bowel cancer] or Humira [rheumatoid arthritis], for example, appear to be relatively safe but these basically turn a response down."

The drug, called TGN1412, is an antibody treatment designed for some forms of leukaemia and rheumatoid arthritis. It stimulates the production of T-cells with the aim of improving control of a malfunctioning immune system. "This is a different sort of antibody and I don’t know of another antibody that is on the market that works in the same way," Sir Gregory said. "It is a different and very potent process and very difficult to predict in advance how mild or severe the clinical response might be."

Sir Gregory is the joint head of the Medical Research Council’s laboratory of molecular biology division of protein and nucleic acid chemistry, at Cambridge. He said that the immune system was extremely complex and naturally had a series of checks and balances.  The new drug turned on a molecule called CD28 which helps to activate the T-cells. "You need to be very careful to be sure that you activate the response by just the right amount. You are on a knife edge: too much and it will attack not just the cells you want to attack but many other cells in the body. Furthermore, because the antibody remains in circulation for a long time the response is difficult to turn off."

Camilo Colaco, the chief scientific officer of the specialist immunology company Immunobiology Ltd, in Cambridge, believes that the disaster may expose the shortcomings of pre-clinical testing on mice and other animals. He told Science Business online: "The more we learn about the immune system, the more we realise that the mouse is not a good model for humans. This mismatch may be a particular problem with CD28, where there is little or no cross reactivity between a human antibody and the mouse immune system."

Scientists were also concerned about the effect on research. 
Prof Chris Higgins, the director of the Medical Research Council clinical sciences centre, said: "Many antibody therapies treat and cure thousands of patients across the world. It would be a disaster if this one very serious incident impeded the development of new antibody therapies for serious diseases such as arthritis and cancer."

Karol Sikora, professor of cancer medicine at Imperial College, said that monoclonal antibodies were very powerful selective tools aimed at specific proteins on the surface of cells. "They have been used extensively as treatments for cancer and they can target specific cells that regulate the immune response."
Copyright©  Telegraph Group Limited
~~~~~~~~~~~~

FAIR USE NOTICE: This may contain copyrighted (© ) material the use of which has not always been specifically authorized by the copyright owner. Such material is made available for educational purposes, to advance understanding of human rights, democracy, scientific, moral, ethical, and social justice issues, etc. It is believed that this constitutes a ‘fair use’ of any such copyrighted material as provided for in Title 17 U.S.C. section 107 of the US Copyright Law. This material is distributed without profit.