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[SANET-MG] collapse of science and ethics
This article is the first of three, the next one will deal with
environmental field test releases of genes producing proteins used in
the failed trials. Such genes have been tested in corn or soybean grown
in the open environment.
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clinical trial based solely on unpublished animal tests.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
and Prof. Joe Cummins
A fully referenced version of this article is posted on ISIS members’
website. Details here
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 [2]: “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 [6]. 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).
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 [2].
TeGenero describes TGN1412 on its website as [7] “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 [8], 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 [9]. 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 [10].
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 [12].
A humanized MAB used to treat colon cancer caused 17 percent of the
cancer patients to experience adverse immune events [13]. 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 [12]. 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
[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.
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 [15] 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 fallout
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
[16].
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 [17].
“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 [16]. 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?
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