London Drug Trial Catastrophe – Collapse of Science and Ethics

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London Drug Trial Catastrophe – Collapse of Science and Ethics

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Fri, 07 Apr 2006 15:42:42 +0100

 

 

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This article can be found on the I-SIS website at

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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been approved for clinical trial based solely on unpublished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

http://www.i-sis.org.uk/full/LDTCFull.php.

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 [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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