TGN1412_Medical Trial and Terror--Reveals the Empoeror Has No Clothes

[Guest guest]

TGN1412_Medical Trial and Terror--Reveals the Empoeror Has No Clothes

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and Accountability

http://www.ahrp.org/cms/

FYI

As the horrifying nightmare of the clinical trial the monoclonal

antibody, TGN1412, unfolds, it is becoming ever clearer that human

beings are being used as guinea pigs even when those conducting the

trial have the vaguest knowledge about the potential risks:

" Even the team who had administered the test drugs could not explain

why the men were slipping in and out of comas, why their heads had

puffed up to twice their normal sizes, why some were vomiting, or why

some were in such pain. Their only real comfort was provided by an

experienced nurse who supervised the installation of drips and

ventilators. "

" The men, who had been contracted by the US drug testing company

Parexel to test the anti-cancer drug TGN1412, were put on

ventilators. Then some began showing signs of kidney failure. Blood

filtration units were brought it to clean out their veins and

arteries. Relatives were called and told to expect the worst. Only a

miracle would see them through, one was told. "

As the UK Observer reports, " By any standards, it is a shocking

story. How could a carefully controlled medical trial have produced

such mayhem in such a short space of time? What exactly happened to

those six healthy young men? Why did the rigorous rules laid down by

the Medicines and Healthcare Products Regulatory Agency (MHRA) fail

to halt last week's dreadful events? And what are the implications

for the chaos triggered by the drug-trial disaster? "

" Doctors have a name for this deadly cascade. It is called a cytokine

storm. "

We have come a long way from looking for medical cures that improve

people's health. The reality that the public needs to understand is

that the current system is NOT geared to protect the subjects or to

adhere to ethical and scientific standards of excellence. The system

is structured to reward those who speed up the process of getting new—

not necessarily better—drugs / vaccines / and medical devices to

market. The entire system is geared toward increasing profits for the

stakeholders involved—including manufacturers, scientists,

physicians, the companies that conduct clinical trials—all are

trained to speed the process. That inevitably means, cutting corners

on pre-clinical testing and on safeguards aimed at protecting humans.

The British MHRA and its American cousin, the FDA have failed utterly

to ensure that safeguards are in place to protect the public health,

instead, they have responded to industry's performance failure—i.e.,

the FDA says 9 of 10 experimental drugs fail in clinical testing that

can cost companies millions. And many experimental drugs go untested

in humans " —by lowering the bar for testing in human beings. The

Boston Globe reported the rationale given by Dr. Janet Woodcock, the

FDA's deputy commissioner for operations, to FDA's relaxed clinical

trial rules adopted to encourage industry to push the envelope to

move clinical trials faster along.

''This will allow us to test a broader variety of compounds in people

early and then pick the best one for taking forward. " See:

http://www.ahrp.org/cms/content/view/126/28/

See, FDA new Guidance for Industry, Investigators, and Reviewers

Exploratory IND Studies http://www.fda.gov/cder/guidance/7086fnl.htm

There is an urgent need for " creative solutions, " to prevent such

disasters in the future. Unfortunately, FDA's new rules will only

exacerbate the situation by exposing (mostly vulnerable, poor) human

beings to highest risk in dangerous, speculative human experiments.

Dr. Glover, a monoclonal expert, and former chief medical

officer for Cambridge Antibody Technology (UK), points out that the

story of TGN1412 spells out many warnings for the pharmaceutical

industry and for the medical establishment. 'If nothing else, the

reaction of these patients tells us one thing - that there are things

going on at the CD28 site, the target for TGN1412, that we do not

understand.'' " Any company who is researching on CD28 drugs today

should stop what they are doing at once until we find out more about

what is going on there. " It is equally clear, he added, that " in an

era in which more and more new medicines are created by biological

means, that new procedures be urgently introduced to prevent any more

disasters. "

Dr. Glover suggests two possible solutions:

Genetically engineered mice with a humanised immune system may be

part of the answer, he added.

A new super-safe technique called 'microdosing' which was just

starting to attract the attention of the pharmaceutical industry.

This involves producing a blister on a patient's arm and exposing it

to tiny amounts of the drug, rather than treating the whole person.

The blister fills with inflammatory fluid, containing cells whose

reaction to the drug can be monitored. Dr. Glover said, 'This allows

you to get a handle on the effect before you expose the whole patient

to it.'

Contact: Vera Hassner Sharav

212-595-8974

veracare@...

The OBSERVER

Trial and Terror

Robin McKie and Jo Revill

Sunday March 19, 2006

The first inkling that doctors were facing an unprecedented medical

crisis began with a call to the critical care unit at Northwick Park

Hospital last Monday afternoon. Patients on the seventh floor were

having strange reactions to a new drug, they were told. Some were

having breathing difficulties, others were losing consciousness.

The news triggered alarm, but nothing more. The unit's six beds were

already occupied by patients who were too ill to be moved. So a

separate bay was taken over and the first patients rushed down. It

was then that staff realised the nature of the calamity they were up

against. Within minutes, the bay was filled with the writhing bodies

of young men screaming for help.

Consultants were summoned from their homes. All were baffled. Even

the team who had administered the test drugs could not explain why

the men were slipping in and out of comas, why their heads had puffed

up to twice their normal sizes, why some were vomiting, or why some

were in such pain. Their only real comfort was provided by an

experienced nurse who supervised the installation of drips and

ventilators.

By the time Ganesh Suntharalingam, director of intensive care,

arrived at the unit in the sprawling, windswept Northwick campus in

Harrow, north-west London, the scene was horrific. Six healthy young

men - including British Asians, an Australian, a New Zealander, and a

South African - were now in the throes of massive inflammatory

reactions.

The men, who had been contracted by the US drug testing company

Parexel to test the anti-cancer drug TGN1412, were put on

ventilators. Then some began showing signs of kidney failure. Blood

filtration units were brought it to clean out their veins and

arteries. Relatives were called and told to expect the worst. Only a

miracle would see them through, one was told.

By any standards, it is a shocking story. How could a carefully

controlled medical trial have produced such mayhem in such a short

space of time? What exactly happened to those six healthy young men?

Why did the rigorous rules laid down by the Medicines and Healthcare

Products Regulatory Agency (MHRA) fail to halt last week's dreadful

events? And what are the implications for the chaos triggered by the

drug-trial disaster?

The MHRA has announced it has begun an investigation into the

calamity of Parexel's trial, one that should provide answers to these

questions. 'This was completely unexpected,' said Simon Gregor,

spokesman for the MHRA. 'There are a number of possibilities which we

have to consider: was there a manufacturing problem or some form of

contamination or was there something about this product that could

not have shown up at an earlier stage?' He predicted it would take

several weeks, possibly months, before any inquiries would produce

results. Few expect a whitewash. This country is one of the world's

biotechnology leaders but that reputation will be seriously tarnished

if it is found there were significant regulatory errors involved in

the medical disaster at Northwick Park.

Consider the simple issue of timing. It is now clear the doses of

TGN1412 used in the trial were given with extraordinary rapidity,

with an interval of only minutes separating each patient's injection.

Normally, doses would be interspersed with waits of hours to give

researchers time to study volunteers for side-effects. Indeed,

sometimes doses are given at intervals of days, even weeks, as Dr

Kate Law, of Cancer Research UK, said.

'We usually give one person a small dose. Then weeks later we give

another volunteer an equally small dose,' she said. That precaution

was clearly not enforced last week. Within minutes of the last

volunteer getting his TGN1412, the first injected recruit had begun

to complain of a severe headache, backache, fever and pain. He tore

his shirt off and yelled he was burning. 'An Asian guy next to me

started screaming and his breathing went haywire as though he was

having a terrible panic attack,' said one of the volunteers, Raste

Khan, who had been given a placebo.

'They put an oxygen mask on him but he kept tearing it off. He was

shouting " Doctor, doctor, please help me! " He started convulsing,

shouting that he was getting shooting pains in his back. People were

fainting and coming back to consciousness. It was terrifying. I kept

expecting it to happen to me at any moment. But I felt fine and

didn't know why.' The whole affair 'is shocking because it is

unprecedented,' said Simon Best, chair of the UK Bioindustry

Association. 'If you think about the number of Phase I trials carried

out in this country, you've never heard of anything having such a

terrible impact.'

In fact, Phase 1 trials - which are carried out merely to determine a

drug's toxicity, its efficacy being assessed at subsequent Phase 2

and 3 trials - can all too frequently sound the death knell for a new

medicine. 'Between 20 to 30 per cent of drug developments go no

further than this stage because of ill-effects suffered by

volunteers,' Ray Noble, a UK medical ethicist, pointed out. However,

no drug has ever seen such an abrupt termination as that of TGN1412.

Not that Parexel are newcomers to the business. The company made more

than $100m last year carrying out clinical trials for researchers and

has plenty of experience in the field, with more than 5,000 employees

in 39 countries. All the doctors and nurses at its Northwick Park

unit are employees and the company takes great care in getting

participants to sign full consent forms and to be given medical

examinations. The company also provides pool tables, digital TVs and

computer games for volunteers.

And that leads us to another vexed issue: money. Khan, like the other

volunteers taking part in the trial of TGN1412, had joined up because

of the fee he would receive: £2,000. Last week, medical ethicists and

trial experts raised serious worries about payments of this

level. 'People should be recompensed for the time they take out of

their lives to become involved in a trial but that is a different

matter from paying inducements,' said Janet Derbyshire, of the

Medical Research Council (MRC).

This point was backed by Ray Noble, a UK medical ethicist. 'People

who are designing these trials have to make sure they do not offer so

much money that young people simply ignore the boxes about their

medical conditions in their consent forms in order to make sure they

get the thousands of pounds they need to pay off their student loans.'

Indeed, it emerged last week that Parexel - which launched the trial

on behalf of the German drug company TeGenero, the manufacturers of

TGN1412 - had breached guidelines laid down by the Association of

British Pharmaceutical Industries, the drug industry's main trade

body, over the offering of inducements. 'Neither payment, nor the

level thereof, should be mentioned in a public notice,' these state.

Yet Parexel's web site for enrolling volunteers to its TGN1412 trials

clearly states that recruits would be 'paid for your time and

inconvenience'.

These issues are serious enough. However, of all the concerns raised

by scientists last week, it was the decision by Parexel to use

healthy volunteers, not cancer patients, as guinea pigs that has

caused most unease. The issue takes us to the very heart of the

crisis that has engulfed Northwick Park and to the nature of TGN1412,

a drug known as a monoclonal antibody or mab.

Mabs were first developed in Britain by Cesar Milstein and

Köhler, who shared the 1984 Nobel Prize for Physiology for the

achievement. They are artificial versions of natural chemicals called

antibodies, proteins that are made in the body and which latch on to

the surfaces of cells. Herceptin, the breast cancer drug, is a

monoclonal antibody. It fits on to a site on a tumour cell, like a

key sliding into a lock, initiating a chemical reaction inside the

cell that causes it to stop dividing. Thus the spread of breast

cancer is halted. It is this specificity, this ability to use mabs as

tiny biological guided missiles that makes them so powerful, and

dangerous. Today, sales of antibody drugs now stand at more than

£7bn a year and there are 17 of them on the market. Most work by

stopping a cell from dividing. But one or two do the opposite. They

stimulate a cell into action. And crucially, TGN1412 is one of these.

The drug targets a site called CD28 which lies on the surfaces of

white blood cells called T-cells, key components of the body's immune

system. In effect, the drug latches on to the T-cell and initiates a

chemical reaction that should fire the body's immune system into

action. Thus it was hoped TGN1412 could be used to treat a disease

called B-cell chronic lymphatic leukaemia (B-CLL), and also auto-

immune diseases which include rheumatoid arthritis and multiple

sclerosis.

'The aim would be to kick the body's defences into a highly active

state so that they could mount a more effective attack on the

proliferating B-cells that were causing a patient's leukaemia,' said

Dr Chiswell, a monoclonal expert and former chairman of the

BioIndustry Forum.

Patients who would be the target of such drugs have weakened immune

systems. Healthy people do not. Hence the puzzle over the decision to

use fit young people for the trial. Instead of prodding weakened

bodily defences into action, TGN1412 let loose a fully armed missile,

unleashing a chain reaction in which T-cells released cytokines -

messengers that control the immune system - that in turn triggered

other T-cells into releasing more cytokines. Doctors have a name for

this deadly cascade. It is called a cytokine storm.

In the lungs, fluids and immune cells accumulate and can block off

air passageways. Blood vessels become inflamed and organs are eaten

up. The effect is often grotesque. Myfanwy Marshall said her partner,

one of the trial's volunteers, had been left looking like 'the

Elephant Man, completely puffed up,' his face and head had swollen

horribly, and were now a 'weird purple and yellow colour'.

So why employ healthy volunteers who would have been susceptible to

cytokine storms? For most experts, the decision seems questionable.

For example, both Cancer Research UK and the MRC remained very

doubtful about the decision. 'We would have been much more cautious,'

said Derbyshire, a sentiment echoed by Law. 'I doubt if we would have

given approval for the trial as it was carried out.'

Only the MHRA probe will reveal the truth, though The Observer can

reveal that when TGN1412 was in pre-clinical studies in animals in

2004, TeGenero was at that stage considering using cancer patients

for initial safety tests. Yet when they began trials last Monday,

they picked eight fit young men. Why?

One answer, put forward by a researcher involved in early work on

TGN1412, suggests the company thought toxicity data from animal

studies of TGN1412, which included experiments on rabbits and

monkeys, was so encouraging it decided to test the drug on healthy

people straightaway, in order to look at the spectrum of potential

side-effects.

Or the company may simply have encountered a problem in recruiting

cancer patients, a process that takes up more more time than any

other part of a clinical trial. Almost half of all trial delays

result from difficulties in finding volunteers, and that can equate

with a company losing millions of pounds in sales for a new drug. In

2004, 11 per cent of all newly diagnosed cancer patients agreed to

participate in some kind of drug trial. However, as more new medical

technologies come on stream, a bigger army of recruits will be needed

to join in research programmes.

Whatever the answer, the issue of financial pressures that bear down

on drug researchers from their boardrooms cannot be ignored in this

grim tale. 'The people behind this company are reputable scientists,'

said one UK immunologist last week. 'I can only think they may have

got carried away and didn't see the apparent dangers in the design of

this trial. But the first question I would have asked is this: how

are you going to avoid a cytokine storm? You know this drug is going

to trigger the T-cells into a burst of maximal activity. Is anyone

surprised by what happened?

Yesterday Dr Hanke, TeGenero's chief scientific officer,

defended the decision to use healthy volunteers. 'We had early

evidence [from animal studies] that the effect of the drug depends on

the status of the patient, so it dampens the immune response for

patients with auto-immune disease and it boosts the response for the

other group [with cancer]. We are so terribly sorry it went so wrong.

We are devastated by the tragic events that have happened.'

Certainly, the story of TGN1412 spells out many warnings for the

pharmaceutical industry and for the medical establishment. 'If

nothing else, the reaction of these patients tells us one thing -

that there are things going on at the CD28 site, the target for

TGN1412, that we do not understand,' said monoclonal expert,

Glover, a former chief medical officer for Cambridge Antibody

Technology. 'Any company who is researching on CD28 drugs today

should stop what they are doing at once until we find out more about

what is going on there.'

It is equally clear, added Glover, that in an era in which more and

more new medicines are created by biological means, that new

procedures be urgently introduced to prevent any more disasters.

TGN1412 is a humanised monoclonal antibody. In other words, it is

made up mostly of human protein. Testing it in animals is therefore a

tricky issue. 'What you need to do is understand what the issues are

that you face and think carefully about them and find creative

solutions.' Genetically engineered mice with a humanised immune

system may be part of the answer, he added. Another idea proposed by

Glover is a new super-safe technique called 'microdosing' which was

just starting to attract the attention of the pharmaceutical

industry. This involves producing a blister on a patient's arm and

exposing it to tiny amounts of the drug, rather than treating the

whole person. The blister fills with inflammatory fluid, containing

cells whose reaction to the drug can be monitored. 'This allows you

to get a handle on the effect before you expose the whole patient to

it,' added Glover.

Certainly, action will be needed to stop any repetition of the

tragedy that unfolded at Northwick Park. The sight of loved ones,

horribly disfigured, will be indelibly fixed in the minds of friends

and relatives who gathered by victims' bedsides. Nor was their

suffering helped by the behaviour of the hospital. At one point,

those watching TVs in the patients' rooms listened to a hospital

press statement which said they might die within hours. One relative,

whose son is an affected volunteer, said friends and families were

left panicking. 'One minute he [his son] was being told that in two

days he would be better. But on the outside they are saying that

there was little hope.'

Yesterday, two of the stricken volunteers had been taken off organ

support after responding to treatment and the conditions of two

others were reported to be improving. Four are now conscious and able

to talk. But two - 21-year-old , of Highbury, north London

and a 28-year-old assistant bar manager - remain in a critical

condition.

Meanwhile, Parexel's recruitment website for its drug trials

continues to urge volunteers to come forward. Yesterday it was still

displaying photographs of happy young people playing pool and chess -

while another showed a cheque for an undisclosed sum being handed

over to a lucky recipient. Guardian Unlimited © Guardian

Newspapers Limited 2006

http://www.timesonline.co.uk/article/0,,2-2112710,00.html

The Times March 31, 2006

I was treated no better than an animal, says drug victim

By on

A STUDENT whose involvement in the drugs trial disaster left him

looking like the " Elephant Man " broke his silence last night to

criticise the company behind the tests. Nav Modi, 24, said that the

company testing the TGN1412 anti-inflammatory drug at Northwick Park

Hospital, London, had treated the volunteers like " animals in cages " .

He said that the drug, developed by TeGenero, a German company, and

tested on him and five other volunteers by another company, Parexel,

caused his head to swell to twice its normal size.

The student, who hoped to earn £2,000 to buy a laptop computer from

the trial, said that when he first asked the testers for help they

gave him a paracetamol tablet. " An hour after the drug entered my

body I was suddenly gripped by pain, " he said. " I felt my head

swelling up like an elephant's. I thought my eyeballs were going to

pop out. I screamed out, `Please, doctor, help me. Help me', but he

told me to lie down then came back with a single paracetamol tablet.

It felt like a terrible nightmare. "

Mr Modi, who lives in East London, said that as the pain had become

more intense and the pressure in his head increased, nurses tried to

put an oxygen mask on him. " I started to think that these people

were killing me and that I was going to die in this terrible place, "

he told The Sun. " As the mask was put on my face I felt that I

couldn't breathe and begged the doctors, `Please, please let me out

of here. I don't want the money any more. I just want to be free'. "

Mr Modi, who was released from intensive care five days after the

trial on March 14, said that scientists had assured the volunteers

that the drug had been tested on two monkeys without ill-effects and

that they would be given only 1/500th of the dose given to the

animals.

The student, who had taken part in two previous Parexel trials at

Northwick Park Hospital, said: " We were assured we would be safe. I

trusted Parexel with my life. But now I know I would be dead if I had

been left in their care and the doctors and nurses had not been on

hand to save me. They treated us no better than the animals in cages

in their laboratories. " In total eight volunteers took part in the

tests. Two were given placebos and of the other six only one,

, 21, remains in intensive care.

After the extreme reaction nurses had sedated the six volunteers who

had taken TGN1412. Mr Modi said that when he awoke he again started

to complain about his discomfort to a nurse. " She said simply, `Mr

Modi, do you realise that you are in a situation where you are very,

very seriously ill? If you do not co-operate with us fully you may

die', " he said. " I lay there terrified, cursing myself for putting

myself in a situation where I was going to die for £2,000 I was never

going to have a chance to spend. "

The following day Mr Modi, who was in intensive care with the other

five volunteers, was allowed a visit from his girlfriend, Divya

Vegda, 22. He said that she had immediately burst into tears. " She's

told me since that — without exaggeration — my head had swelled up to

at least twice its normal size, just like the Elephant Man in the

movie, " he said.

After a course of steroid drugs to reduce the swelling Mr Modi was

the first of the six volunteers to be allowed home. Mr Modi — who

suffered diarrhoea and temporary hair loss after taking part in a

malaria drug trial for Parexel last year — said that his days as a

guinea pig were over. " I should have realised the risks and shied

away from doing drug tests for a third time. I've left hospital but

the physical effects and mental anguish are still with me. But though

I'm still suffering, I know I'm probably the most fortunate of the

men affected by the drugs. I even feel the luckiest man alive. "

TRIAL AND ERROR

Healthy volunteers accepted for clinical trials are normally between

18 and 40, weigh between 60kg (9st) and 100kg and have a body mass

index that ensures they are not overweight

The six volunteers were injected with TGN1412, an experimental drug

based on monoclonal antibodies. The antibodies sought out T cells

from the immune system and locked on to the CD28 receptor; this

triggered production of a cascade of killer T-cells, the warriors of

the immune system, in an inflammatory response. Killer T-cells

normally attack bacteria and virus-infected cells, but here they

attacked the organs of the body, causing the damage.

A week after taking the drug four of the volunteers no longer

required " organ support " ; relatives of the two more seriously ill

patients have been told they could be in a coma for up to a year

Copyright 2006 Times Newspapers Ltd.

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.