Disasterous Drug Trial_FDA New Rules Ensure More Disasters to Follow

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Disasterous Drug Trial_FDA New Rules Ensure More Disasters to Follow

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and Accountability

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FYI

Unless Congress acts to overrule the FDA, research disasters such as

occurred in London, when six healthy men were exposed to an

experimental substance that brought them close to death, are likely

to occur with increased frequency. The FDA has quietly adopted a

radical policy to boost the biotech-pharmaceutical industry.

The drug, TGN1412, a monoclonal antibody, was being developed by

TeGenero of Germany, to treat leukaemia and certain autoimmune

diseases such as rheumatoid arthritis. The clinical trial was being

conducted by the US-based, Parexel at Northwick Park Hospital in

London.

Excerpts from The New Scientist, News Inferno, and Nature below,

focus on the agony of the subjects, the science of what is known and

not known about how monoclonal antibodies work, and the ethics of

exposing healthy human beings to potentially deadly substances.

Nature reports about the new rules that FDA issued that allow

industry to expose people in ever higher risk exploratory " phase 0 "

toxicology experiments. The substances have never been tested in

living organisms, so the hazards are to be discovered in the flesh.

" The rules on testing in people will mostly benefit the large

pharmaceutical companies, by allowing 'phase zero' or 'exploratory'

trials. These are brief

trials--of seven days or less--in which human subjects are given very

low doses of experimental drugs before standard in vitro and animal

testing is

complete. "

" Phase zero studies do not examine safety or effectiveness; instead,

they gather data on the targeting, action and metabolism of a drug in

the body. The goal is

twofold: to allow drugmakers to identify and jettison failing

candidates early, and to generate data that will help them design

smarter phase I studies of

promising compounds. "

Not surprisingly, Nature reports, FDA's new rules have drawn

plaudits from drugmakers. " We are very interested in pursuing this, "

says Tim , the deputy head of

exploratory clinical development at Swiss drugmaker Novartis. " It's a

tremendous opportunity for us to rapidly explore multiple compounds "

with limited

laboratory and animal testing… "

" Pfizer has already conducted two phase zero studies, and is planning

more, according to Liam Ratcliffe, the company's global chief of

clinical research and

development. He estimates that one of the studies, conducted on eight

volunteers last September, shaved five months off the development

time of an anticoagulant.

" It's a welcome change, " he says.

This is beyond cowboy mentality – this irresponsible policy change

demonstrates the lawless, Anything Goes, mentality at the FDA.

Senator Chuck Grassley (Iowa, Republican) put it bluntly:

" The FDA is loosening the reins on drug companies, " he said. " I'm

concerned for those who will be receiving these experimental drugs. "

Highest level administrators at the FDA are unconcerned about human

lives--they are as irresponsible as reckless drivers racing to

disaster.

Contact: Vera Hassner Sharav

212-595-8974

veracare@...

1. The New Scientist reports: " One drug trial, six men, disaster… " by

Shaoni Bhattacharya Andy Coghlan, 23 March 2006:

http://www.newscientist.com/channel/health/mg18925444.100.html

" Within minutes six of [eight] were reportedly writhing in pain,

tearing at their clothes, screaming and retching. The two others

waited in terror for their turn, but they were in luck: they had been

given placebos and escaped. "

" It is unprecedented for such serious and rapid symptoms to appear in

all volunteers given a drug in a phase I trial, its first human test

for safety. All six men, reportedly suffering from multiple organ

failure, were transferred from the clinical trials unit …to the

hospital's intensive care unit. As New Scientist went to press, four

of them were conscious, three of whom no longer needed organ support.

Two were still in a critical condition. How could such a horrific

reaction have occurred? "

TGN1412 was being tested " to treat leukaemia and certain autoimmune

diseases such as rheumatoid arthritis, in which the body's immune

system turns upon its own tissue and attacks it. It was intended to

work by stimulating immune cells called T-cells to multiply in a way

that would eventually dampen down the immune system. But published

studies examined by New Scientist suggest that its action on T-cells,

far from having the intended effect, led to the violent and

uncontrolled reactions seen in the drug trial. "

" Earlier trials in animals suggested that as well as boosting total T-

cell numbers, TGN1412 was particularly effective in increasing the

number of regulatory T-cells in the body. Unlike normal T-cells, the

regulatory cells dampen down the immune response rather than

stimulate it. Changing the balance of T-cells in this way could

counter the overactive immune system associated with autoimmune

disease, the researchers thought.

Initial experiments conducted by TeGenero looked promising. Company

founder Hünig and his colleagues published a review last year

in ls of the Rheumatic Diseases (DOI: 10.1136/ard.2005.042564)

which reports that the highest dose of the drug boosted regulatory T-

cells from 5 per cent of all T-cells to 20 per cent in healthy mice

and rats. It also boosted overall T-cell numbers 20-fold. Similar

results were seen in rabbits and monkeys, the company says. Two out

of 20 monkeys had swollen lymph nodes, indicating that extra T-cells

were being produced as expected, but there was no suggestion of the

violent reaction seen in the six men.

It was this boost to T-cell numbers overall which may hint at what

went wrong in the human volunteers, according to some experts

contacted by New Scientist. "

~~~~~~~~~~~

2. News inferno reports: " As Investigators Seek Answers and Victims

of UK Drug- Trial Disaster Recover, All Clinical Testing May Suffer a

Setback " By Diph, March 27th, 2006 at:

http://www.newsinferno.com/archives/1019

" Although the drugs manufacturer and the outside testing company have

maintained that all procedures and protocols were followed and that

the occurrence was completely unexpected, the fiasco is raising

questions as to whether the drug was ready for human testing and the

accuracy of the documentation upon which the testing was approved. In

addition, the already troubled drug-testing industry has suffered a

severe setback.

While none of the victims (or the MHRA) ever imagined what would

happen, it now appears more and more likely that the manufacturer and

medical experts associated with the trial should have anticipated the

very problem that occurred since a similar drug had produced equally

horrendous adverse reactions less than a year ago. "

The catastrophic results, which are unprecedented in British drug

trials, have raised many serious medical and ethical issues. It is

already regarded as a scandal for a number of reasons.

The " first stage " or Phase I clinical trial was simply designed (as

all early trials are) to prove the safety, quality, and efficacy of a

drug. Potential side-effects are also monitored. Small groups of

healthy volunteers are used in these early tests. In the case of

TGN1412, however, even the incredibly small doses administered to the

six test subjects may have caused permanent, or even fatal, injuries

to the otherwise healthy young men involved.

After taking the drug, the men all experienced excruciating pain. At

the same time their necks reportedly swelled to several times their

normal size making them appear to be grotesquely deformed like

the " Elephant Man. "

Immediately, questions were raised as to the reason why such an

experimental drug was given to healthy young men instead of

terminally ill cancer patients who had already failed to respond to

all available treatments and medications. Using the healthy young men

as " guinea pigs " has outraged many experts in the UK. One top cancer

expert has even accused the firms involved of risking volunteers'

lives to find a cancer cure.

The unnamed expert, who has been quoted in the British press,

stated: " They were going for the holy grail of not just containing

cancer like some other drugs, but killing it. The risk was that they

could have also killed the volunteers. " He also said that

the " company developing this drug would have known that there was a

risk and that it could get out of hand because of the way it has been

developed. "

" 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.

The possibility of civil actions by the volunteers or their families

is also a possibility. "

" Questions also surround the approval of the test by British health

authorities and ethics commission. Reports coming out of the UK state

that the volunteers were told there had not been any significant

adverse effects in prior (animal) tests. Documents in the possession

of the Daily Mail appear to confirm that fact. In addition, TeGenero

had apparently claimed that there had been " no drug-related adverse

effects " during those prior animal trials.

It now appears that, during the animal trials, TGN1412 caused

monkeys' necks to swell and that this reaction was considered serious

enough by TeGenero officials to order the monitoring of the human

volunteers' immune systems in order to react immediately in the event

of any swelling. It also appears that earlier concerns had been

raised by an article in Clinical Immunology wherein medical

researchers warned of the possibility that human cells would be

adversely affected by the drug. Another possibility being considered

is that differences between a human and animal cell signaling protein

may explain the violent reactions in the volunteers. "

" Now, however, an article in DrugResearcher.com has added a new twist

to the story. According to that report, a test in 2005 of another

monoclonal antibody known as MDX-010 produced a severe toxic reaction

in 12 of 20 subjects. That drug too was designed to target immune

system protein receptors and block the CTLA4 and CD28 engagement. The

severe reactions that included enteritis, hypophysitis, and

meningitis were the subject of a study entitled " Tumor regression in

patients with metastatic renal cancer treated with a monoclonal

antibody to CTLA4 (MDX-010), " and was presented at a meeting of the

American Society of Clinical Oncology in May 2005.

Angus Dalgleish, a professor of cancer at St 's hospital

medical school, south London, told The Sunday Times: " The previous

studies which caused similar severe side effects were in patients

already suffering from cancer, but [the researchers] should have

known they would get a meltdown because this drug was hitting exactly

the same immune response pathways. "

3. http://www.nature.com/news/2006/060320/full/440406a.html

Nature March 22, 2006

Drive for drugs leads to baby clinical trials

US regulators are moving sharply to ease the early stages of drug

development,

despite safety concerns.

Meredith Wadman reports

Curiel has just spent four years and US$4 million building a

state-of-the-art plant to make molecules that could deliver gene

therapy to

patients.

Now it may never be needed. Earlier this year the US Food and Drug

Administration (FDA) announced new rules that will allow small doses

of

experimental drugs to be tested in people before full-scale clinical

trials

begin. At the same time, it loosened manufacturing requirements for

early-stage

drug candidates so Curiel will be free to make his delivery molecules

in a

cheaper and more convenient workshop.

" We built a palace, " says Curiel, director of the gene-therapy centre

at the

University of Alabama, Birmingham. " If these guidelines had been in

place five

years ago, we would have saved a lot of time and effort. "

Nonetheless, like other medical researchers, Curiel warmly welcomes

the rules,

which will let him walk down the hall to pick up a batch of vector

molecules,

instead of crossing eight blocks of the Birmingham campus. And he

won't have to

scramble for more money to run the centre: the FDA had told him that

it would

need five dedicated staff. " Who was going to pay for that? " he asks.

Not everyone is so thrilled with the change. In London last week, six

healthy

men suffered multiple organ failure after taking part in a phase I

trial of a

biological drug candidate (see page 388). In light of this, some

question

whether this is the time to ease up on controls.

Keep the balance

The London event was " absolutely horrific " , says Murray, a

bioethicist

and president of the Hastings Center in Garrison, New York. " There

will be a

profound desire not to repeat this experience, and to make sure that

the FDA

policy changes do not tip the balance too much towards speed and

risk. "

The rules are part of an FDA drive to open bottlenecks and streamline

drug

development as estimates of the cost of bringing an original drug to

market soar

above $1 billion.

" The problem is that researchers conducting very early studies were

required to

follow the same manufacturing procedures as companies that mass-

produce products

for broad-scale distribution, " explains Janet Woodcock, the FDA's

deputy

commissioner for operations.

The changes should benefit academics, she notes, by allowing them to

make small

batches of experimental drugs and do early testing in people giving

them a

better shot at snaring industrial partners to take drugs further.

It's a tremendous opportunity for us to rapidly explore many

compounds.

The manufacturing guidelines relax strict requirements for early-

stage

drugmaking. For instance, they allow more than one drug to be made at

the same

facility, and specify that production and quality control can be done

by the

same person in small operations. Until January, requirements about

everything

from ventilation to staffing levels had put drugmaking beyond the

reach of most

university researchers.

The rules on testing in people will mostly benefit the large

pharmaceutical

companies, by allowing 'phase zero' or 'exploratory' trials. These

are brief

trials--of seven days or less--in which human subjects are given very

low

doses of experimental drugs before standard in vitro and animal

testing is

complete.

Phase zero studies do not examine safety or effectiveness; instead,

they gather

data on the targeting, action and metabolism of a drug in the body.

The goal is

twofold: to allow drugmakers to identify and jettison failing

candidates early,

and to generate data that will help them design smarter phase I

studies of

promising compounds.

That has drawn plaudits from drugmakers, who are frequently forced to

use animal

data alone to choose the one drug from a panel of candidates that

will be

propelled into phase I trials.

" We are very interested in pursuing this, " says Tim , the

deputy head of

exploratory clinical development at Swiss drugmaker Novartis. " It's a

tremendous

opportunity for us to rapidly explore multiple compounds " with

limited

laboratory and animal testing, he says, adding that his company hopes

to start

several of the early trials within a year.

Pfizer has already conducted two phase zero studies, and is planning

more,

according to Liam Ratcliffe, the company's global chief of clinical

research and

development. He estimates that one of the studies, conducted on eight

volunteers

last September, shaved five months off the development time of an

anticoagulant.

" It's a welcome change, " he says.

Time or money?

The phase zero trials eat up some time before phase I can begin,

however, and

this may deter small biotechnology companies from doing them. n

, an

organic chemist and chief scientific officer at Infinity

Pharmaceuticals, a

Massachusetts developer of cancer drugs, says that he has had two

opportunities

so far to run phase zero trials. He rejected both. " It just wasn't

worth it for

us, " he says. " It saves some money up front. But it doesn't save you

time. "

At the US National Cancer Institute, however, plans are under way to

make use of

both changes to the system, says Joe Tomaszewski, deputy director of

cancer

treatment. He says that production and preclinical toxicology now

cost between

$1 million and $1.5 million for a typical cancer drug. " To get into a

phase zero

trial, you could cut that in half. So you could put twice as many

compounds in

the clinic. "

Some cancer specialists point out that, at the tiny doses

administered in phase

zero trials, there isn't going to be any benefit to trial

participants. In

healthy volunteers, this need not be an issue. But in cancer, " you're

dealing

with dying patients, " says Cy Stein, an oncologist at Albert Einstein

College of

Medicine in New York. " In phase I, at least we can tell them: 'We

really think

we've got something here'. " But in phase zero, he says, " you're

offering

nothing. I can't agree to that. Certainly not to save big pharma some

time. "

Others, including Sidney Wolfe, director of the health-research arm

of Public

Citizen, a Washington-based advocacy group, have argued that phase

zero studies

are ethically troublesome. By reducing the preclinical testing

required before

an experimental drug goes into humans, says Wolfe, the FDA " increases

the risk

to the subjects " .

Senator Chuck Grassley (Iowa, Republican) put it more bluntly in a

statement

when the regulations were released. " The FDA is loosening the reins

on drug

companies, " he said. " I'm concerned for those who will be receiving

these

experimental drugs. "

But Woodcock says the approach will protect patients. " Study in

people early in

the process is going to decrease human exposure to compounds that

ultimately

fail, " she says, " Which right now is the majority of them. "

Curiel, for his part, hopes to capitalize on the manufacturing

changes,

cannibalizing the first-class hardware and equipment of his white-

elephant

facility and moving it to a corner of his existing lab. Complying

with the old

rules was " complicated, difficult and time consuming " , he says. " The

new

guidelines will make all of this dramatically easier. "

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