Disasterous Drug Trial_FDA New Rules Ensure More Disasters to Follow

[Guest guest]

SSRI-Research@

Tue, 28 Mar 2006 20:35:57 -0500

[sSRI-Research] Disasterous Drug Trial_FDA New Rules Ensure

More Disasters to Follow

 

 

 

 

Disasterous Drug Trial_FDA New Rules Ensure More Disasters to Follow

 

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and Accountability

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

 

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

Wright, 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 Thomas Hünig and his colleagues published a review last year

in Annals 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 Steven DiJoseph, 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 Crimeate 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 George'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

 

David 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 Thomas 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 Wright, 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. Julian Adams, 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. "

 

 

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.

 

 

 

 

 

Drug-Free School Zone? Just Say NO to Prozac for Children.