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
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 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 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.”
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
March 22, 2006
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
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
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
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
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
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
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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