While Investigators Continue to Search for Answers, Drug-Test Victim May Lose Toes and Fingers

By Steven DiJoseph

Although there have been some isolated reports that experts have an idea of what went wrong last month when a Phase I drug trial being conducted at the clinical research facility at Northwick Park Hospital in northwest London went haywire, the situation remains unsettled with respect to the investigation as well as the condition of at least one of the victims.

When eight healthy young men volunteered to enter a drug trial of an investigational medication, no one expected the disaster that was about to follow. Six of the men were given the drug (in very small doses) and two were given a placebo. All six who received the drug had violent, life threatening reactions and were rushed to the hospital’s intensive care unit (ICU).

As soon as the reactions occurred, the trial was stopped and an intense investigation was launched by British authorities. The Medicines and Healthcare products Regulatory Agency (MHRA) sealed off the testing facility, seized documents, and notified other European regulatory agencies of the problem.

The unusual circumstances surrounding the case also brought Scotland Yard into the investigation.

Everything related to the drug was to be reviewed including the compound itself; all research and development documents; the manufacturing, transport, and storage of the samples; possible contamination; and possible human error in administration.

An interim report from regulators found no contamination or improper practices but does not give an explanation as to what actually may have happened.

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 raised 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 current drug, known as TGN1412, is made by the German pharmaceutical company TeGenero AG and is designed as a cure for chronic lymphocytic leukemia as well as a treatment for rheumatoid arthritis and multiple sclerosis.

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 (1/500 the amount administered to monkeys) given 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” 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 was 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 assigned officers from its elite Specialist Crime Directorate to the case thereby raising the possibility that criminal charges may be brought. The possibility of civil actions by the volunteers or their families is almost assured.

Questions also surround the approval of the test by British health authorities and ethics commission. Reports from the UK stated 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.

TGN1412 is a monoclonal antibody designed to bind itself to specifically targeted molecules of an immune system protein known as CD28

One expert in antibody research believes that this unexpected problem should cause any trials of drugs targeting the CD28 protein to be carefully reviewed and even halted until more data is obtained that might explain what went wrong with TGN1412.

An article in DrugResearcher.com 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 sever 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.”

While health officials in the UK attempted to justify the trial by claiming there was “nothing to suggest that this product would be hazardous to man at the doses to be used in the clinical trial,” the evidence may be to the contrary.

Parexel International Corp., the American firm running the human trials for TeGenero, said in a statement: “We believe that best practices were followed and the appropriate policies and procedures were adhered to.”

“Best practices,” however, may not be the issue if it is determined that a red flag was already waiving due to the multiple similar severe toxic reactions produced by precisely the same type of monoclonal antibody.

If that is the case, and there is no reason to believe that it isn’t, there is much explaining to do with respect to the haste with which this trial was approved and the protocols used.

In addition to the immediate problems related to TGN1412, which will now probably lead to the MHRA banning any further clinical trials of the drug (TeGenaro has already stated that, “there is no further human testing of TGN1412 being pursued”), are the broader implications the disaster will have on the clinical testing industry itself.

Parexel is only one of many testing companies to which clinical trials and research are outsourced by drug manufacturers. In fact, over 30% of Phase I, II, and III trials are now outsourced under contract.

Many drugmakers may now rethink the outsourcing of clinical trials where they relinquish control over their products to independent companies.

Finally, there is the problem of recruiting subjects for clinical trials. The recent surge in the number of drugs being pulled from the market because of health concerns, and the widely-publicized law suits involving injuries and deaths allegedly linked to drugs that were believed to be safe, have made it difficult to find adequate numbers of volunteers.

This problem was discussed in a new report by the market intelligence firm Cutting Edge Information, which found recruitment to be the single most time-consuming aspect of clinical testing. Some 30% of clinical trial time is now spent on recruiting subjects and almost 50% of the delays associated with the clinical trial process are due to enrollment difficulties.

These delays have added significantly to the time needed to conclude most Phase II and III clinical trials, which translates into additional expense and lost sales revenue.

In the world of prescription drugs, even a short delay in getting a product approved and on the market can add millions of dollars to the cost of a particular medication. The disaster at Parexal’s clinical research facility this month will not help the problem.

In the case of TGN1412, one report has now stated that investigators believe the effect of the drug on humans is significantly different than it is on animals and, as a result, it is possible that the drug triggered a “cytokine storm” (massive release of inflammatory molecules) in the human subjects. This would have then caused their organs to shut down.

The ordeal appears to be far from over with respect to at least one of the victims as well.

Ryan Wilson, 20, who was critically ill for days following the trial, has told reporters that he is probably going to lose parts of his toes and fingers.

According to published photographs, Wilson’s toes and the tips of his fingers are black. He remains in St. Mark’s Hospital in London recuperating, while doctors wait to determine which parts of his fingers and toes will heal and which parts will not be saved.

There appears to be a long way to go before the reason for the catastrophe is pinpointed and the victims know the final extent of their injuries. Following that, civil lawsuits and modifications of clinical trial protocols are sure to occur.

(Sources: BBC News; Daily Mail; edinburghnews.scotsman.com/uk, Associated Press, Sunday Times (UK); DrugResearcher.com, in-PharmaTechnologist.com, newsinferno.com archives)

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