clinical-trialsPART ONE

Most people associate the name Frankenstein with the classic movie monster first made famous by Boris Karloff. Ultimately inspiring some 82 feature films, 11 made for television movies and four television series, Mary Shelly’s gothic tale created one of the most enduring images in literature. But her book “Frankenstein, or the Modern Prometheus“ was far more than a mere horror story. It was intended as a cautionary tale, warning about the dangers of technology and the temptation to lose sight of our humanity in its pursuit. Indeed, in her last revision of the book, published in 1831, Shelly wrote

“…for supremely frightful would be the effect of any human endeavour to mock the stupendous mechanism of the Creator of the world.“

It is ironic that the central character of the book Shelly wrote to convey her warning was a research physician – Dr. Victor Frankenstein – because contemporary medical research seems to have fallen victim to the same sort of tunnel vision and arrogance that caused her protagonist’s downfall. More and more, the well being of patients is being ignored by medical researchers in a mindless pursuit of power, prestige and profits. The result is, as Mary Shelly suggested, frightful. Worse, to a large degree, the excesses of medical research are being financed by the taxpayers who sometimes become its casualties.


Indeed, today there are over 4,000 federally funded research institutions in the United States. They are conducting an estimated 80,000 clinical trials with some 20 million participants! Federal funding for medical research in 2002 will total almost $23.9 billion. Next year it is slated to increase to $27.3 billion! While the outlays for research are enormous, the funding of oversight to assure that human research subjects are not endangered or abused is minimal.

Until last year, the federal Office for Human Research Protections (OHRP) had just two full-time investigators. Although its funding was been tripled this year, even with the increase, the OHRP budget is only $5 million. As a result, the agency only has about 40 employees to review all 80,000 ongoing clinical trials. The FDA, which shares some of the responsibility for overseeing clinical trials does a little better, but still only manages to make site visits to about 10% of the Institutional Review Boards (IRBs) that approve medical research projects at federally funded institutions.

Even this scant oversight, however, has turned up serious problems.

To illustrate the point, in just the first four months of 2002, the newly restructured OHRP, with its limited staff, issued no less than 60 warning letters to major medical centers and universities conducting medical research. The deficiencies identified encompassed a wide range of issues, but among the most common was the failure to assure the informed consent of the subjects – making sure they knew what they were getting into. Nor were these just mere paperwork snafus. They were often substantial omissions – for example the failure to tell subjects in one experiment that the drug they were being given could increase their risk of endometrail cancer! In another case, the agency found an institution allowing individuals with Alzheimer’s disease to sign informed consent documents for an experiment that carried significant risk without considering whether or not they were truly competent to do so.

Moreover, the institutions cited were among the most prestigious in the nation, including the Harvard School of Public Health, Yale University and the University of Pittsburgh.

The routine failure to assure that research subjects give properly informed consent is an ethical disgrace that strikes at the most fundamental responsibility in medicine: first, do no harm. Indeed, in case after case, researchers have routinely lied to human subjects about potentially life-threatening risks, concealed information of prior fatalities and withheld critical information about serious adverse effects from oversight authorities.

But that’s not all.

In a growing number of cases, researchers are arbitrarily altering their experimental protocols – the only safeguard a patient has against being harmed – without first obtaining clearance from the Institutional Review Boards that are supposed to oversee their work. Sometimes the results are fatal.

Indeed, it was just such a violation that led to the death of Jesse Gelsinger, the 18-year-old young man who died as a result of a gene therapy experiment at the University of Pennsylvania. On the day he received what turned out to be a lethal dose of the adenovirus, tests revealed that the level of certain enzymes in his bloodstream exceeded the limits set forth in the study protocol. The researchers ignored the test results and hours later he died. But, the Gelsinger case was not an isolated example.

Prior to Jesse’s death, it was believed that few people had experienced adverse effects from gene therapy research. Only 40 incidents had been reported among some 4,000 research subjects. Following the report of his death, however, a very different picture emerged. A flood of reports poured into the federal government raising the total number of adverse events from 40 to 691. Among these were at least seven fatalities. In other words, less than 6% of the adverse reactions had been reported.

It is not just gene therapy where the problem exists. Some of the worst abuses have taken place in the field of cancer research – and at some of the nation’s most prestigious institutions. Among the most egregious examples took place at Seattle’s renowned Fred Hutchinson Cancer Research Center.

In two separate experiments at Hutchinson researchers pursued worthless cancer therapies, ignoring clear evidence that they did not work, and the experiments ultimately caused the deaths of at least two dozen patients. Worse, in both cases, there were safer alternatives available that might have allowed the patients to survive. In both cases, federal funds helped to underwrite the deadly research.


Called “The Hutch,“ the Fred Hutchinson Cancer Center is among the largest recipients of federal research funds. Some $140 million a year of taxpayer dollars flow into The Hutch every year to underwrite hundreds of clinical trials. The Hutch employs some 2,300 people in its imposing brown brick buildings, but they are only the tip of the iceberg. According to one analysis, private companies valued at more than $18 billion have been formed by researchers exploiting the taxpayer-funded research they performed at The Hutch. Individual doctors have enriched themselves to the tune of $100 million through stock options, consulting and drug development deals.


The Hutch is not unique in this regard. In fact, Johns Hopkins University won a $15.6 million settlement from a former Hutch researcher claiming his company had stolen a medical technology developed there. What went unsaid was how many taxpayer dollars Hopkins had received to develop that technology.

Against this background it is not surprising that financial conflicts of interest may have played a major role in the abuses that occurred in two cancer drug experiments at The Hutch: Protocol 126 and Protocol 681.


While it is involved in many aspects of cancer research and treatment, the Hutchinson Center is particularly well known for bone marrow transplants. It performs about 450 of these highly sophisticated procedures each year. One of its founders, Dr. E. Donnell Thomas, a 1990 Nobel Laureate in Medicine participated in the world’s first bone-marrow transplant in 1956.

Risky and expensive (up to $300,000), bone-marrow transplants are often seen as the last hope for patients with leukemia. The procedure involves literally destroying the patient’s bone marrow, the blood producing cells in our bones, and then replacing it with marrow cells from a donor. If successful, the new healthy donor marrow produces normal blood cells. This outcome, however, is not guaranteed. The donor’s bone marrow must closely match that of the recipient, or the host’s body will reject the foreign tissue. In closely matched donors, however, such as siblings, the transplants are rejected only about 1% of the time.

Even with a successful transplant, though, the patient is not out of the woods. About 25% of the patients who have a successful transplant end up experiencing a relapse of their disease. Moreover, initial success is no guarantee of renewed health. About half the time, even when a bone marrow transplant does take hold, or “engraft“, the patients develop what is called “Graft Versus Host Disease,“ or GVHD. Between 20% and 30% of the patients that develop GVHD die..

Clearly, if there were some way to prevent GVHD, the prospects for transplant patients would be greatly enhanced. In 1981, three doctors at The Hutch thought they had come up with the answer. They believed that if they could kill the T-cells – the cells that fight off disease – in the donor marrow, they could avoid GVHD. The researchers claimed that the process had been successful in several studies using mice and in the only known study that used dogs. This second bit of information was important. If a procedure worked successfully in more than one animal species, the odds that it would also work in humans were greatly improved.

The only trouble was that the statement wasn’t true. In another study using dogs the treatment failed and several of the test subjects died. Although the research results from that study had not been published, they were widely known among specialists in bone marrow transplants – including Dr. Ranier Storb who was actually the resident expert on GVHD at The Hutch.

He was not, however, a member of the Human Subjects Review Committee that was considering the T-cell proposal. Other Hutch employees, who were, however, had similar concerns. Among the problems identified by the HSRC were:

  • The lack of sufficient animal testing – especially the lack of testing on higher species.
  • The intent to use relatively healthy patients – many were in remission – instead of sicker patients as test subjects.
  • The selection of subjects who were receiving marrow from siblings – the least likely individuals to get GVHD.
  • The concern that removal of T-cells from the donor marrow might actually increase the likelihood of rejection.
  • Deficiencies in the “informed consent“ document. Of particular concern was the document’s statement that in the event of rejection or graft failure a second transplant could be required. The problem with this statement was that it left an impression that a second transplant would entail minimal risk, when in fact 95% of the time second transplants were fatal.

In addition to the deficiencies identified by the HRSC, there was another factor that might have entered into their deliberations, except it was kept from them: the researchers had a financial interest in the experiment. It would employ a number of monoclonal antibodies owned by a company they had founded. They wanted federal dollars from The Hutch to underwrite the research that would make their product marketable.

The HSRC rejected the proposal, and that should have been the end of Protocol 126 – but it wasn’t.


Dr. E. Donnell Thomas, one of the Center’s founders wanted the proposal to be approved. Another HRSC was empanelled, and a revised experimental protocol with minor changes was submitted. A key change was that the ability of the antibodies to kill T-cells was reduced.

As with the initial HSRC, the reconvened panel was not told of the researchers’ financial interest in the experiment.

This time it was approved.

The first results from the experiment, however, did not match the researcher’s high hopes. The antibodies did not perform as expected and kill the marrow’s T-cells.

Worse, the patients still developed GVHD in the same proportions that they would have without the treatment..

Going back to the drawing board, the researchers postulated that if they added certain enzymes to the antibodies, they would become more lethal and kill the T-cells as intended. They took their modified proposal to the HSRC.

As had happened twice before, the HSRC was not told of the researcher’s financial interest. But there was something else as well. The panel was not told that The Hutch itself had acquired a financial stake in the antibodies being used in the experiment.

They also did not tell the new committee that the original HSRC had raised concerns that killing all of a patient’s T-cells could cause the marrow to be rejected. That is why the initial experiment had used a weakened form of the antibodies. Adding the new enzymes effectively reversed this modification. But even without this information there were concerns.

One of the committee members immediately raised a red flag. The enzymes the researchers wanted to use were associated with the emergence of new cancers. He wanted to require that the experiment be stopped if such a problem arose. He also wanted the informed consent document to include a clear statement that some adverse events had occurred using the enzyme in question.

Again the researchers were given the go-ahead, but behind the scenes the ethical issues surrounding Protocol 126 were about to come to a head.


In 1983, The Hutch, like many other institutions, reorganized its Human Subjects Review Committee as an Institutional Review Board. With this change came a new chairman, Dr. Henry Kaplan of Seattle’s Swedish Medical Center. He was appalled at what he discovered at The Hutch. Another board member, Dr. John Pesando summed up the situation for the Seattle Times. He said the IRB “found problems everywhere we looked.“

Among the most serious problems were those associated with Protocol 126. One of the Board’s greatest concerns were rumors of financial conflicts of interest, but when Kaplan tried to raise the issue with officials at The Hutch he was strongly chastised and accused of trying to impede research.

In a strongly worded reply, Kaplan pointedly stated that the IRB had only one purpose “To protect the rights of the human subjects.“

Kaplan sought help from NIH but got nowhere. It was all too clear that no one outside the IRB was interested in assuring patient safety. Every time Kaplan came up with a new suggestion to curb what was beginning to appear as an out of control experiment he was rebuffed. Sadly, clinical evidence of just how out of control Protocol 126 was would soon surface – in the form of fatalities.


In January of 1984, the first reports of deaths from graft failure (the rejection of donor marrow by the recipient’s immune system) came to the Board. This should have been the signal to end the experiment. Normally grafts among siblings like those being performed for Protocol 126 only failed 1% of the time. Ultimately, the failure rate in the experiment at the Center would be 35%! Worse, many of those who died would have had a good prognosis for survival.

For example:

Ruth Agnes Fisher, a computer programmer with a perfect match from a sibling and a relatively mild form of leukemia stood a 60% likelihood of being cured by a transplant. Her transplant failed to take and she died.

Jacqueline Couch, a New York attorney also had a good prognosis. She, too, died.

The same was true for Lourdes Caridad Llera of Tampa, Florida and Carol Sue Obermeyer of Oldenberg, Indiana.

Lawrence Haspel, a New York orthodontist, Bina Bidsaria, a housewife from India and Paul Mahler, Chairman of the Anthropology Department at CUNY’s Queens College all died following second transplant attempts when their first transplant failed to take.

Although federal rules did not require that the deaths be reported to the FDA, they did require that they be reported to the IRB – they were not. Also, state law required that they be reported to local officials. Again, they were not.


By the third year of the experiment, it was clear that there was a major problem: fully 40% of the patients were experiencing graft failure – a rate 40 times normal! Despite this fact, the researchers continued their experiment.

But there was something else as well.

Dr. Storb had been working on another treatment for GVHD and was having considerable success. He had cut the rate of acute GVHD from 54% to 33% and increased the 18-month survival rate from 55% to 80%. Most important, his patients were not experiencing graft failure. His treatment clearly gave patients a much higher chance of survival than Protocol 126. They only trouble was they were never told about Strob’s alternative.

As the graft failures mounted, the IRB demanded that the Protocol 126 researchers change their consent form to reflect the risks patients were facing – especially the risk of graft failure.

A change was made, but it hardly met the requirement.

Where the original form indicated that Protocol 126 would not damage “cells necessary for engraftment,“ the new form said that it “may damage the cells necessary for engraftment.“

The form went on to say that if that happened, a second transplant might be required. What the form did not say was that second transplants failed 95% of the time and the patients died. It still made no mention of Dr. Storb’s alternative or any alternative for that matter. It also failed to mention the financial interest of the investigators. In short, it was tailored to conceal some of the most vital information concerning the experiment.

At this point seven people had died from graft failure. The IRB laid down an ultimatum: if two more people died, the experiment would be terminated.

Within months, there had been two more deaths.

Dr. John Draheim, a U.S. Navy physician, and Seci Cay, a Turkish businessman both died as a result of graft failure. Again the experiment was suspended.

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