PART TWO

Scientific Ambition Eclipse’s Ethics

For most Americans, the concept of medical research conjures up visions of gray-haired scientists in white lab coats selflessly searching for test tube miracles to help humankind. Implicit in this image is the belief that reverence for human life is the cornerstone of their labors and a desire to heal the mortar that binds them together. But, as is too often the case, the reality of medical research falls far short of its lofty image. Indeed, in many instances, it is characterized by greed, ambition and arrogance rather than altruism.

Last month, Protocol 126, a bone marrow transplant experiment with deadly consequences conducted at the Fred Hutchinson Cancer Center demonstrated what can happen when researchers are motivated by greed. In the end, 15 patients died, and none benefited. All were misled about the safety and effectiveness of the treatment they were to undergo. Worse, authorities who were responsible for ensuring the safety of patients failed at every level to fulfill their mandate.

But, as terrible as the consequences of Protocol 126 were, they might be dismissed as an aberration, a failure of the system to weed out one out-of-control experiment. Unfortunately, as the history of Protocol 681 demonstrates, the excesses of Protocol 126 were no aberration, they appear to have been business as usual.

PROTOCOL 681: AN ETHICAL OUTRAGE

The most basic rule physicians live by is “First do no harm” at least, it’s the most basic rule for the majority of physicians. Some of the scientists at The Hutch, however, seem to believe that the rule doesn’t apply to research. An experiment they ran, labeled Protocol 681, not only did harm, it proved fatal. While Protocol 681 was initially a clear example of taxpayer-funded research for profit, it evolved into something else. Even after the scientists initially involved abandoned the drug they were using because it might be doing more harm than good, their successors continued the research. Worse, when these researchers realized the drug they were giving patients was killing them, they increased the dose! Not only that, even as the researchers were continuing to administer the drugs to unwitting test subjects, they were working on an article that said the drugs might be doing more harm than good. It was almost as though the experiment had taken on a life of its own, continuing regardless of the clear evidence of failure or the potential danger to patients!

THE GENESIS OF A NIGHTMARE

Breast cancer is the second leading cause of cancer deaths in women with approximately 182,000 new cases diagnosed each year. Efforts to promote early detection have greatly improved survival rates with 96% of women with localized breast cancer surviving five years. These figures decline in direct proportion to the extent the cancer has spread. If it is metastasized only one in five victims reach the five-year survival mark. The high incidence of breast cancer has made it one of the “hot” areas for research funding. It is small wonder that it was attractive to The Hutch.

One problem facing breast cancer survivors is that like other cancers, breast cancer often returns. More important, when it does, it may have become resistant to chemotherapy drugs. As this occurs there are fewer and fewer treatment options available. Ultimately, some breast cancer patients are advised to undergo stem cell transplants.

Similar to bone marrow transplants, stem cell transplants involve infusing immature cells into a patient whose bone marrow has been destroyed through high-dose radiation and chemotherapy. The idea is to have new marrow grow from the stem cells. The only trouble is that the combination of high-dose radiation and massive doses of chemotherapy can destroy a patient’s organs. Doctors essentially bring the patient to the brink of death in an attempt to save them. If a way to protect the organs could be discovered, stem cell transplants might become more practical. A 34 -year old researcher at The Hutch, Dr. James Bianco thought he had come up with the solution.

In a preliminary study of 30 patients, it appeared that a drug called PTX, normally used to treat leg cramps, might protect the liver, kidney and digestive system from the effects of chemotherapy. In other words it could be used as what they call a “rescue drug” – a way to keep the treatment from killing the patient. His claims were so dramatic they were hard to believe – for example that only 3% of the patients on PTX suffered kidney damage from chemotherapy.

A second test showed the doubts to be justified. Rather than 3%, 39% of the patients taking PTX suffered kidney damage – more than were taking the placebo. But Bianco was undeterred.

WISHFUL THINKING?

Reviewing the files of the previous experiment, he saw that 10 of the patients who did not suffer kidney damage were also taking the antibiotic Cipro and the steroid prednisone. This combination, Bianco postulated was what provided the protection. How Bianco came to this conclusion is a mystery to experts on medical research. Pulling ten files at random hardly constitutes proof – it is more in the realm of wishful thinking. But the lack of real evidence didn’t seem to phase the ambitious doctor. He knew that there was enormous commercial potential in a drug that could make chemotherapy less destructive.

He set up a company, Cell Therapeutics Inc., or CTI, to research and develop a drug based on a combination of Cipro and prednisone. He and another doctor left The Hutch to pursue the research full time, but not before he had cut the Center in on the deal and recruited two of its founders for his board.

A NEW PLAYER BUT OLD PROBLEMS

At this point, Dr. William Bensinger, a researcher working on stem cell transplants became interested in PTX. Two of his four patients had died as a result of high-dose chemotherapy, and he hoped that this new “magic bullet” might be the “rescue drug” that would solve his problem. He was told that PTX didn’t seem to work, but that there was hope that in combination with Cipro and prednisone it would.

That’s all he needed to hear. He submitted a proposal to the Center’s IRB to use PTX as a “rescue drug.” There was, however, one detail he left out: the fact that PTX didn’t seem to work, and might even be harmful.

Even as Bensinger was beginning his research using PTX and Cipro, CTI, the company founded by Dr. Bianco, its initial advocate, was in the process of abandoning it.

There were a number of reasons why Bianco had thrown in the towel on the combination drug. First, the FDA had serious questions about the way it worked. Bianco and his colleagues had postulated that the two drugs interacted to change the way the body processed other drugs. Citing the fact that individual body chemistries varied, the FDA felt there was no way to guarantee it would work in the same way in everyone who took it. Secondly, the FDA was also concerned that giving Cipro to patients might cause them to develop a resistance to antibiotics – a potentially fatal problem for immuno-compromised transplant patients. Also, different companies owned the drugs, and it was unlikely that they would approve of the combination.

With all these problems, CTI decided to strike out in a different direction and create a drug that was actually the compound created when PTX and Cipro interacted in the body. With two prominent Hutch officials on the CTI board, it is difficult to believe that Bensinger was unaware of the compound’s failure. Still, he persisted. But the CTI decision to abandon their original line of research was about to create a new and ultimately deadly problem in Bensinger’s experiment.

FATAL OMISSIONS

Because many patients who have high-dose chemotherapy suffer from terrible nausea and vomiting, it was critical that the so-called “rescue drug” could be administered in an intravenous form. The only trouble was that the intravenous form of PTX was not approved by the FDA for use in the United States. While still working at the Center, Bianco had gotten special permission from the FDA to use the IV form of PTX for clinical research. When he left The Hutch to form CTI, the permission to use IV PTX went with him. Therefore, researchers at The Hutch had to obtain their IV PTX through Bianco. When CTI decided to go in a different direction, Bianco no longer had a need for the intravenous form of the drug and gave up his special rights – The Hutch no longer had access to a supply.

Bensinger could have gotten the same permission from the FDA, but chose not to do so. As a result, the IV form of PTX would not be available to his patients.

This fact, however, was never revealed to patients enrolled in Protocol 681.

Instead, the informed consent document given to prospective patients mentioned the IV version of PTX in three different places, leaving the clear impression that it was a readily available option.

There were other critical omissions in the form as well.

It did not mention that two of the four patients in the previous experiment who were given high doses of chemotherapy but not given “rescue drugs” had died.

It also said, “ Recent studies suggest that PTX (pentoxifylline) prevents kidney, lung and liver damage in patients receiving transplants.” This despite the clear knowledge that the statement was untrue!

Finally it did not mention that while the new patients were going to be given 18 milligrams of the chemotherapy drug bulsufan per kilogram of body weight, even the smaller dose of 16 milligrams per kilogram of body weight used in the previous study was found to be “too toxic.”

In other words, they were going to give new patients an even more lethal dose!

The first of these was Kathryn Hamilton.

A DEADLY WEB OF LIES CLAIMS AN INNOCENT VICTIM

The 48-year old mother had first been diagnosed with cancer fourteen years earlier. After receiving conventional treatment – surgery, radiation and chemotherapy, she believed she was out of the woods. For a decade it seemed she was right. Then, after eleven years her cancer came back. A second course of conventional treatment – more surgery, radiation and chemotherapy gave her a couple of years of respite. But then her cancer returned again, and this time conventional treatments offered no hope. All that remained was a stem cell transplant.

On January 6, 1993 Kathryn Hamilton was admitted to the Hutch. It was a logical choice for the Bellingham, Washington resident where she was director of emergency health services. Like most people in Washington State she was aware of the Center’s reputation as the leading institution in the field of bone marrow and stem cell transplants. Moreover, with a Master’s Degree in health administration she knew what questions to ask.

Of course, asking questions is of little value if the answers conceal the truth, and a number of key facts were concealed from Hamilton:

She was not told that previous participants in the experiment had died.

She was not told that the Center and the researchers had a financial interest in the drug being tested.

She was not told that one of the key “rescue drugs” would not be available in IV form.

She was not told that the same doctors running the experiment were about to publish an article saying the drugs they proposed to use on her might actually do more harm than good.

At 7 AM on January 7, 1993, Kathryn Hamilton was given the first, ultimately lethal dose of busulfan. Almost immediately she developed severe nausea. Virtually every time she took the dose of PTX that was supposed to protect her organs, she threw it up. When her family asked why the PTX wasn’t being administered in its IV form they were told that the FDA had withdrawn approval of the drug.

When questioned about why researchers at The Hutch hadn’t obtained permission to use the IV form of PTX they said it would have involved too much paperwork. Yet, the truth is that a simple phone call to the FDA could have provided that permission on an emergency basis. They just didn’t want to bother.

Nine days after being admitted to The Hutch Hamilton received her stem cell transplant.

Her condition continued to deteriorate.

Her liver was damaged and she had trouble breathing. She began to bleed from her eyes, ears and nose. Her kidneys began to fail.

On February 19, 1993 she died in agony.

Six days later, the researchers running the experiment published an article in the journal “Blood.” It said PTX didn’t work.

But that didn’t stop the research. The researchers claimed that Hamilton’s death proved nothing. It didn’t prove that the combination of PTX and Cipro would protect against damage from chemotherapy or that it wouldn’t.

Protocol 681 continued for five more years until it was finally shut down in 1998.

Ultimately four women would die of so-called “regimen-related toxicity.” In other words they were killed by the treatment that was supposed to save them. Normally regimen-related deaths are extremely rare, but in the case of Protocol 681, it claimed one in seventeen subjects.

THE HUMAN COST OF ARROGANCE

The combined death toll of Protocols 126 and 681 is 24 – two dozen needless fatalities – two dozen unwitting victims. What is most disturbing is not the fact that patients died in the course of experiments intended to develop therapies that might save them. This is an unfortunate aspect of the search for new cures. Rather, what is disturbing is that the participants were put into life-threatening situations without their full knowledge and consent – that researchers in the mindless pursuit of their goals discounted the value of human life. Even more disturbing is the fact that what happened at the Fred Hutchinson Cancer Center is not an isolated example of abuses at some of our nation’s most prestigious research institutions.

At the University of Pennsylvania, 18-year old Jesse Gelsinger died when researchers changed the rules for their experiment after failing to tell him that there had been serious reactions in several previous research subjects.

At Johns Hopkins University, a 24-year old young woman died in what was supposed to be an innocuous experiment. The doctors running the experiment had failed to adequately research the adverse effects of the drug they were testing.

In a lawsuit concerning another Johns Hopkins study which was measuring lead levels in children, a court chastised the institution for knowingly endangering their health.

At the University of Kansas research on an experimental cancer vaccine was suspended after the discovery of numerous deficiencies in the production and monitoring of vaccine purity among other things.

The prestigious Harvard School of Public Health was cited by the Office of Human Research Protections for failing to obtain proper informed consent for study participants in an experiment being run in China. Investigators questioned the fact that handwriting on all of the informed consent documents appeared identical.

The list goes on and on, but in every case there is a common theme: patients enrolled in human trials are not being told the truth.

They are not told that in 95% of phase I trials there is no medical benefit to the patient.

They are not being told of potentially life-threatening risks they face.

They are not being told of financial conflicts of interest.

They are not being told about other, safer alternatives.

As if to add insult to injury, most of these trials are being funded by the taxes paid by the very people who ultimately become their victims!

It’s important to conduct medical research. But it’s just as important to do so in an ethical and open fashion. Many people are willing to take risks if it will bring benefit to others – but they should know what the risks they are undertaking really are. To do otherwise is to fall into the same trap of arrogance that ultimately destroyed Mary Shelly’s fictional researcher in her classic book “Frankenstein,” and to create human suffering instead of alleviating it.

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