In the Name of Healing

Unwitting test subjects in clinical trials often kept in the dark

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One morning,  hospital workers began infusing a solvent also used as a gasoline additive into Laura Michalski’s abdomen.

She died within hours.

Eight years later, her family learned the truth: It had been an experiment.

(The Cleveland Plain Dealer)

December 15, 1996 (Day 1 of 4)

By KEITH C. EPSTEIN and BILL SLOAT

She was given a code name, “TE3.”To this day, the federal government won’t say who she was or what it knows about how she died.

It hasn’t even told her family.

Laura Michalski’s husband, naturally, knew her as the center of his life.

They met one night in 1938 at a 15-cent jitterbug dance. He recalls “we floated on that floor as if it was ours. I thought right then: This girl I have to marry.”

Laura and Alexander taught their five children to be proud Polish Catholics and oversaw their chores in the family’s grocery a floor below their Philadelphia apartment.

Come Christmas and Easter, she would stuff kielbasa for the store, and still manage to assemble a lavish holiday spread for her own large family.

“You could have invited the president,” Alexander would say.

At suppertime, everyone was expected at the table. No excuses allowed.

She was strict, but spiritual, too. She knitted angels, crocheted angels, collected figurines of angels.

By the time Laura Michalski checked into Philadelphia’s Hahnemann University Hospital, she was 64, the beloved grandmother of 19. Her kidney system was failing. There were gallstones, the pain intense.

“I can’t find a comfortable place in this bed,” she would say. “Sometimes, I wish to God the angel would come for me.”

One morning, “they told me she was going to have this new treatment,” said Alexander.

It was June 7, 1988. Around 10:40 a.m., the medical records show, hospital workers began infusing a solvent also used as a gasoline additive into Laura Michalski’s abdomen.

A pioneering radiologist, Dr. Steven K. Teplick, believed the solvent, methyl tertiary butyl ether, held promise as a method of dissolving gallstones. Physicians at the Mayo Clinic, and in Germany, had conducted similar experiments.

The idea was that MTBE would help patients avoid surgery. Researchers had to convince the federal Food and Drug Administration that it worked and was safe.

By midafternoon, records show that from 142 to 360 cubic centimeters of the solvent, nearly enough to fill a small coffee cup, had been infused.

Michalski’s heart speeded to between 140 and 150 beats per minute. Her blood pressure fell. Her fingernails began turning blue. After she was rushed to intensive care, her heart weakened, then gave out.

At 6:50 p.m., a few hours after the infusion ended, Laura Michalski was pronounced dead.

“When all my kids got there, I was still crying,” Alexander said. “This was my love, my friend. We’re together 47 years. I’d hoped to God for 50. . . . Then, suddenly – after it seemed like there was going to be no problem – she’s not there.”

Listed on her death certificate as contributing causes: heart arrest, aspiration of body fluids and a disease of the gallbladder known as cholangitis.

The Plain Dealer identified Laura Michalski as TE3 by matching information from an FDA file to her death certificate. The documents matched on time, place and cause of death.

“We were never told it was ^after] an experiment. We had no idea what was going on,” or what the federal government eventually learned about the clinical trial, said Michalski’s daughter, Bernadette McCloskey.

A year later, inspectors from the FDA happened to be conducting a routine audit when they found out about TE3 – as well as TE4, TE7, TE8, TE10, TE11, TE15, TE19, TE21 and TE25.

Both before and after Michalski’s death, nine of 29 patients suffered “adverse effects . . . in close proximity” to infusions.

The forms had stated “the drug will probably be effective.” Consent forms “failed to adequately address the foreseeable risks and discomforts,” the FDA found.

Teplick said he had obtained consent from every patient and did not believe that any harmful side effects were caused by MTBE.

The FDA halted further research “due to unreasonable and significant risk to human subjects.”

It was hardly the first time the government had made such a discovery.

And after the fact.

On the frontiers of medical science, for the greater good of society, well-meaning doctors sometimes employ an ounce of salesmanship for a pound of cure.

Since 1977, the FDA has conducted 4,154 inspections of researchers testing new drugs on people. More than half the researchers, 53 percent, were cited by FDA inspectors for failing to clearly disclose the experimental nature of their work, a Plain Dealer analysis shows.

The risks, alternatives or uncertainties were obscured or incompletely explained.

In 46 clinical trials, drugs were tested on people without written evidence they had consented. The records are key safeguards required by law, signed receipts showing patients agreed to roll the dice with their health.

Altogether, at least 1,000 men, women and children were participants in the 46 pharmaceutical studies questioned by the FDA. The experiments, in 23 states, were sponsored by federal agencies and drug companies.

The analysis of the FDA files is strikingly similar to what a White House advisory committee discovered in 1995 when it examined patient-consent documents from more than 100 ongoing government research projects. The experiments, or clinical trials as they are more commonly known in scientific circles, are research studies designed to evaluate the safety and effectiveness of new treatments.

“Some consent forms currently in use are flawed in morally significant respects, not merely because they are difficult to read but because they are uninformative or even misleading,” the Advisory Committee on Human Radiation Experiments concluded.

Asked about the FDA’s inspection reports, Mary Pendergast, the agency’s associate commissioner, said she considered them “representative of biomedical clinical research as a whole.”

Many experiments do occur with appropriate safeguards. The fact that nearly half of all inspected research is conducted without deficiencies in informed consent suggests that following proper procedures is hardly impossible.

Ruth Macklin, bioethics professor at Albert Einstein College of Medicine in New York, said even complex human research could be conducted in an ethically responsible manner. The challenge is to determine needed changes to ensure that clinical trials are “in accord with the highest standards,” she added.

Each year, government and industry spend at least $20 billion financing research on hundreds of thousands of human beings, yet the government discloses surprisingly little about those people, the risks they face, the injuries they endure or the benefits to them.

“Most people don’t understand they’re in clinical research. They think it’s therapy,” said Case Western Reserve University bioethicist Thomas Murray, appointed this year to a new National Bioethics Advisory Commission.

How many experiments are there? How many people take part? At best, the experts can hazard little more than wild guesses.

Asked how many clinical trials take place, senior FDA official Paul Goebel Jr. replied with an ancient riddle. It has no answer. “How many angels can dance on the head of a pin?”

What the government lacks in hard data about humans, it more than makes up for with volumes of statistics about laboratory animals. Wonder how many guinea pigs were used in U.S. research? The Agriculture Department knows: 333,379. How many hamsters in Ohio? 2,782.

“There are more inspections for laboratory animals carried out by the Department of Agriculture than there are for human subjects carried out by the entire Department of Health and Human Services,” observed Charles McCarthy, a consultant on the use of laboratory animals and until 1992 director of a federal office meant to safeguard people in government research.

His successor, Gary B. Ellis, a University Heights native, is the first to acknowledge the government is more aggressive about protecting laboratory animals than humans. “Research subjects are real people, our fellow Americans. But in 1996, we do not have the tools necessary to ensure that they – and all human subjects – are protected.”

Only this month, the FDA for the first time required consent forms to be dated “in response to problems . . . verifying that informed consent was obtained” before clinical trials started.

Just one of the clinical trials in the FDA files, obtained under the Freedom of Information Act, involved at least 500 adults and children at a Miami Beach hospital who were injected with a radioactive dye without their permission.

Researchers acknowledged to the FDA they didn’t think consent was necessary.

The FDA’s Pendergast said it was a “company-to-researcher miscommunication. We got strong assurances and “mea culpas’ from the researchers that they recognized the problem and that they wouldn’t do it again.”

The experiment took place at Mt. Sinai Medical Center between 1980 and 1982.

The investigational drug, known as pipida, was mixed with a radioactive tracer and injected.

Dr. William M. Smoak, who worked on the team studying pipida, said he knows of no one harmed by the drug.

Earlier tests “convinced us it was a safe material, and then we were just doing tests adding volume [numbers of patients], looking for more unusual side effects. What are you supposed to tell people about hazards if you don’t know any for sure?” Smoak said.

“Juveniles as young as 15 years of age received injections and there was no informed consent,” an FDA supervisor, Melvin Zymash, noted in an internal report.

As for the men, women and children who received the injections – the FDA abandoned efforts to identify them when it closed the case in 1983.

By then, the era that allowed the use of unwitting patients for the sake of science and the greater good was supposed to be history.

What happened in Tuskegee, Ala., is still the most widely talked about medical experiment of our time. The U.S. Public Health Service wanted to find out what happened to men with syphilis. So, starting in 1932, the government diagnosed more than 400 black men with the disease but didn’t tell them.

It just observed them.

While distinguished scientists collected data, at least 28 men died.

When the world learned about Tuskegee in 1972, the outrage triggered new rules. Explicit informed consent was required. Ethics committees had to weigh predictable risks against anticipated benefits.

Today, every human subject is supposed to understand hazards, uncertainties and – even if chances of physical harm are remote – be able to say no.

As Yale University Professor Jay Katz, who served on the advisory committee that examined the Tuskegee experiment 22 years ago, puts it: “Research is a voyage into the unknown.”

Last month, for the first time, the FDA relaxed the nation’s informed consent rules. In an emergency, medical researchers can administer experimental drugs without a patient’s permission. The patient must be insensible, relatives unavailable and the condition life-threatening.

It was a sea-change in policy and eroded the first principle of an ethics code enacted by The American Medical Association on Dec. 11, 1946: “The voluntary consent of the person on whom the experiment is to be performed must be obtained.” The code of ethics was developed for prosecutors at the Nuremberg medical trial in Germany at the end of World War II. It evolved into a system of rules, laws and international standards governing informed consent.

Before a drug can be tested on people, it must be tested on animals. If the animal studies go well, the sponsor, usually a drug company or government agency, asks the FDA for permission to begin a clinical trial of the “investigational new drug.”

The experiment, normally in three phases, each involving a larger number of people, is intended to answer: What happens to the body? What is the best dose? What side effects surface? How does the drug compare to those already approved?

Only one in five investigational drugs makes it to market.

Thus, test subjects are critical to medical advances.

That pressure to recruit, says CWRU’s Murray, may tempt some researchers to camouflage risks and uncertainties.

Mary Poppins would have called it a spoonful of sugar.

In 1992, nearly 16,000 women across the United States and Canada were being asked to take part in a test of a synthetic hormone called tamoxifen. The National Cancer Institute wanted to learn if the drug could prevent breast cancer in healthy women.

A variety of consent forms were prepared. Some stated the pill had been approved by the FDA; it was, but only as a follow-up therapy for women already diagnosed with breast cancer.

Some consent forms said nothing about lab mice on tamoxifen developing liver cancer.

The FDA’s Goebel found another problem: It wasn’t clear in every consent form that the drug was being tested for safety.

“The toxicities are minimized and the positive benefits emphasized, resulting in undue influence being placed on women to enter the trial,” an internal memo said. “Use of the word “therapy’ to describe this study is inappropriate, as it implies treatment of a disease rather than the conduct of well-controlled research.”

Contemporary experiments on people for the pharmaceutical industry are more shrouded in secrecy than the radiation studies of the Cold War.

The existence of a clinical trial involving an investigational drug, and the identity of the sponsor, “is confidential, commercial information,” said Pendergast.

The names of errant researchers, too, are closely held. They rarely face severe consequences.

Neglecting to fully inform test subjects. Failing to disclose deaths or injuries. Failing to get permission from ethics committees of their peers. Faking data. In each instance, written criticism and a letter usually satisfies the FDA.

Those who face the harshest penalty, having their names added to a list of 82 researchers barred from obtaining investigational new drugs, need have little fear of being found out by peers or patients.

Names of “Disqualified Investigators” – the FDA’s “blacklist” – are distributed only among an inner circle of agency bureaucrats.

As Bernadette McCloskey studied the 47-page FDA file on the Philadelphia experiment, provided to her by The Plain Dealer for the first time last summer, she turned the pages slowly.

Whatever emotions she felt, she tried to keep to herself. Only for the briefest moment did her forehead wrinkle, chin quiver, eyes water.

She fought for composure, laboring to absorb this new picture of her mother’s last hours.

“We had no idea,” McCloskey said. “No one has ever told us anything. It’s certainly upsetting to find out there’s something we weren’t told.”

Six years after her mother was buried in Philadelphia’s Holy Redeemer Cemetery, the agency “disqualified” Teplick from conducting clinical trials with investigational new drugs.

FDA Commissioner David A. Kessler signed the formal notice. “You have repeatedly and deliberately failed to comply with the regulatory requirements regarding investigational new drugs,” Kessler wrote. Besides “failing to document informed consent,” he noted, Teplick had not reported adverse effects “probably caused by” the investigational drug.

Teplick, now on the faculty of the University of South Alabama in Mobile, said he never saw Kessler’s order, nor had the opportunity to challenge it. Every patient consented, he said, and MTBE caused no harmful effects.

McCloskey, the administratrix of her mother’s estate, has hired a lawyer, whoin September filed a malpractice lawsuit in the Court of Common Pleas in Philadelphia County against the hospital and the doctor. In a preliminary ruling Dec. 6, a judge dismissed the portion of the lawsuit dealing with informed consent, on grounds that under Pennsylvania law “a claim for lack of informed consent only applies to surgical procedures. The administration of a therapeutic drug is not a surgical procedure.”

Alabama granted him a medical license in 1994 as a “distinguished professor,” after peers from around the country wrote letters of praise. “Conscientious, honest and thoughtful physician,” one Wisconsin professor wrote. “Well-respected.”

“It’s amazing that the FDA, with all the expertise at its fingertips, can’t tell the state what it finds out about a researcher,” said John M. Goldberg, a lawyer with the Illinois Department of Professional Regulation. He learned of FDA action against a doctor while Illinois prepared its license revocation case against her.

The Illinois doctor, Chavonee Aroonsakul, had been reprimanded by Kessler for “repeatedly and deliberately” failing to comply with the regulations. “You failed to obtain informed consent,” Kessler stated when he placed her on the “blacklist” in 1991.

She said the charges were “false and unfounded” and that she always got consent from her patients. She says her only goal was to help people – administer her patented treatment for Alzheimer’s disease – and that the government had conspired to stop her.

“The FDA didn’t want to tell us anything,” said Goldberg. “Who are they trying to protect? The doctor? Some drug company? The system is nuts.”

——

Other stories in this series:

“They Used Our Kids as Guinea Pigs.” An investigation of medical research records shows the U.S. government is still in the business of conducting and paying for clinical trials on unsuspecting Americans.

Foreign Tests Don’t Meet U.S. Criteria The cycle of hype, hope and heartbreak surrounding clinical trials has become a chronic condition in the global pharmaceutical industry, which now initially tests two-thirds of all products for Americans overseas. The experiments often involve fraud, concealed side effects, improvised experiments and human rights abuses.

Research Standards Overseas Vary Greatly With human lives and huge investments at stake, the global pharmaceutical industry increasingly relies on research from outside the United States, where fraud and the use of unwitting test subjects is commonplace. “It’s our little secret…frightening,” acknowledges an overseer of experiments on four continents.

Overseers Operate in the Dark Institutional Review Boards, which oversee clinical trials, were supposed to wrest the monopoly on decision-making from the scientific establishment, placing it in the hands of a group that could balance the interests of medicine, human beings and the community. Average time spent reviewing each clinical trial? Two minutes.

Secrecy in Tests Led to Trouble Doctors confront a dilemma when they experiment on people: Are they healers or scientists? Should they give a patient the best treatment possible? Or do they use their patients as a means to discover better treatment for others?

Other stories in a subsequent series that took a still closer look at medical experimentation around the world:

Living Proof: U.S.-Run Study Gave Ugandans Dummy Pills Instead of Treatment American researchers let tuberculosis worsen, unchecked by an effective drug, in a control group of 500 Ugandans with HIV, as they charted its deadly progression. Some thought “placebo” was a medication that would help them. In the U.S, the practice would have been unethical.

U.S. Medical Researchers Flout Rules Around World On nearly every continent, the U.S. government and its clinical trials partners have hidden risks and undertaken medical experiments without legally required  agreements to avoid human rights abuses.