Being a Co-Adventurer
Clinical trials involve risks, rights, responsibilities
by Margaret Wahl

Twenty-year-old Carlie Brinker of Millersburg, Ohio, knows what it’s like to have a chronic, disabling condition and to have to take medications that come with a panoply of side effects.

When she was 8 years old, she learned she had dermatomyositis, an inflammatory muscle disease involving weakness, pain, rashes and calcium deposits under the skin that can lead to serious infections.

Over the years, she’s taken anti-inflammatory corticosteroid drugs, such as prednisone and methylprednisolone (intravenous prednisone); methotrexate, an immune-system suppressant; intravenous immunoglobulins, which redirect the immune system; and several other medications. All of them have potentially serious side effects. Prednisone had caused significant weight gain, severe mood swings and high blood pressure.

In 2006, at the suggestion of her doctor, she entered a phase 2 trial of rituximab, a drug used to treat rheumatoid arthritis and lymphoma that blocks B cells, which are part of the immune system.

Willing to try anything

Brinker learned she would get four intravenous infusions, two of rituximab and two that would be a placebo (inactive, look-alike substance). “They said it might or it might not work for me,” she recalls.

She remembers signing papers that warned of the risk of infection and described blood tests and a muscle biopsy. She learned she would have to discontinue her intravenous methylprednisolone, her immunoglobulins and her colchicine, a drug she was taking in hopes of warding off further calcium deposits. “I was a little scared about that,” she says, recalling that she did develop more calcifications.

Discontinuing the immunoglobulins also worried her. “Since I can usually tell by the third week that it’s time to get it, I was scared about that. I was really tired and worn out.” Likewise for the IV methylprednisolone. “I didn’t have a lot of the energy that I had while I was getting it,” she says.

Despite these concerns, Brinker decided to enroll in the trial. “At that time, I was willing to try anything,” she says. “Not only for me but for the other kids, to try to give hope to us to find a cure and not have so much pain.”

In fact, Brinker says, rituximab didn’t help her, but it did help others in the trial. One boy, she says, “was in a wheelchair, and now he can walk. After only two infusions, they were able to lower his prednisone. Although it didn’t work for me, I have a couple of friends getting ready to start it, and I’m hoping it works for them.”

A ton of documents

Anyone who’s participated in or conducted a clinical trial — a test of a medication or other treatment in human volunteers — in the last several years knows that the enterprise is highly regulated.

There are papers to be signed and filed showing that patients have consented to the trial’s procedures and understand the risks; institutional review boards looking over investigators’ shoulders to make sure everything is in compliance with regulations; reports to file with the U.S. Food and Drug Administration; and data and safety monitoring committees standing ready to interrupt a trial if there are signs of danger.

“We were given tons of documents; it was like reading a book,” says Hank Santini, 54, of Bolton, Mass. Santini, who has the late-onset form of the metabolic muscle disorder Pompe disease, recently participated in a trial of Myozyme, a synthetic enzyme developed by Genzyme Corp. that had been proven effective in infantile-onset Pompe. (The results of this trial ultimately showed Myozyme to be effective in late-onset Pompe disease as well.)

“They told us about all the problems that they had with the children [in the previous trial],” says Santini. Every single mishap was detailed. It was all in black and white: These are things that have happened; these are things that could happen.”

Such thoroughness may seem excessive or even obstructive. “Any time anything happened, anywhere at any of the test sites, you were given another set of forms to read,” Santini recalls.

But the evolution of the rights of human subjects in research, like those of minorities and women, is based on historical events, many of which are tragedies.

A century of tragedies led to current regulations

At the turn of the 20th century, drug regulation in the United States was nonexistent. Anyone could brew up a batch of fermented fruit, animal urine or sugar water, claim it would cure cancer or any other disease, and sell it legally. Common sense and skepticism were the buyer’s only protection.

Then, in 1906, Congress passed the Pure Food and Drugs Act, which prohibited foods and drugs from being “misbranded” or “adulterated” if they were sold through interstate commerce.

In 1930, when the Food and Drug Administration came into being, the law required only that drugs meet standards of strength and purity, not safety or effectiveness. There was no requirement that a company submit information to the FDA before selling its wares, and the burden of proof was on the government to prove a drug’s labeling was false and misleading.

Then came the case of the poison liquid sulfa drug, elixir sulfanilamide. By 1937, sulfa drugs had shown promise in fighting infection, and they seemed reasonably safe, at least in tablet form. But the S.E. Messengill Co. of Bristol, Tenn., decided to market a sulfa drug as a liquid. Unfortunately, the substance in which the drug was dissolved (diethylene glycol) is a deadly poison, although the company didn’t know that and was under no obligation to do any testing. More than 100 people died, many of them children.

The tragedy was the trigger for the Federal Food, Drug and Cosmetic (FD&C) Act of 1938. For the first time, manufacturers were required to show the FDA that a drug was safe. However, if the agency didn’t act within a certain time period, the drug was automatically approved. Effectiveness was considered the consumer’s problem.

Meanwhile, drug testing, though required, was itself almost entirely unregulated. In the 1950s, researcher Jonas Salk was able to test the first polio vaccine at an institution for children with mental retardation before it was tried on schoolchildren in the general population.

At about the same time, doctors routinely performed crude brain surgeries called lobotomies on unsuspecting patients in state mental hospitals. And the first birth control pill was tested on uneducated women in Puerto Rico who were not told they were in a clinical trial or that there could be dangerous side effects.

Then, in the early 1960s, thousands of babies, mostly in Western Europe, were born with severe limb deformities, the cause of which was found to be a drug called thalidomide that their mothers had taken to ward off morning sickness and to help them sleep during their pregnancies.

The U.S. FDA never approved thalidomide, thanks largely to the efforts of medical officer Frances O. Kelsey, who had concerns about the drug’s safety.

But photos of thousands of children with arms and legs that resembled seal flippers and the knowledge that the tragedy had resulted from an innocuous-seeming pill given to their mothers was enough to spur Congress to pass legislation with some teeth in it.

In October 1962, the Kefauver-Harris Drug Amendments to the Federal FD&C Act of 1938 were passed. The amendments required drug developers to conduct well-controlled trials and to prove that a drug was not only safe but effective for its intended use before it could be sold.

They required that adverse events in trials be reported to the FDA and transferred regulation of prescription drug advertising to the agency from the Federal Trade Commission. The amendments asked the Secretary of Health, Education and Welfare (now Health and Human Services) to establish rules of investigation of new drugs, recommending that “informed consent” of study subjects be a requirement. That concept would be further defined, debated and amended over the next several decades.

Assessing risks through informed consent

In the 1970s, ethicist Paul Ramsey, author of The Patient As Person (first published in 1970 and revised in 2002) developed the concept that, through the process of informed consent, trial participants could be transformed from passive and potentially exploited subjects to co-adventurers with study investigators.

Today, informed consent is the principal tool through which adults participating in clinical trials are asked to weigh potential risk and benefits. (Parents provide consent for children in trials, although the FDA recommends that children as young as 7 be asked to “assent” to participation when feasible.)

The FDA, through local institutional review boards (IRBs), oversees informed consent documents and requires that prospective trial participants be told that the study involves an unproven drug or treatment; what will happen in the study and how long it will last; any possible risks, discomforts or benefits; and that they can leave the study at any time without penalty. (See “A right to know”.)

Although regulations have come a long way since doctors could test new brain surgery techniques on unsuspecting patients or administer drugs to women who didn’t know they were in a clinical trial, some observers believe there’s still room for improvement.

Is it OK to hope for benefit?

At the top of the list of concerns of ethicists, sociologists and others who study clinical trials is a concept called the “therapeutic misconception.”

Put simply, therapeutic misconception is the mistaken belief that the purpose of a clinical trial is to benefit the individual patient rather than to gather data to increase scientific knowledge.

Gail Henderson, a sociologist at the University of North Carolina at Chapel Hill who studies clinical trial participation, says she’s found that most people entering trials are in a “gray zone between thinking a trial is research and thinking it’s treatment.”

“There’s nothing wrong with hope,” Henderson says. “Hope is extremely important. It’s what keeps researchers going too.” However, she says, research subjects often have unrealistic expectations of the benefits they may derive from an experimental treatment. They may imagine that, even though most people in the trial won’t benefit from the new treatment, they themselves might have a dramatic response.

Carlie Brinker’s statement that she was “willing to try anything” would be construed by Henderson and other observers of clinical trials as meaning she expects to get better from the study medication, even though she also expressed concern for others in her predicament and clearly understood the nature of the research study.

Brinker’s perceptions place her in Henderson’s “gray zone” between believing a trial will help her and believing it’s only going to answer a scientific question.

But trial participant Hank Santini’s statements place him squarely in the “white” zone — or whatever color represents an ethicist’s idea of the clearest perception of a trial’s purpose.

Santini already was doing well on a regimen of diet and exercise when he entered the Myozyme trial. Unlike Brinker, he didn’t feel he had run out of options. He did in fact receive Myozyme, but he knew there was a chance he would get a placebo instead, which he says wouldn’t have bothered him. (He says he doesn’t think he benefited from Myozyme.)

“I figured, why not be a trail blazer?” Santini says of his reason for participating in the study.

Kenneth Getz at the Tufts Center for the Study of Drug Development in Boston also studies clinical trials, but he sees things differently from Henderson.

“I have yet to meet someone who is confused,” says Getz, who wrote The Gift of Participation (Jerian Publishing, 2007) and co-authored Informed Consent (Thomson/Centerwatch, 2002). “I think the public is smarter than that. I think the public knows that it’s in testing. They need more credit.”

Getz says there’s nothing wrong with hoping to benefit from a trial and that he doesn’t see the hopeful person as someone with a misconception but rather as “someone who acknowledges that they have to think more broadly.”

When in a desperate situation, he says, people find “hope and promise in all the fringes of medical intervention,” including clinical research.

You need to be informed about the risks, he says, but there is a chance that an experimental treatment will help people, and it shouldn’t be discounted.

The other side of the coin: responsibilities of trial participants

In Informed Consent, Getz emphasizes that prospective participants should never lie to qualify for a clinical trial; they should never disregard the study requirements once they have agreed to them; and they should not drop out of a trial on a whim or for a trivial reason.

Dishonesty about one’s health history or lifestyle, for instance, to qualify for a trial, could seriously distort trial results and endanger the health of the participant.

Similarly, failure to comply with study procedures or carrying them out dishonestly can have similar data-distorting consequences as well as safety risks.

If participants have agreed to avoid certain foods or alcohol or medications, use birth control, keep a diary of symptoms, or come to the study site at specific intervals for evaluations, they have to do so for the trial results to be meaningful.

And although, in principle, trial volunteers can leave at any time for any reason, dropping out of a trial because study site visits become slightly inconvenient or diary keeping is boring is considered a betrayal of the agreement made when the informed consent document was signed.

Neurologist Merit Cudkowicz, who has conducted several treatment trials in ALS (amyotrophic lateral sclerosis) at the MDA/ALS Center at Massachusetts General Hospital in Boston, says 99 percent of people she’s met in trials are honest and follow study procedures. However, she says, dropouts can be a problem, because they decrease the reliability of any observed differences, such as between the treatment and placebo groups, or between different drug dosage groups.

Co-adventurers

Getz believes better public education about trials will go a long way toward achieving what Paul Ramsey had in mind when he first introduced the idea that trial participants should be co-adventurers with investigators. In addition to his work at the Tufts center, Getz has founded a nonprofit organization, the Center for Information & Study on Clinical Research Participation (CISCRP.org), based in Dedham, Mass.

“Our goal is to give people information and education,” he says, and “to raise public literacy about clinical research.”

Getz views clinical research participation as “a partnership and a commitment that a patient makes with professionals.” He says prospective trial participants should become as educated as possible about a study and be very aware of their rights; but, once involved, they should “stick it out and be compliant with the protocol to the end of the study” unless they have a compelling reason not to.