At the age of forty-one, Floyd Skloot was a healthy man — a busy writer and public policy analyst who ran competitively every chance he could get. Then, almost overnight, he found himself struggling to perform even such familiar tasks as washing dishes or finding his way around town. After months of visits to the doctor, Skloot finally received a diagnosis for his mysterious ailment: he was suffering from Chronic Fatigue Syndrome (CFS), a disease with no known cause, treatment, or cure.
In “An Unbelievable Illness” [September 1992], Skloot described how CFS has affected him. “Swollen and scarred, my brain works in strange ways now,” he wrote. “Washing a soup pot in the kitchen sink, I’ve extended the rinsing hose and pointed its nozzle down the neck of my shirt instead of into the pot, drenching and astonishing myself. I’ve put talcum powder instead of Crest on my toothbrush, ice cubes in the cupboard, and a salad in the oven to cool. . . . I break mugs, plates, and glasses so often that I no longer risk clean-up duty. I see obstacles in my path and walk into them anyway.”
His illness forced him to leave his job and quit running. He continues to write — “though incredibly slowly, for only two hours a day” — and depends on extensive notes to compensate for his enfeebled memory.
After trying various drugs and alternative treatments for more than a year, all to no avail, Skloot volunteered to be a subject in the trial of a promising new drug. “I never imagined that I’d be a medical research subject,” he wrote. “That was for other people. But it’s astonishing how quickly serious illness can rearrange your imagination.”
— Pamela Tarr Penick
Concern for the interests of the subject must always prevail over the interests of science and society.
— The Physician’s Oath of the World Medical Association
Welcome to the solarium. It’s always this warm in here, even with the blinds drawn, even with all the Oregon rain. That machine in the corner is hooked up to a blind man snoozing in the next room. It knows when he enters deep sleep and warns the nurse to jolt him awake. Every hour or so, I see him walk down the hallway, hand against the tiled wall, and turn back when he reaches those swinging double doors that separate the rest of the hospital from the clinical research center.
The elderly man to my right wearing a leather, snap-brim cap is sitting on his hand because he’s trying to hide Parkinsonian tremors. He listens distractedly to the young woman asking questions.
“Do your symptoms make you irritable?”
The man in overalls and slippers who cannot hear is watching “The Price Is Right” while he waits for his morning meal. An indwelling catheter is strapped to the crook of his elbow so his blood can be drawn as soon as he’s finished. From time to time, he looks away from the television and stares at the catheter, as though trying to measure which is worthier of attention.
I have come to hate “The Price Is Right,” which I loved above all other game shows when I was ten. My mother used to watch it with me on Monday evenings, guessing the price of a new Amana range or baby grand. She had a cousin who was a buyer for the show, so she saw herself as virtually part of the cast. But now in the solarium “The Price Is Right” drives me nuts. The beeper that signals an end to a segment of the show is identical to the alarm sounded by my infusion pump whenever there’s a blockage in the line. The alarm sounds often because these volumetric pumps are cheap: vacuums get created in the tubing, which causes the pump to stop, the alarm to sound, and sometimes blood to be sucked out of my arm into the tubing. I get very uncomfortable when my blood turns the tubing pink and bubbly as Pepto-Bismol. So despite the beige recliner and the pillow cushioning my elbow, it’s almost impossible to relax during “The Price Is Right” because I’m repeatedly convinced by the show’s beeper that air bubbles are being infused into my veins. But we can’t turn the show off; it’s the favorite of that choleric patient with Parkinson’s.
I’ve been a medical research subject for two years now. A human guinea pig. There never really was a choice. I have Chronic Fatigue Syndrome (CFS), an illness for which there is no cure or treatment, an illness so misunderstood and misnamed that it has been virtually ignored by most medical practitioners and researchers. Calling this Chronic Fatigue Syndrome is like calling Parkinson’s disease Chronic Shaking Syndrome: the name addresses the symptom not the cause of the disease.
So I was quite willing to offer myself for the study of an experimental drug as soon as I heard about it. Willing? Hell, I’d have done anything to get in.
Since his face seems as though it would never need a shave, Dr. Mark Loveless’s thick mustache looks like it must be glued on. Wearing his white lab coat and stethoscope, he calls to mind a boy playing dress-up.
I’m sure that’s something he’s had to deal with as long as he’s been in practice. Loveless was virtually a real-life Doogie Howser. Since the sixth grade, when he cataloged all infectious diseases that had caused major outbreaks throughout history, he knew he wanted to be a doctor. In junior high, when I was riveted by the Hardy Boys, he was reading Berton Roueche’s Eleven Blue Men, a book about epidemiologists.
Loveless is forty-one. Early in the day — before his office fills with the AIDS patients who comprise most of his infectious diseases practice — you’d guess he was half that. He’s gentle, almost shy in the examining room, with a milky voice and sweet smile. But as lead guitarist for the rock group Windfall, he sings a fierce “Born to Be Wild” on the bar mitzvah and wedding circuit.
When I met him in May 1989, Loveless put me at ease. He was the first physician who’d done that in the five months it took to get my strange illness diagnosed. His uncle is the brother-in-law of a lifelong friend of my ex-wife’s father back in Illinois, though we didn’t know that at the time. Hell, we were practically family. Standing close to me, looking into my eyes when he talked, he touched me on the arms and it felt neither forced nor generic. The man knew what was wrong with me and cared. I trusted him.
“We’re gonna get you well,” he said.
I believed him.
More than a year later, in July 1990, Loveless stood before two dozen sick people in a room borrowed from Oregon Health Sciences University’s pediatrics department. Next to him on the desk like a stack of test papers were clean copies of patient consent forms for participation in medical research. We were evaluating whether to sign. I was glad he’d brought extra forms; with my memory and reasoning powers ruined by brain lesions, I’d had to mark up my copies using four different colors of ink in a frantic effort to comprehend and retain what they said.
As of that summer day, Loveless was not exactly my doctor anymore and I was not his patient. He was a researcher and I was his subject. The distinction is acutely important. For a doctor, by oath the patient comes first. For a researcher, the product — a drug, a specimen, a protocol — comes first. Henceforth, I was being studied, not treated.
Loveless was answering questions about the clinical field trial of a new drug that might treat our illness. Like a lot of other CFS patients, I’d been hearing rumors about the drug for months. In an early trial, seven of ten CFS patients in Nevada had shown improved performance on treadmill exercise testing and a reduction in symptoms of brain dysfunction on neurological testing. These were only preliminary results, but researchers and clinicians were encouraged. The drug was called Ampligen, which sounded positively electric to me. It had been developed by a small company in Philadelphia, HEM Pharmaceuticals Corporation.
“What happens at the end of the study?” Loveless was asked. “Will the drug continue to be available?”
“Yes. A second study is going to be backed up on to this one, in which everybody gets the drug.”
“So it won’t just stop?”
“No, that’s unethical. We can’t do that.”
He was asked for further clarification. How long would we get the drug? Would it continue to be provided for free?
He was growing impatient. “Because it’s unethical to stop releasing an effective drug prior to marketing, the open-label phases of these tests will go on until the drug is licensed. That has always been the ethical thing to do. Now, a few companies have decided not to do that. So all I can tell you is that as researchers we’re advocating that those people who are receiving benefit from this drug should be continued on it and have it paid for by the company until it becomes licensed and available. Since I’m not part of the company, I can’t tell you that’s what’s going to happen.”
“I find that real risky,” one of the patients said. “Say I get the placebo for six months. But the study’s successful, and everybody gets the drug for another six months, and then the study’s over —”
“No, no, no. That second study’s open-ended. There is no determined end point on that.”
“So who determines when it ends?”
“It ends when the FDA approves the drug and it becomes licensed.”
“And there won’t be any charge during that time?”
“Right.” Loveless looked at his watch.
The deal seemed straightforward and worth the risks. If I were one of the 120 people accepted into the nationwide trial, I would be given either Ampligen or a placebo for six months. If the drug were proven to be effective in that time, I would be placed at once in a second phase of the study and given Ampligen until it was approved by the FDA for general distribution. It would be provided free of charge during the study. This was important because no insurance company would pay for the use of an experimental drug, and its cost was estimated at up to $4,000 a month, which was certainly beyond the means of someone living — as the patients sick enough to qualify would be — on disability or welfare payments.
In other words, I’d let them experiment on my body with this new drug, and if it worked I would get the drug for free until it was approved for distribution. That’s what the man said. Sign me up.
By signing the patient consent form, I entered into a contract. I understood that it would bind me to this clinical field trial for the duration, but I felt the benefits were worth the risks.
Five months prior to that meeting, having been sick for more than a year and trying everything available in the way of treatment, I felt like a mountaineer lost in a storm. Every way I looked seemed the same as where I’d been, and the footing was growing slick. Then there was sudden hope when I was invited to participate in the Ampligen trial.
I had read how the director of the National Institute of Allergy and Infectious Diseases, Dr. Anthony Fauci, described the goal of a randomized clinical trial: “It’s not to deliver therapy. It’s to answer a scientific question so that the drug can be available for everybody once you’ve established safety and efficacy.” Sure, guys, I get it. You’re after knowledge, not curing Floyd Skloot. But the drug’s mine after six months, right? Count me in.
I also heard that Ampligen was administered intravenously, like the solution I’d received upon collapsing after the Chicago Marathon in 1983. It was not something I could take as a pill or a shot. But I already knew I could deal with an IV. It would require a huge commitment of my time and energy to receive the drug twice a week, to go through rigorous testing procedures, to fill out paperwork. But my eyes were on the prize: get the drug, get better, get back my life.
As soon as Loveless had mentioned the Ampligen trial, I’d begun preparing myself to participate. He’d said I would not be allowed to use any other medications during the trial and suggested that I ought to begin living without them now, months before the screening and selection process began. That wasn’t much of a challenge, I’d thought, since I’d found that most drugs failed to alleviate my symptoms enough to justify the side effects, which seemed exaggerated in me, as they did in many CFS patients I knew. But one day shortly before the screening, for no apparent reason, I became violently ill — nausea, vomiting, diarrhea, intense muscle and joint pain, deep headache, fever up from my now-customary 97 to 103, cold sweats. It must have been a flu, although my overactive immune system usually spares me such illnesses. Before I fell into a frenzied sleep during the night, I apparently scribbled a bedside note: Don’t eat Vietnamese toilet paper rolls. Next morning, foremost in mind despite my condition was the thought, I can’t blow the Ampligen trial. So I took no ibuprofen, no Pepto-Bismol, no Kaopectate. I lost ten pounds in three days.
When the illness was over, I had a dream in which I was being hooked up to a machine lodged inside a refrigerator. It had a digital readout that told my story: 238.
The technician said, “That’s terrible. Don’t breathe.”
I stopped breathing and the readout went to 0. As soon as I breathed, it rocketed to 238, which the technician kept saying was terrible. It seemed that the only way for me to be all right was not to breathe.
After three months of delays and two more months of screening procedures, I was notified that I’d been chosen to participate in the Ampligen field trial on July 23, 1990. I became Patient 002. Then there were two more months of delays and baseline data collection, the process by which our individual health pictures were established prior to our being administered the drug or a placebo, so that our progress in the trial could be measured. Baseline required that we walk to the point of collapse on an exercise treadmill. We did this on three separate occasions in order to measure how long it took before collapse and how our bodies responded throughout the physical challenge. It required a lengthy neurocognitive exam, which focused on all the things I could no longer do — jigsaw puzzles, abstract reasoning, memory challenges — and a psychological exam and interview. It required a spinal tap, after which I needed emergency treatment and was immobilized by side effects for nineteen days. There were hours of extensive laboratory work that was lost and had to be redone.
I was quite willing to offer myself for the study of an experimental drug as soon as I heard about it. Willing? Hell, I’d have done anything to get in.
Finally, I received my first infusion of either Ampligen or a placebo on October 1, 1990, in the solarium at Oregon Health Sciences University. The solarium, in what used to be the maternity ward, has a clear view of Mt. Hood and the Cascades to the west. It’s where new mothers once came to nurse their babies. That day I was sitting in a recliner, holding my daughter Becka’s hand. It was eight months after I’d been invited to participate.
Quite helpfully, we were informed that Ampligen was a modified nucleotide. It’s a mismatched double-stranded RNA molecule that can cross the blood-brain barrier, which exists to protect the brain from bacteria and toxins in the bloodstream. A drug capable of both immunomodulatory and direct antiviral effects, Ampligen sounded good enough to eat. But unfortunately it could be neither eaten nor injected, which of course I knew but now began to understand.
The drug was fragile, which was both good and bad. Good because it meant that my immune system wouldn’t have time to form antibodies against Ampligen before it disappeared on its own. That meant its therapeutic properties would be maintained even at high doses. But Ampligen’s fragility was bad because it meant that time was of the essence in getting it mixed and into the body; it had a short life and there was no flexibility in the schedule. It was going to be a challenge to be where I was required to be, at the time I was required to be there, several times a week. At least I didn’t have to travel from out of town, like several other patients.
Then suppose I was getting the placebo? The word placebo is Latin for I will please, of all things. Dr. Andrew Weil, in his book Health and Healing, notes that the word, which “entered English first as a Roman Catholic Church word designating a particular vesper service, came to mean ‘flattery’ and ‘flatterer,’ then found a home in the technical vocabulary of physicians. An 1811 edition of one medical dictionary identified it as ‘an epithet given to any medicine adapted more to please than benefit the patient.’ ” As if that weren’t bad enough, Norman Cousins in Anatomy of an Illness calls the placebo “an imitation medicine” and describes its use in testing new drugs this way: “Effects achieved by the preparation being tested are measured against those that follow the administration of a ‘dummy drug’ or placebo.’’
Listen to that language: flattery, fakery, dummy drug. Anybody who responded to a placebo had to be a head case. But on the other hand, as Dr. Arthur Shapiro wrote in the American Journal of Psychotherapy, “placebos can have profound effects on organic illness, including incurable malignancies.” My own doctor had said that the placebo effect could amount to as much as a 30 percent improvement in symptoms. People respond to being cared for, even with salt water.
Oh boy. Here I am with an illness that too many people already suspect of being psychosomatic. What happens if I get better during the clinical trial and it turns out I’ve been getting the placebo? I’ll be glad to be better, but humiliated by the implications (which will probably make me sick all over again). How will I know?
This line of reasoning marks the path of placebomania that every patient in a clinical field trial must travel. You become nutso, examining every scintilla of your body’s reactions to everything. I developed a cough the other night; was that the drug working? My elbow is tender to the touch, so I’ve got to be on Ampligen. I fell asleep during the infusion; now tell me I’m not getting the drug!
Since I was the only man among the eleven participants in Portland, someone christened us Floyd and the Ampligettes, like a fifties rock group. (CFS strikes women far more frequently than men, at an estimated rate of four to one.) Every Monday and Thursday morning at ten, I and my fellow participant Lisa, a twenty-nine-year-old former world-class race walker and mother of three, studied the plastic bottles and peered at their yellow labels for clues. They were identical in every way. We studied ourselves and one another’s every twitch, every fluctuation in temperature and blood pressure. I became jealous of her symptoms as she went through painful reactions to whatever she was getting. Did her legs really itch that much or was she imagining things? Didn’t my legs itch just a little too? I began to talk with the other patients in my study, then with several from the other three trial sites across the country: Charlotte, North Carolina; Houston, Texas; and Incline Village, Nevada. The other sites had started before us. They ought to know sooner how effective Ampligen was.
By Thanksgiving I suspected, and by Christmas I was positive: I was getting the placebo. I knew this the way I’m told a woman knows she’s pregnant. At the very center of my being. Fine, Floyd, just hang in there. You’ll get the drug.
For six months, enduring twice-a-week intravenous infusions and a third day’s worth of tests, I waited for phase one to end. We had assumed that early April would be the end date. But then additional patients began to participate as well, receiving infusions three times a week, as though the trial had no real beginning and end dates and no set structure, so it was difficult to figure out when the first phase would actually conclude. We didn’t worry. HEM Pharmaceuticals had said phase one could last for up to a year, and as fall ended and winter began I was prepared to go that long, despite being sure I was getting the placebo, because I knew I’d get the drug in phase two. The veins in my arms were beginning to collapse, but there were veins elsewhere. Then things changed.
On April Fool’s Day, most of us were suddenly dismissed from the trial. Although the study was technically still in progress, and therefore the results were still “blinded,” HEM had categorized some of us as “significant responders” and others as “nonresponders.” But how did they know, if they couldn’t peek at the results? Nonresponders — which of course included those on the placebo as well as those who had been receiving Ampligen but had only just begun responding to it — were told not to come back for infusions. No one knew what standards were used to determine significant response, but only two patients in Portland continued in the study. Since everyone had been given the same dosage, regardless of body size or severity of illness, it seemed logical that people would respond at different rates. Why should they be punished for responding more slowly?
We were given no indication why the change had happened. We were given no indication of when the promised second phase would begin. Thanks, it was fun, see you around.
In the months following, confusion and anger assaulted us like another virus. We were not the kind of patients able to swing into quick action, since most of us were bedridden by the combination of our illness and the rigors of the Ampligen trial. Why had HEM changed the rules? What could we do to get them to live up to their obligations and give us the drug as they promised? Should we sue? Was their problem economic, and would legal action force them into bankruptcy? If it did, would this mean that Ampligen, which we had seen working, would not be available to the people who needed it? Was their problem greed? Was it some kink in the regulatory process of which we hadn’t been aware? What were the doctors at each site saying? What was the FDA saying? Was HEM responsible for the medical costs of treating relapses in those who’d been receiving the drug, as well as the effects of this new stress on all of us, just as they were responsible for my emergency medical costs following the spinal tap they required of me? Would they tell us what they’d learned about us from their lab work, or follow our health situations in the interim? HEM was silent.
Of the 120 patients across the country who initially qualified for the clinical field trial, ninety-two had endured through April Fool’s Day only to be dismissed from the trial. The ninety-two of us tried to decide how to respond to HEM’s behavior. We asked a national CFS action group to act as our patient advocate. We established links with successful AIDS patient advocates and with a few congressmen. Litigation was begun by eighteen patients in federal district court in Nevada seeking to force HEM to provide Ampligen as promised. Simultaneously fighting for our health, our contractual rights, and the validity of our illness experience, we had to keep focused on the goal that had brought all of us into the study in the first place: getting an effective drug approved for use against CFS.
Meanwhile, at the annual conference of the American Society for Microbiology in Chicago, HEM released the findings of its clinical field trial. They were proclaiming the trial a success: Ampligen was both safe and effective. Even the prestigious Journal of the American Medical Association carried the story.
By reading news reports and research summaries, we were confirmed in some things we already knew: Ampligen worked, it had some side effects, and those who, like me, were on the placebo got worse over time. We also learned some things we didn’t know: the chaos in our immune systems was measurable and getting progressively worse if we weren’t receiving Ampligen; we had holes in our brains that might or might not heal; and without Ampligen we were deteriorating.
According to their reports, HEM knew that “a significant number of placebo patients clinically deteriorated during the course of the clinical test,” but the company failed to follow through with the promised drug. They knew that “more than two-thirds of the patients have extremely high and abnormal levels of natural immune fighting compounds. . . . Thus, we have gotten to the root of this disorder.” Yet they denied us a drug to which we had been promised access, though their study of us had shown that “within a number of weeks these patients [who received Ampligen] get out of bed and begin to live a more normal life again.” In regard to the holes in our brains, they “do not know whether the holes will heal, but we do know that with Ampligen there is a long-term recovery of certain memory functions.” Yet they denied us the drug.
HEM applied to the FDA for approval of Ampligen for further testing. They continued giving it to some CFS patients who were not part of the clinical field trial, to some who were “significant responders,” and to a scattering of AIDS patients under a separate field trial. They denied it to the remaining members of our trial. In court, they were ordered to provide Ampligen to those who had sued, but as of now — more than two years after that April Fool’s Day — they have not complied.
Sure, the patient consents to participate, but what real choice is there? The drug, with its wisp of hope, is often the only option for those who place their faith in traditional medical practice.
How could something like this happen? Society has a need for experiments on sick patients to further biomedical science and conquer disease. As Hans Jonas for The New School for Social Research has noted, “the very destination of medical research, the conquest of disease, requires at the crucial stage trial and verification on precisely the sufferers from the disease.” But society also is obligated to protect the human dignity and civil rights of individual patients, perhaps none more so than the seriously ill. The problem is how to control human experimentation adequately without closing off the possibilities of research on human subjects.
Regulation of medical research became a major public policy issue in America in the mid-sixties. Widespread unethical practices among medical researchers were exposed in a 1966 New England Journal of Medicine article by Dr. Henry Beecher titled “Ethics and Clinical Research.” He described twenty-two examples of practices such as physicians feeding live hepatitis viruses to patients in a state institution for the mentally retarded in order to study how the disease worked, or injecting live cancer cells into uninformed elderly and senile patients so that the body’s immunological responses could be studied.
I think people now believe that human experimentation is done ethically, safely, and compassionately in this country. They believe that legal and regulatory safeguards protect those involved as subjects in medical research, that the law and the government ensure that abuses do not occur. That’s probably because medical research has not been written about from the subject’s point of view. The other side — researchers, physicians, medical ethicists, philosophers, jurists, theologians, politicians — has been heard. But the view is different from in, rather than beside, the bed. I believe that my experience as a research subject is atypical, but it happened and can happen again.
Given the current drug approval process, even the best-designed double-blind clinical trials have built-in ethical problems. An experimental treatment is given to a group of patients, though it may actually harm them; at the same time the treatment is withheld from a similar group, though it may actually help them. In the interests of medical science, patients that might have improved faster are denied that possibility by the clinical protocol. Sure, the patient consents to participate, but what real choice is there? The drug, with its wisp of hope, is often the only option for those who place their faith in traditional medical practice.
The paradox is clear: randomized trials like the one I was involved with can never be reconciled with the best treatment for the individual participant because of random selection into experimental and control groups; and yet without such trials physicians cannot know what the best treatment for that particular patient actually is.
I hear that argument all the time. It doesn’t wash. My experience suggests that in practice neither clinical field trials nor their findings are as pure as one might think. It seems both more humane and more realistic — as well as more affordable than the current multistep procedures — to enroll an adequate number of patients, give them all the experimental drug, and conduct ongoing studies using disinterested third parties to assess findings.
The system must change. It doesn’t take an ethicist, a philosopher, or a physician to see what’s wrong with the present way of approving new drugs in this country.
The Sun attempted to reach HEM Pharmaceuticals Corporation for comment, but company officials failed to return numerous calls.