Human Subject: An Investigational Memoir

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20. Unwanted

“Je crois, en un mot, que la vraie méthode est celle qui contient l'esprit sans l'étouffer, et en le laissant autant que possible en face de lui-même, qui le dirige, tout en respectant son originalité créatrice et sa spontanéité scientifique qui sont les qualités les plus précieuses.”

Nearly five months after beginning my career as a human subject, I had completed one study, had been kicked out of another, and had flunked the initial screening for two others. Now that the herpes study was in its more demanding phase (taking pills three times a day instead of just once), I had little enthusiasm for seeking more research opportunities. But I decided to make one last effort to find one of those lucrative studies for healthy volunteers.

I turned again to Big U’s list of studies seeking healthy subjects. This time I read the descriptions more carefully and found that, while many required volunteers with a certain disease or trait, some of the others had a sentence like this buried in the descriptions of required ailments: “Also seeking healthy controls.” But I was demographically excluded from a lot of those studies. Sometimes the research involved a designated age group, such as older adults (like the oxycodone study) or teenagers, but many were seeking adults up to some seemingly arbitrary age. I had noticed this phenomenon before, but hadn’t thought much about it. Now it occurred to me that in a lot of ways I was at an awkward, in-between age: too old to be a desirable research subject (or employee or soldier or exotic dancer), but too young to be eligible for senior discounts and low bus fares. I guess that’s why they call it middle age.

I decided to ask a few of the study coordinators why people beyond a certain age weren’t eligible for their studies. Choosing studies semi-randomly from (limited to my local area and to those that gave an email address), I wrote to each study coordinator, stating that I wasn’t eligible for the study, but that I wondered how the maximum age had been selected. The implication of my message was that I was too old, but in reality I was ineligible for various other reasons, including not having the required disease and not being of the right gender. Most of the study coordinators or PIs wrote me back within a day or two.

One study was testing a drug for urinary tract infections. The upper age limit was 40, and the PI wrote me that the main reason was that they were recruiting mainly through the student health service. A secondary reason was the possibility of “peri/post menopausal hormonal changes.” I went back and actually read the study description; it did say “pre-menopausal women aged 18-40 years.” So why not just require pre-menopausality? This was definitely discriminatory against 40-somethings whose ovaries still had plenty of healthy eggs.

Another study was looking for people with “metabolic syndrome,” a collection of conditions, including high blood pressure and obesity, that increase one’s risk for heart disease. This study had a maximum age of 75, because, the study coordinator explained, people metabolize their food differently “after a certain age.” I was amazed to learn that reaching a particular age could have such a dramatic effect on one’s metabolism. The sudden change at age 76 conveniently eliminates the need to run expensive tests to ensure that the metabolism of each subject is of the right quality.

The third person I heard from, who was conducting a nutrition study, had probably the lamest excuse of all: “The age range we selected allows us to easily compare our findings with those of other studies in the area, conducted both here in our laboratory and others.” In other words, the first person to do this type of study chose the age range 20 to 35, and everyone else has had to use that same age range ever since. It’s the old “we’ve always done it that way” excuse. What if Rosa Parks had said, “Black people have never sat at the front of the bus before, so I’d better not”? What if Susan B. Anthony had said, “Women have never voted before, so we’d better not suggest it”? Come on, folks, let’s see a little of that pioneering Yankee spirit!

The fourth reply mentioned both metabolism and menopause as potential “confounding” influences. That was for a study of how various forms of garlic (oil, powder, etc.) interact with prescription drugs. The study was sponsored by the National Center for Complementary and Alternative Medicine (NCCAM), an NIH center that gets less respect in some quarters than its more traditional siblings. A 2003 article in Skeptical Inquirer magazine states that most of the research being funded by NCCAM “is either so implausible as to not warrant spending public monies or has already been disproved in other settings.” Therefore, the article argues, all such research done on human subjects is unethical. (Atwood, 2003)

The last response I got (two people never wrote back to me) was from a nurse working in an HIV vaccine study. He told me that their studies all had an upper limit of 45 or 50 years old, because they can get a better immune response from younger individuals. “The investigators are trying to get the best immune responses,” he wrote. Did he really mean that researchers choose the subjects who are most likely to give them good results? And isn’t it unethical not to test a treatment in someone from every age group that’s likely to get it? I didn’t ask, but when I got an unexpected reply from another nurse involved with that study, I did write back to her with my ignorant questions.

The second nurse made some good points. She explained that immune systems do decline with age, but, more importantly, immune responses become harder to detect. Since they don’t know yet what the response “will look like” (I wondered how many different colors and styles were available), it makes sense to try to find it in younger people, where it will be easier to see, before trying it on old folks like me. As for other populations, she implied that the extra ethical barriers to using prisoners and children just didn’t make it worthwhile to try to test the vaccine on them.

One study had the weirdest set of requirements I’d ever seen. It involved taking blood from subjects and then transfusing platelets back in, so it required that volunteers be at least 18 years of age and eligible for platelet donation. That made perfect sense, but then there was this: “Male subjects must weigh a minimum of 130 lbs and be at least 5’1” tall and female subjects must weigh a minimum of 150 lbs and be at least 5’5” tall.” There was no explanation as to why they were looking for smaller-than-average men and larger-than-average women, but I felt that I had bothered enough researchers with my questions, so I never found out.

Once the FDA approves a treatment, doctors are free to prescribe it to anyone for any purpose. For example, if a drug has been proven effective at relieving the symptoms of Lyme disease, a pediatrician can prescribe it for diaper rash. This kind of use is called “off-label.” Since the old and the young are usually excluded from trials, they’re the most likely to get drugs and other forms of treatment that haven’t been tested on anyone in their age group. In fact, most hospitalized children receive at least one drug that has only been tested and approved for use in adults. (Shah et al., 2007)

People 75 years and over are seriously underrepresented in clinical trials of potential antidepressants, according to a recent review. The authors recommended that at least 25 percent of the subjects in future studies be at least 75 years old. (Giron, Fastbom, & Winblad, 2005) About 10 years ago there was a similar finding for studies of drugs to treat Parkinson’s disease. That is, very few of the subjects were over 75. Excluding the elderly seems particularly ill-advised for a disease like Parkinson’s, because the chance of getting it increases with age. (Mitchell, Sullivan, & Lipsitz, 1997)

It didn’t surprise me to learn that the research community was ignoring whole segments of the population. Until recently, the treatment that women got for heart disease was based solely on studies of men with the disease, when in fact the diagnosis and treatment of heart disease is very different in women. In 1991, to make up for this embarrassing oversight, the National Institutes of Health launched a 15-year, multi-million dollar project called the Women's Health Initiative, which investigated the most common causes of death and disability in postmenopausal women: cardiovascular disease, cancer, and osteoporosis. More than 150,000 women, ages 50 to 79, participated in studies of hormone replacement, dietary modification, and the effects of calcium and vitamin D supplements.

In 1993 the FDA reversed a policy it had implemented in 1977, which required that Phase 1 and 2 drug trials exclude all women of “childbearing potential.” The policy was reconsidered after the 1978 release of the Belmont Report, with its emphasis on subject autonomy, and after women’s health advocates pressured the FDA to make the change. (I don’t know why it took so long to implement it.) The current guideline on gender inclusion requires that drugs be tested on the population for which they are ultimately intended. Instead of completely excluding women, the guideline now requires that women of childbearing potential either use a reliable form of contraception or abstain from sexual intercourse during the study. Studies of some drugs even require that a woman use two forms of contraception or abstinence.

It puzzles me that abstinence is considered to be as reliable as using two forms of contraception. After all, a study commissioned by the U.S. Congress demonstrated that abstinence-only sex education has no effect on the sexual behavior of teenagers (Stepp, 2007). Many adults are no better at controlling their impulses than the average teenager, so why trust them to remain abstinent?

Despite the revised FDA policy, women are still underrepresented in many clinical trials. For example, a 2006 review of 67 studies that tested antipsychotic medication in schizophrenics found that the median proportion of women in the studies was 33 percent, even though men and women are afflicted with schizophrenia in approximately equal numbers. (Chaves & Seeman, 2006)

There is still one group of women that regulators and researchers routinely exclude from studies: those who are pregnant. As one FDA spokeswoman put it, we accept the fact that “every pregnant woman is her own experiment.” Most women and their doctors are so afraid of drug use during pregnancy that even life-saving drugs are withheld for fear that they might harm the fetus. Some women have committed suicide after discontinuing Prozac or other antidepressants during pregnancy. The HHS regulations list ten requirements that must be met before research can be performed on pregnant women and fetuses, but the FDA has begun to allow pregnant women into a few clinical trials of drugs to treat life-threatening illnesses. (Simpson, 2001)

One of the studies I found that was seeking healthy volunteers involved nonalcoholic steatohepatitis, a fairly common condition in which otherwise healthy people develop fat and inflammation in their livers. Healthy volunteers were needed to take part in three days of study procedures. The pay was $250, which was less than the minimum demanded by professional guinea pigs but on par with most of the studies I’d seen. This was supposedly an outpatient study, but the description said that one overnight stay would be required. That could be interesting.

I sent an email to the PI. She responded that she already had enough healthy women for her study, but she might need additional controls in the future. She asked for my height and weight, because she wanted to match the controls to the patients by size. After I sent her that information, she wrote back that I was “actually much leaner “ than any of her cases would ever be. In other words, I was too thin to be of any use to her.

Rejected again. It was definitely time to retire from the human-subject business. I got more serious about job-hunting and eventually landed an interview at a company that provides an array of technological services to libraries. The pay and benefits were pathetic compared to the job I’d given up, but maybe I’d be happier there.

My ex-to-be had been dragging his feet on the divorce paperwork, but we finally agreed to meet and draw up the documents together. Our meeting was scheduled to take place immediately after my job interview.

The preparations and trepidation that preceded my day of dual reckonings took their toll on my immune system: I had that unmistakable tingling that indicates an imminent herpes outbreak. But I hadn’t really felt all that stressed, so I was a bit surprised at my body’s reaction.

Could it have been something I ate? There is some speculation, and a bit of research to back it up, about the role of two amino acids in the frequency and severity of HSV outbreaks. Lysine, which is plentiful in dairy products, fish, and meat, supposedly has an inhibitory effect on the virus, while arginine, found at high levels in many nuts, seeds, and grains, may cause more frequent and severe outbreaks. What’s most important is the ratio of one enzyme to the other in the foods you eat.

When I first learned about this alleged connection, about five years ago, I tried taking lysine supplements, and I assiduously avoided foods with a high arginine-to-lysine ratio. After a while I concluded that this nutritional therapy wasn’t very effective, but I still try to moderate my intake of nuts and seeds. For years I refused to eat hazelnuts, because they have one of the worst ratios and because I was convinced that they had been directly responsible for my suffering on at least one occasion.

My roommate had recently brought home a loaf of what he said was buckwheat bread. It came from a local organic bakery that caters to sensitive people, i.e., those who can’t or won’t tolerate wheat, gluten, yeast, nuts, meat, eggs, dairy products, or anything that isn’t organically produced. It was probably the most peculiar bread I’d ever tried to eat. “Tried” because, without gluten or yeast, there wasn’t much to hold it together; it definitely wasn’t sandwich-making material. It also tasted very odd.

The day I first consumed some of this “bread” I felt the onset of a herpes outbreak, so I began to wonder what it had in it. The bakery was closed that day, but at its Web site, I found the actual name of the product, Buckwheat Seed Bread, and a list of the ingredients. The name was ambiguously misleading: the bread had no buckwheat seeds but plenty of other seeds, including pumpkin, flax, and sunflower, all of which have high arginine-to-lysine ratios. Buckwheat flour also has a high ratio, as does quinoa flour (whatever that is), which was the second ingredient listed.

My favorite source for food-composition data is the USDA’s National Nutrient Database for Standard Reference, There are also various lists and tables online that give the arginine-to-lysine ratio of many foods, and I consulted one to refresh my memory on what to avoid. To my surprise, I saw that walnuts and hazelnuts have about the same ratio and the same arginine content. I hadn’t been avoiding walnuts and hadn’t noticed any deleterious effects after eating them. So I was still pretty skeptical of the arginine connection. Just to be safe, however, I didn’t eat any more of the buckwheat bread.

The dreaded herpes attack fizzled, and I survived both the interview and the interspousal negotiations with no obvious ill effects. Even if I didn’t get the job, the divorce settlement would allow me to live frugally for years to come—as long as I didn’t require a lot of medical care.

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