Human Subject: An Investigational Memoir

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3. The Pharma Team

“Je pense qu'il n'y a pour l'esprit qu'une seule manière de raisonner, comme il n'y a pour le corps qu'une seule manière de marcher.”

After spending two days at the CRC, I was fascinated by the whole research-industrial complex. And because I was unemployed and soon to be uninsured, I was ready to dedicate myself to helping with the quest for cures—as long as I could be rewarded with free drugs.

There were three prescription medications that I eventually hoped to get refilled or, perhaps, replaced with something equally effective:

There was no question about which drug had the highest priority. I figured that my bones and mammary glands could survive for a while without intervention, and the acyclovir would be inconvenient to forgo but not life-threatening. Only the thought of losing the anti-anxiety drug caused me any anxiety.

Paxil, a selective serotonin reuptake inhibitor (SSRI), is prescribed for a number of psychiatric conditions, but most often for depression. It was approved for panic disorder about the time that I first had what I later self-diagnosed as a panic attack: nausea, intense anxiety, difficulty breathing. The ER staff thought I was just a malingering troublemaker, but I later came across some information about panic attacks and became convinced that I had experienced one. After I had a second one a few months later, I got a referral to a psychiatric nurse practitioner, who prescribed 10 mg per day of Paxil. That was enough to stave off the “panic” (health professionals convinced me later that it was “only” severe anxiety), but the nurse gradually increased my dose to 40 mg to treat the concomitant depression.

Paxil has a number of unwelcome side effects. The worst ones for me were lethargy, weight gain, and loss of interest in sex. Even after cutting back to 20 mg, then 15, I still had little energy, too much excess fat, and no libido. Finally, about a year before beginning my career as a guinea pig, I had reduced the daily dose to 10 mg, the original amount that had curtailed my panicky tendencies. At this dose I was able to function, but I had many of the symptoms of major depressive disorder, including apathy, hopelessness, and suicidal thoughts. I had been thinking for quite some time that I should try one of the newer drugs that supposedly had a lower incidence of the side effects I found intolerable.

I searched at for studies on depression in the metropolitan area where I was living. The most intriguing study was a Phase III trial of agomelatine, a relatively new antidepressant that appealed to me because of its alleged lack of side effects.

Agomelatine wasn’t approved for human consumption yet, but I saw that it had yielded good results in the “forced swimming test” (FST) in mice. This test consists of injecting mice or rats with an antidepressant and then observing their behavior when placed in a cylinder of water from which they cannot escape. Antidepressants shorten the duration of the animal’s periods of immobility, i.e., the times when it isn’t actively swimming (it still moves enough to keep from drowning). Here are a few of the factors that can affect a mouse’s immobility time (Petit-Demouliere, Chenu, & Bourin, 2005):

My first thought on reading about the FST was that depression must be the natural state for all mice and rats. They aren’t screened first for depressive tendencies, but all are expected to exhibit the symptom of becoming virtually immobile when overwhelmed by stress. Then I remembered Peter Kramer’s suggestion that even people who aren’t depressed can benefit from the personality changes produced by antidepressants. (Kramer, 1993) And if anyone leads a stressful life, it’s the creature who gave us the term “rat race.”

Human clinical trials are traditionally divided into four phases: In Phase I, the experimental treatment is usually tested on healthy volunteers to assess its safety. Phase II tests the efficacy of the treatment by giving it to dozens or hundreds of patients, usually in a randomized, controlled trial. In Phase III, the treatment is tested in a much larger group, often comparing it to another known treatment, to confirm its efficacy and gather data on side effects (which the researchers and drug companies call “adverse events” or AEs). Finally there’s Phase IV, which occurs after the treatment has been approved; it usually combines the gathering of data on patient progress with marketing the drug to doctors.

Sometimes phases are linked together, as in a Phase II/III trial or a Phase III/IV trial. The trend these days is to include the sick people from the very beginning, even in Phase I trials, rather than relying solely on healthy volunteers. As a result, that income source could soon be drying up for rent-a-pigs like Robert Helms.

I called the company that was conducting the agomelatine study and made an appointment for the following week. The company, which I’ll call PsychoPharm, seemed to be hurting for subjects: The receptionist told me they pretty much had slots open whenever I wanted, and she called me on a Sunday afternoon to remind me of my appointment the next day.

The Food and Drug Administration has not adopted the Common Rule to govern the conduct of clinical trials. Instead it has its own set of rules for protecting human subjects, CFR Title 21, Parts 50 and 56. Researchers must follow those rules if the treatment they’re testing is being submitted for FDA approval. Unlike the Common Rule, the FDA regulations apply to all research, regardless of the source of funding. There are some other differences between the two sets of regulations. For example, Part 54 of Title 21 contains rules for disclosure of financial conflicts of interest; the Common Rule doesn’t address this issue. Generally the two sets of rules are pretty much the same, but there are enough differences to have prompted calls for the two sets of rules to be “harmonized.” (Williams, 2005)

The FDA doesn’t actually approve or oversee clinical trials. That’s left up to IRBs (if you’re thinking, “IR whats?” then you skipped chapter 2; you may want to go back and read it now), whose job it is to review the qualifications of those who conduct the trials.

Most research companies contract with independent, commercial IRBs to approve their protocols and provide oversight of their studies. PsychoPharm uses a local commercial IRB, which I’ll call ProtoCorp. While InvestiGuard uses its Web site to recruit IRB members, ProtoCorp relies mainly on word of mouth. When the company was first founded, it recruited members from the local Rotary club; apparently those Rotarians told their friends how much fun it was to review research (they especially liked the free lunches and free parking), so the IRB rarely had to do any recruiting. Incidentally, since 2005, InvestiGuard has contracted with ProtoCorp for the review and oversight of most of its industry-sponsored clinical trials.

Perhaps commercial IRBs have less trouble recruiting because they pay members more for attending meetings. In 2003, ProtoCorp was paying medical doctors $300 per meeting, while other scientists and nonscientists received $250. InvestiGuard never used to offer monetary rewards to members, but I think they may have started doing that. (Aungst, Haas, Ommaya, & Green, 2003) One thing I know for sure is that most IRBs charge a fee to review industry-sponsored research, whether it’s conducted at a private research firm or in an institutional setting. These fees can range from several hundred to several thousand dollars per study.

Apparently the sponsor of pharmaceutical research, not just the IRB, is expected to review the invesigators’ credentials. When a New York Times investigation in Minnesota revealed that drug makers were hiring doctors who had been disciplined or suspended, the reporters put all the blame on the drug makers, who said it was up to the doctors to report to them any disciplinary actions. The IRB seemed to be off the hook.

According to the article, an FDA audit of some studies led by one doctor (prior to his employment by a pharmaceutical firm) found that he had violated the protocol of every single study. “He routinely oversaw four to eight drug trials simultaneously, often moved patients from one study to another, sometimes gave experimental medicines to patients at their first consultation, and once hospitalized a patient for the sole purpose of enrolling him in a study, the F.D.A. found.” Most of the disciplined or suspended doctors were being paid to give marketing lectures rather than conduct clinical trials, but an FDA spokesperson acknowledged that the system needs to be reformed. (Harris & Roberts, 2007)

The unethical doctors who went on to conduct clinical trials may have been subscribers to Physician Executive, a journal published by the American College of Physician Executives. An article in 2002 explained the fundamentals of becoming an investigator. While the text of the article only hinted that conducting research could “enhance diminished revenue streams,” the title was obviously designed to appeal to the reader’s acquisitive side: “Research provides golden opportunity for physicians: An overview of clinical trials and how to conduct them” (Nylen, 2002).

In 2005 the journal published another article aimed at physicians who were “looking for a change of pace from clinical practice.” The author, who gave up his medical practice to conduct clinical research full time, writes that there is a serious shortage of “good clinical investigators who can meet enrollment goals and produce reliable data.” (This was news to me, as I thought it was a shortage of eligible subjects that was the problem.) Instead of financial rewards, this article touts “the intellectual stimulation and satisfaction of advancing the field of medicine.” Unlike the earlier article, it doesn’t even hint at enhancing revenue streams, perhaps so as not to encourage those unethical doctors I had just been reading about. (Tonkens, 2005)

Revenue streams were definitely a key consideration at PsychoPharm, but the first psychiatrist I met there seemed the antithesis of the greedy, unscrupulous “physician executive.” A pleasant and somewhat befuddled-seeming woman with a soft Southern lilt to her voice, Dr C ushered me into one of several small and sparsely furnished offices that didn’t seem to belong to anyone in particular. She explained that we would go over my symptoms and medical history and then see if there was a study that I would be suited for. The interview went well, except for one moment when Dr. C accused me of lying.

“What do you do for a living?” she asked.

“I used to work as a librarian.”

“Oh, I just wondered because of the way you rattled off the symptoms of depression. It seemed like maybe you'd worked with the condition.”

“No, but I've lived with it for 40 years,” I said, “so I’m pretty familiar with the symptoms.”

After I'd dispelled her skepticism, there was only one potential glitch: I made the mistake of telling her that I would be participating in another drug study at the same time. Apparently (and sensibly—I don't know why this hadn't occurred to me) drug makers would prefer that study subjects not mix the experimental drug with another pharmaceutical substance, especially if the other medication is also experimental.

Because PsychoPharm was desperate for depressives, Dr. C said she would check with the manufacturers of the drugs they were testing to see if the simultaneous use of another experimental drug would be OK. She called me the next day to say that at least one of the companies was perfectly fine with it, so I made an appointment to return for a screening visit in two days.

Since the mid-20th century, the use of placebos has been an accepted feature of clinical trials. In the last few years, however, members of the medical profession have been attempting, indirectly at least, to put the placebo manufacturers out of business. At its 2000 meeting, the World Medical Association adopted a new policy on the use of placebos, adding this paragraph to the Helsinki Declaration (World Medical Association, 2004):

C29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.

The main impetus for the change was the discovery that placebo-controlled trials were being conducted on HIV-positive pregnant women in Africa, even after a treatment (administration of AZT) had been definitively shown to prevent transmission of HIV from mother to child. (Lurie & Wolfe, 1997)

A footnote added later—due at least in part to pressure from the pharmaceutical industry, FDA, and other groups—waters the guideline down quite a bit:

However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:

—Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or

—Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.

There were definitely established methods for treating depression, but in both of the studies for which I might be eligible there was at least a 25 percent chance that I would be getting a placebo rather than a drug. One of the studies had four “arms” to which subjects would be randomly assigned: Two groups would get differing doses of the study medication, a third group would get an alternative drug that was a proven treatment for depression, and the fourth group would get a placebo. Even though only one-fourth of the subjects were getting a placebo, it seemed both unnecessary and unethical to have a placebo control group at all. The people at Wyeth must have had a “compelling and scientifically sound” reason to do so, since they had gotten their protocol past an IRB.

A 2002 review of 75 antidepressant trials discovered that, on average, about 30 percent of patients who got only a placebo showed improvement in their condition, while only 50 percent of those receiving medication improved. Both proportions show a strong positive correlation with the year of publication. That is, studies published in recent years report a higher rate of improvement for both the placebo and medication groups, with the correlation being especially strong for placebo. The authors conclude that the inclusion of placebo groups has “major scientific importance in trials of new antidepressant medications.” (Walsh, Seidman, Sysko, & Gould, 2002)

The generally accepted view of clinical trials that compare one treatment with another is that the study should be in “equipoise,” which means that the investigator must have no reason to believe that one treatment is better than the other. As soon as the investigator knows that one treatment works better, all the people in the study should be given that treatment. There’s a lot of disagreement about just how to apply the concept of equipoise, or even how to define it, and the debate gets downright rancorous in the case of placebo studies. Some researchers claim that placebo-controlled trials are never in equipoise, but Robert Veatch argues that the subject’s evaluation of the options available, rather than the doctor’s view, is the only appropriate measure. As long as the subject has adequate information to make a decision, Veatch writes, equipoise is irrelevant. (Veatch, 2007)

Was I willing to risk getting no drug at all, or getting one at an insufficient dose? Would knowing that I was contributing to “generalizable knowledge”—and that I might have an experience worth writing about—be sufficiently rewarding to compensate for the possibility that I would remain a suffering and insufferable freak? In other words, just how far was I willing to go in the pursuit of my own and somebody else's research goals? Should I instead find a doctor who would prescribe me a known drug in a known quantity?

I postponed thinking up answers to any of those questions, because one of my depression symptoms is an inability to make decisions. Research ethicists recognize the paradox of expecting someone who is “decisionally impaired” to give informed consent. Major depression is just one of the conditions that can result in impairment. Others include Alzheimer's disease and schizophrenia.

In 1998 the National Bioethics Advisory Committee, a group appointed by President Clinton, recommended that the federal regulations be amended to include special protections for people whose decision-making ability may be impaired by mental illness. The NBAC recommended that IRBs reviewing research that involves such subjects should have at least two members who are familiar with the disorders of the study population. (Shamoo & Khin-Maung-Gyi, 2002)

As far as I can tell, these recommendations were never implemented, perhaps because some people in the mental-health field object to imposing more restrictions. As one researcher put it: “The focus of the NBAC report is that the inability of such persons to provide full informed consent may leave them vulnerable to exploitation. The greater problem is that too little research is conducted on their behalf.” (Michels, 1999)

Unable to make a decision, I put my future in the hands of the PsychoPharm staff and whatever forces might determine which group I would be randomized into. Meanwhile I had some unfinished business back at Big U.

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