The results of the analysis are summarized in the .
Motivation for Participation
Despite the fact that the GAD gene transfer study was a phase I study, the prospect of potential therapeutic benefit was a prominent theme for all but one subject. Five subjects clearly stated that their primary motivation for participating in this phase I study was a desire for therapeutic benefit. For example, S2 stated that “it was more of a selfish thing” and that his “biggest motivator was that outside long shot chance that this thing would work.” Some of these five subjects did mention a motivation to help others but overall that motivation appeared to play an uncertain role. S4: “My main goal, the bottom line, was to get better. The second goal was to help other people… I: So your first goal was to get better yourself? S: Yeah, get better. Absolutely.” Or as another subject put it, “Really, I must say I wasn’t altruistic. I wasn’t. To be perfectly honest, I didn’t think in those terms about doing it for the science and the world, although later on I said, ‘well, if I could help somebody else, if this helps somebody else, it would be fine.’”(S7) Another subject (S3), when asked whether he would have considered participating if he knew ahead of time that he would not benefit and that the only benefits would be scientific and societal, replied, “On a scale of 1 to 5, it probably would have been a 3.”
There were two subjects (S1 and S8) who expressed therapeutic benefit as at least one of their motivations but who did appear to have another active motivation. As one subject (S1) put it, “My feeling was that I wanted to be involved in something that if I didn’t get help, maybe my contribution would help other people;” he went on to say the two motivations “were a tie.” What distinguished these two subjects was that when asked whether they would have participated even if they had known that there was no chance of personal benefit, they stated they would have. S8 gave an affirmative answer even though he said his primary motivation was a benefit to himself. But he made it clear that self-benefit was not his only motivation, at one point noting that his primary care doctor had tried to dissuade him from enrolling in the gene transfer study, asking “why not let someone else try it?” S8 explained that if no one volunteers, then we’d have no progress in advancing research, and that someone has to “step up to the plate.” Thus, these two subjects were qualitatively different from those who mentioned helping others as a reason but for whom altruism as an independent motivating role was less certain.
We categorized one person (S6) as an altruist because his primary motivation was the desire to help future patients with PD by volunteering for the study. Although he stated that hope for personal benefit was a motivator, he added it “would be ridiculous” to expect benefit. He talked about how scientific advance is incremental, about how he wanted to “give back,” and spoke extensively about how he could not imagine being selfish and how he wanted to help advance research and science of PD. Indeed, he felt that he was a good candidate for the study because he had no family to worry about.
Understanding of Purpose of Study
Thus, at least one element that often raises concerns about TM—subjects’ focus on therapeutic benefit in a phase I study—was present among these subjects. How did this focus on personal therapeutic benefit affect the subjects’ understanding of the purpose of the research?
We found one subject (S7) in whom the desire for therapeutic benefit affected his understanding of the purpose of the research. His lack of understanding seems to have resulted from a lack of caring about the purpose of the study because he was so focused on what might happen to him: “I: What did you think was the main purpose? S7: Umm. You know the truth is I don’t know. I don’t know what I thought…I really don’t remember thinking about what they were trying to accomplish as much as how it was going to affect me”; and, “I wasn’t sure at the beginning, to tell you the truth, even though I went through the study. Then I realized that what they were trying to do was to see if there was any harm done. That was really the basis of the study.”
The remainder of the subjects, despite some variations, understood that the primary purpose was scientific or for the benefit of future PD patients. Three subjects unambiguously identified the primary purpose of the study as safety testing (S1, S2, S6): “…they wanted pretty much to prove, in my mind anyway, that it was a safe procedure.”(S2) Three others (S3, S4, S8) identified safety testing as a purpose but also mentioned assessing “efficacy.” One subject (S5) mentioned only the test of efficacy as the purpose. Of those four who mentioned efficacy as a purpose, further probing revealed that they all understood that the primary purpose was to help future patients with PD rather than to help the participants of the phase I study. It appeared that some subjects mentioned testing efficacy as a purpose because they were also including the overall process of developing GAD gene transfer as a therapy for PD beyond the more limited scope of the phase I study (despite the fact that the informed consent document clearly distinguished between the two). As S4 stated, “Well, generally in the long run, it was to help Parkinson’s. In the short run, it might help me, but mainly they were emphasizing this is a new procedure and they didn’t know what was really going to happen, so let’s see.” Likewise S5 identified the purpose as “To see… what effect the gene therapy had on the progress of Parkinson’s” and when asked specifically whether it was to help him or to increase knowledge to help other Parkinson’s patients, he said, “To help others.” Finally, one subject (S3) mentioned “efficacy” in a way that raised the question of how he understood the meaning of “efficacy” as he seemed to use “safety and efficacy” as a shorthand for “scientific purpose”: “They were trying to see if a Parkinson’s patient would actually get any benefits from the gene therapy and then, more importantly than that was the safety and efficacy of the actual procedure.”
Perception of Potential Benefit and Other Influences on Decision to Participate
Because therapeutic desire was such a common motivation, we examined the subjects’ perception of potential therapeutic benefit and the bases for that perception. We asked each subject: “Realistically, what did you think your chances were of your PD improving as a result of participating?” with five response options, and the responses were distributed as follows: No chance (no subject), very low chance (S6), modest chance (S2, S3, S4), good chance (S1, S5, S7, S8), and very good chance (no subject). We asked the respondents to commit to one of the five response choices but an examination of the subjects’ full responses surrounding their answer contained considerable nuances that would have been missed had we recorded their answers simply as a multiple choice question. S1’s response choice was, “I would say I went into it thinking there was a good chance…”(S1) But what S1 says before and after expressing that choice is quite telling: “I went into it with a positive mind. I would say I went into it thinking there was a good chance, but that was a guess, gut feeling. I went into it with great confidence. I went in and I was very calm and very hopeful.” In other words, the true meaning of this subject’s answer (even to a direct multiple choice question) is not captured well by simply looking at the response option he chose. This tendency to express the likelihood of benefit as part of one’s need for optimism can confound our understanding of subjects’ perception of benefit, and requires an analysis of the subject’s statements in the context of his overall approach to the research study, rather than judging those statements in isolation. As S8 noted, “Optimism, positive thinking is something you have to have.” Otherwise one has to accept the disease and its progression, and “[he, S8] didn’t want to.” This need to understand the context (and perhaps the purpose) of a subject’s statements regarding likely therapeutic benefit was echoed in S2 who stated that he felt there was a “modest chance” of direct benefit when asked directly with the above question but later talked about it as an “outside long shot chance” in the context of how his motives fit in with the overall scientific purpose of the study.
We also examined whether the subjects’ perception of potential benefit was based on what they read in the informed consent form or what they were told by the researchers. For most subjects, they made a point of saying that they were not
promised or told to expect therapeutic benefits. During a discussion of what information from the researchers mattered to him most, one subject (S2) talked about what he wanted to hear:
“S2: Well, what I wanted was that after I was all healed [from the surgery], that I’d have significant improvement or just some improvement. Either one of the two I’d take.
I: Okay. Do you remember what they did tell you, you know, about your chances for…
S2: Well, the chances were that I wasn’t going to improve.”
Others expressed the uncertainty and lack of information regarding benefits, (S3) “They told me that, you know, they didn’t have a whole lot of information on it, first of all. They had only done one patient at that point, and they gave me the information as to how he had felt before and after he had had the procedure done, and it was very, very new.” S4 pointed out that the neurosurgeon told him “the first time he saw me he’d rather I do the deep brain stimulus than the other one [i.e., gene transfer] … He just felt that I’d have more guaranteed results.”
One common theme was a sense of confidence that the subjects developed toward the surgeon (or the study team in general). “His personality—I had great confidence in him… his thoroughness, his patience, his time with us…” (S1) Another subject had “blind faith” in the surgeon (S8) while another subject felt he was someone “that they can do what they say they’ll do.”(S6) Thus, we found that a trusting relationship was important to most of our subjects.
Although one subject (S6) specifically did not want to know what was happening with other subjects in the study, for most others, knowing that persons who had gone before them in the study were “doing OK” was a very important factor. Knowing that there were “no negative happenings” (S2) was something that greatly interested the subjects, and played an important part in their ‘chance worth taking’ reasoning (see below). “… I felt pretty comfortable with it, you know, the fact that I was the [nth] one and nothing had happened to the other [i.e., others who went before].” The information about other subjects came from sources outside the study as well because this was a high profile gene transfer study with prominent media reports. The first subject’s identity became known and was featured in the news. Some subjects mentioned this: S3 said, “And the information I had gotten also from, you know, the news article they had with him on CNN, and I felt pretty good about that…”
Relationship Between Motivation and Understanding of Purpose
One of our subjects (S7), at least at the time of enrolling in the study, appeared to be under a misconception that was driven by his desire for therapeutic benefit. This subject was so focused on “how it was going to affect me” that he disregarded the scientific purpose of the study. In fact, he felt that “they [researchers] were going to be my doctor, but that wasn’t the case. The case was that [his own doctor] was still my doctor… I was very confused about where [his own neurologist] fit in and where the other doctors fit in at [the research hospital].” Thus, at least in this one case, the subject resolved the tension between his motivation (for benefit) and the study’s purpose by focusing on the desire for therapeutic benefit, to the point of ignoring and therefore misunderstanding the stated purpose of the study.
For S6 who primarily had an altruistic motive, there was a natural congruence between his motivation and his understanding of the purpose of the study. In fact, as we saw above, he tended to talk about his motivation specifically in relation to his statements about the scientific purpose of the study. For S6, his purpose in participating was the study’s purpose; there was no tension.
For the two subjects who were motivated by both benefits to self and societal/scientific benefit, the reconciliation of the understanding of the purpose and their motives was not that difficult. As Subject 8 put it, although he stated that the desire for personal benefit was a stronger motivation than the desire to help others, the latter is a firm conviction as well, as when he said, “I want to stop this [PD]” and “I’m just a piece of the puzzle… If it helps me, it’s a bonus.”
What about the four remaining subjects (S2-S5)? Their primary reason for participation was the desire for therapeutic benefit and yet all of them evidenced an understanding that the purpose of the study was scientific rather than therapeutic (despite ambiguities regarding whether “efficacy testing” was a goal). These subjects tended to frame their decision as a chance worth taking, a kind of a gamble, which acknowledged the long odds (congruent with their understanding of the study’s purpose as not to benefit them directly). Indeed, one subject (S2) stated: “I always go with the voice that is going to benefit me maybe, but the chances are pretty slim. It’s like throwing the Hail Mary pass. You know it’s probably going to be missed by the guy in the backfield. He’s not going to make the catch, but he’s there anyway. Give it a shot.” Objectively he understood that the purpose of the study is scientific; subjectively, he saw participation in it as a personal gamble worth taking. He went on: “Not that they ever gave an indication that it was going to cure me. As a matter of fact, they did just the opposite, but I always had that little bit of hope that, you know, that maybe something would happen.” Another subject (S4) recognized that his decision was based on his subjective reasons: “I: What would you say overall, what motivated you the most as far as your decision to participate? S4: Uh, just an intuitive feeling that it would work. 80% of the time, my intuition is very strong. This time I was wrong‥‥” and “[i]ntuition and some inner belief. Some spiritual sense. I don’t know. I don’t know what really determines.”
Other Notable Themes: Action Orientation, Decision-Making Approach, and Risk Tolerance
Our primary goal in our research program is to understand how a subject may or may fall into a misconception about the study, in the context of his or her overall decision-making process about research participation. In this regard, one of the most notable themes was the “action orientation” of these participants, something that has been noted in the literature.19
Seven of 8 persons reported that even at the very earliest stages of decision making, they were already inclined to participate: “As soon as I read it in the paper, I was interested”(S4) and “As soon as I read the ad. I thought it had my name on it.”(S5)
Most of our subjects started from a position of strongly wanting to participate, and filtered and weighed information they encountered in relation to that initial inclination: “I: Do you remember, did this initial inclination ever change along the way? In other words, were you ever leaning away from participating at any point? S3: No, I did not. I was pretty much the whole time just more and more excited.”(S3) They filtered information through a premise they already held: “There wasn’t enough information to tell me to don’t do it.”(S2) Thus, our subjects did not begin their contact with the researchers as tabula rasa; rather, they were ‘motivated’ listeners.
In fact, although the perception of and tolerance for risks is an obviously important theme, what was notable in our interviews was that risk was not a strong influence on their decision-making. Partly this was the result of our design: we interviewed only enrollees who had already made a decision to tolerate the risks. But the subjects’ attitudes toward risk and potential adverse events are best understood in this action-orientation framework: for them, risks were important only in so far as whether they were sufficient to defeat their initial inclination. For example, S4 stated that “I was pretty confident. There wasn’t much they could say to disincline me [to participate].” S4 said in response to a question about his views about the risks: “There was a 1% chance you’d get a stroke, 1% chance you’d get a heart attack, 1% chance you’d get bleeding in the brain? These were tiny percentiles. They were not going to happen. I wasn’t really concerned about that.” Or S1: “I: Were there risks? S1: Sure. I didn’t worry about them, but yes. I mean, they were going into my brain…” In this regard, as noted above, the fact that other participants had gone before them without major adverse events was often sufficient to answer the question of whether the risks were too high.