Cooperation and Medical Research

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Why do patients cooperate with medical researchers? So asks sociologists Mary Dixon-Woods and Carolyn Grant in a study analysis appearing in the June 2009 issue of Social Science and Medicine. You might think the answer is simple: they think they will benefit; they want to contribute to medical knowledge; or, they trust researchers who invite them. These are the simple and pat answers that have dominated the research ethics literature until now. However, Dixon-Woods and Tarrant probe deeper by asking why it is that patients feel safe and justified in joining research studies.


Using interviews from three different clinical studies, Dixon-Woods and Tarrant identify five recurring themes:

1- Research as Moral Act: Volunteers perceive participation as a moral act: they are willing to participate and cooperate only insofar as they are “able to defend the moral character” of their actions

2- Research as Risk: There was an awareness of risk and research scandals, and volunteers perceived a need to defend their choice to enter a study (rather than feeling like the choice was an obvious one that needed no explanation)

3- Trust in Regulation: Volunteers perceived that the research enterprise was regulated- that transgression of errant researchers would be “subject to punishment,” though they had no familiarity at all with specific oversight structures

4- Signals of Trustworthiness: Participants sought “cues” and “signals” as to the values and trustworthiness of researchers. Informed consent, for example, was taken less as a substantive process than as a signal of the researcher’s openness and integrity. Participants had strong expectations that researchers and affiliated institutions shared values of cooperation. And they saw the healthcare setting and affiliation of research personnel as “signaling” a kind of trustworthiness.”

5- Trust of Professions: Building on item 4, participants made “swift” judgments about the trustworthiness of research personnel- not so much on the basis of their personal characteristics as their affiliation with trusted professions and institutions

The report helpfully contextualizes these findings within a broad sociological literature on giving, cooperation, and trust. Though the authors shy from offering specific prescription, two key themes emerge: oversight systems should focus on meeting these expectations; and regulation (whether external or internal to the profession), far from impeding research, creates social conditions in which patients can feel comfortable bearing risks imposed by strangers for the sake of strangers. (photocredit: Lucas 2008)

BibTeX

@Manual{stream2010-73,
    title = {Cooperation and Medical Research},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2010,
    month = feb,
    day = 14,
    url = {http://www.translationalethics.com/2010/02/14/cooperation-and-medical-research/}
}

MLA

Jonathan Kimmelman. "Cooperation and Medical Research" Web blog post. STREAM research. 14 Feb 2010. Web. 20 Nov 2017. <http://www.translationalethics.com/2010/02/14/cooperation-and-medical-research/>

APA

Jonathan Kimmelman. (2010, Feb 14). Cooperation and Medical Research [Web log post]. Retrieved from http://www.translationalethics.com/2010/02/14/cooperation-and-medical-research/


Finding Skew: Informed Consent and Bias in Clinical Trials

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Clinical researchers have long claimed that patients who enter clinical trials are better off medically than those who don’t. I’m open to the notion that patients might derive personal meaning from trial participation, but I’ve always been dubious of the suggestion that trial participation in itself is therapeutically beneficial–above and beyond drugs received– in part because this has never been demonstrated in a convincing way. I’ve also worried about the way the “trial effect” has been occasionally mobilized to recruit patients, or to apologize for studies of dubious design. Last, I’ve worried about the ethical implications of the prospect that, in order to receive top quality care, patients should be enrolling in (or have access to) clinical trials.


One reason I have been skeptical of the “trial effect” is that trials do not enroll a random sample of patients. Ethical research requires informed consent, and if patients who consent to trials have different characteristics than those who decline, it seems plausible that they will have different medical courses. UK researchers led by Andrew Clark recently put this thesis to the test (Eur J Heart Failure; also reported in the December issue of Nature Medicine). In their study, they asked a large sample of patients whether they were willing to enter a clinical trial. They then followed the clinical course of patients who declined, and compared them with patients who consented to participation but were never enrolled in a clinical trial. They found that patients who accepted enrollment had better clinical outcomes- even when factors like age, other sicknesses, or drug use.

The finding raises a number of interesting questions about tensions between study validity and informed consent. It does not suggest that we should relax consent standards to reduce bias- though some may be tempted to view the study in this way. It does, however, raise questions about how findings in clinical trials should be interpreted when applying them in real clinical settings. And it provides another problem for those who are attached to the position that trial participation is, in itself, therapeutic. (photo credit: funkandjazz, Skew, 2007)

BibTeX

@Manual{stream2009-76,
    title = {Finding Skew: Informed Consent and Bias in Clinical Trials},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = dec,
    day = 4,
    url = {http://www.translationalethics.com/2009/12/04/finding-skew-informed-consent-and-bias-in-clinical-trials/}
}

MLA

Jonathan Kimmelman. "Finding Skew: Informed Consent and Bias in Clinical Trials" Web blog post. STREAM research. 04 Dec 2009. Web. 20 Nov 2017. <http://www.translationalethics.com/2009/12/04/finding-skew-informed-consent-and-bias-in-clinical-trials/>

APA

Jonathan Kimmelman. (2009, Dec 04). Finding Skew: Informed Consent and Bias in Clinical Trials [Web log post]. Retrieved from http://www.translationalethics.com/2009/12/04/finding-skew-informed-consent-and-bias-in-clinical-trials/


Disclosure in Phase 1 Cancer Trials

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Followers of this blog may recall my continuing concern with the way informed consent is obtained in phase 1 trials involving patient-volunteers (typically, these patients have exhausted standard care options and enter phase 1 trials as a final shot at managing their disease). Language used by investigators in these studies is often suggestive of therapeutic benefit, even though meta-analyses of phase 1 studies show that chances of major clinical benefit in phase 1 studies are exceedingly low. In previous posts, I described my own experience with an ethics review committee that actually defended giving patients vague and almost meaningless information about the therapeutic benefits of phase 1 trial participation. Meantime, evidence from surveys indicate that phase 1 cancer patient-volunteers tend to overestimate the probability of therapeutic benefit.


In the July-August 2009 edition of the ethics journal IRB, Shlomo Koyfman and co-authors at NIH offer up a “Consent Form Template for Phase I Oncology Trials.” Their recommendations are comprehensive and excellent. Among the items they recommend are:

• use of more therapeutically neutral language, like “research agent” instead of “therapy”

• disclosure of dose escalation design; in particular, the authors recommend that patients be informed about risks and benefits relative to the cohort they are entering.

• a statement (where appropriate) that patient-volunteers will not have the option of adjusting their dose assignment in the study

• a statement that “the chances that this agent will… allow you to live longer [is] very low.”

One can quibble with various particulars (I think, for example, discussion of subtherapeutic dosing should be more explicit). But on the whole, these recommendations provide an excellent standard– along with NIH Guidance on Informed Consent for Gene Transfer Research– against which typical phase 1 cancer study consent forms should be measured. (photo credit: banlon1964)

BibTeX

@Manual{stream2009-83,
    title = {Disclosure in Phase 1 Cancer Trials},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = oct,
    day = 26,
    url = {http://www.translationalethics.com/2009/10/26/disclosure-in-phase-1-cancer-trials/}
}

MLA

Jonathan Kimmelman. "Disclosure in Phase 1 Cancer Trials" Web blog post. STREAM research. 26 Oct 2009. Web. 20 Nov 2017. <http://www.translationalethics.com/2009/10/26/disclosure-in-phase-1-cancer-trials/>

APA

Jonathan Kimmelman. (2009, Oct 26). Disclosure in Phase 1 Cancer Trials [Web log post]. Retrieved from http://www.translationalethics.com/2009/10/26/disclosure-in-phase-1-cancer-trials/


Keeping Alive with Hope

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Hope has been a consistent theme in Barack Obama’s campaign, which thankfully came to a glorious end (many of us can now “hope” to actually get some work done after weeks of checking fivethirtyeight.com every ten minutes). His book was titled The Audacity of Hope. In the close of his victory speech, he stated “Let us keep that promise, that American promise, and in the words of scripture hold firmly, without wavering, to the hope that we confess.” Newspaper headlines proclaim “Elections Unleash Flood of Hope Worldwide (NYTimes) and “Time to Hope Again” (Washington Post).


Hope is also a central theme in translational research, driving research advocates (“Hope for a Cure”), perseverance at the lab bench, and for better and for worse, the participation of gravely ill patients in trials that offer the slimmest prospect of serious medical benefit. Hope in many settings– particularly in the political– is an unalloyed good. 

But in the context of enrolling patients in early phase trials, hope becomes morally ambiguous.  Or at least, so Penn philosopher Adrienne M. Martin would seem to suggest in her critical analysis of hope (“Hope and Exploitation,” Sept / Oct issue of Hastings Center Report).

Martin begins her essay with a set of consensus observations about hope: 1- it involves a desire for an outcome; 2- it involves imaginative engagement with a desired outcome– like praying or fantasy; 3- it often frames how people interpret and use information.  She then goes on to explore the various ways that hope can lead to exploitation in clinical research.

Much has been written about “hope” in bioethics, and much of it is drivel. I have a number of reservations about Martin’s article. For my money, however, this is the most compelling analysis of the phenomenon that I know of. I highly recommend this article to anyone who takes seriously the moral dimensions of how translational research engages hope. (photo credit: San Diego Shooter, Tattered Hope, 2008)

BibTeX

@Manual{stream2008-125,
    title = {Keeping Alive with Hope},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = nov,
    day = 6,
    url = {http://www.translationalethics.com/2008/11/06/keeping-alive-with-hope/}
}

MLA

Jonathan Kimmelman. "Keeping Alive with Hope" Web blog post. STREAM research. 06 Nov 2008. Web. 20 Nov 2017. <http://www.translationalethics.com/2008/11/06/keeping-alive-with-hope/>

APA

Jonathan Kimmelman. (2008, Nov 06). Keeping Alive with Hope [Web log post]. Retrieved from http://www.translationalethics.com/2008/11/06/keeping-alive-with-hope/


On Not Getting It…

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Here is the scenario: you have cancer, and your doctor has told you there is no way to treat it. But there is an experimental drug that is being offered in a phase 1 study. Your doctor asks if you’re interested.


You join the study because its your best shot. You know there are likely to be side effects–there always are with cancer drugs. You know the drug might not work–no cancer drug works all the time for all people.

If your doctor knew that entering the phase 1 study was unlikely to eradicate your cancer– or even extend your life– would you want to be told, or would you prefer that the doctor keep this information from you?

The question came up in a recent research ethics committee (IRB) meeting I attended, in which a phase 1 cancer study consent form contained language to the effect of “you may or may not benefit from joining this study.” I proposed that the language be changed to “this study is unlikely to significantly affect the course of your cancer.” My preference was based on the following reasons:

1- “may or may not benefit” does not contain any information about probability. Indeed, there is a subtle rhetorical partity, wherebt most readers view “may” as having equal weight as “may not” such that they view this as suggesting a 50% probability of benefit.

2- two recent, large mete-analyses showed that studies of the type reviewed here result in tumor shrinkage for about 10% of patients. There is no evidence that tumor shrinkage in these studies actually translates to longer life or improved comfort. So, in fact, we do have information about probability of benefit.

3- Patients enter these studies not because of a desire to further cancer research, but rather, because they are seeking cure. This has been shown in numerous surveys.

4- Patients who enter these studies significantly overestimate the probability that they will benefit clinically. Also shown in numerous surveys.

5- Informed consent requires, at a minimum, that volunteers be provided information that a reasonable person would consider material to their decision to enroll.

A reasonable, terminal cancer patient would probably want to have some information about the probability that a drug that is likely to have strong side effects is unlikely to work against their cancer.

Incredibily, most of the members of my IRB disagreed, saying (among other things) that it would discourage patients (hmmm. I thought medical paternalism went out with Buicks with tailfins); that nothing in the original language implied benefit was a sure thing (yes, the original language made it very clear that instead of 100% chance of benefit, chance of benefit was somewhere between 0 and 99.999%);  that no one would enroll in the study with my language (wow! I thought our job was to protect volunteers, not investigators); that we’ve never done that before (let me make sure I understand this.  It’s ok to withhold relevant information from volunteers, as long as you’ve done it before).

Yes, Virginia, the IRB system really is broken! (photo credit: Kenoir 2007)

BibTeX

@Manual{stream2008-146,
    title = {On Not Getting It…},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = jun,
    day = 27,
    url = {http://www.translationalethics.com/2008/06/27/on-not-getting-it/}
}

MLA

Jonathan Kimmelman. "On Not Getting It…" Web blog post. STREAM research. 27 Jun 2008. Web. 20 Nov 2017. <http://www.translationalethics.com/2008/06/27/on-not-getting-it/>

APA

Jonathan Kimmelman. (2008, Jun 27). On Not Getting It… [Web log post]. Retrieved from http://www.translationalethics.com/2008/06/27/on-not-getting-it/


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